Diabetic Neuropathy: Advances in Pathophysiology and Clinical Management [3 ed.] 3031156129, 9783031156120

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Contemporary Diabetes Series Editor: Aristidis Veves

Solomon Tesfaye Christopher H. Gibbons Rayaz Ahmed Malik Aristidis Veves   Editors

Diabetic Neuropathy

Advances in Pathophysiology and Clinical Management Third Edition

Contemporary Diabetes Series Editor Aristidis Veves, Beth Israel Deaconess Medical Center Boston, MA, USA

The Contemporary Diabetes series focuses on the clinical aspects of obesity and diabetes and provides the practicing health provider with all the latest information regarding their management. The series also targets both basic and clinical researchers. The audience includes endocrinologists, internists, cardiologists, neurologists, nephrologists, podiatrists, ophthalmologists, family physicians, nurse practitioners, nurse educators, and physician assistants.

Solomon Tesfaye Christopher H. Gibbons Rayaz Ahmed Malik  •  Aristidis Veves Editors

Diabetic Neuropathy Advances in Pathophysiology and Clinical Management Third Edition

Editors Solomon Tesfaye Royal Hallamshire Hospital Sheffield Teaching Hospitals and the University of Sheffield Director of Diabetes Research Sheffield, UK Rayaz Ahmed Malik Weill Cornell Medicine Cornell University Doha, Qatar

Christopher H. Gibbons Beth Israel Deaconess Medical Center Boston, MA, USA Aristidis Veves Department of Surgery Beth Israel Deaconess Medical Center Boston, MA, USA

ISSN 2197-7836     ISSN 2197-7844 (electronic) Contemporary Diabetes ISBN 978-3-031-15612-0    ISBN 978-3-031-15613-7 (eBook) https://doi.org/10.1007/978-3-031-15613-7 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Humana imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

To Sophie, Aida and Sami—thanks for your unfailing support

Contents

Part I Clinical Features and Diagnosis Introduction����������������������������������������������������������������������������������������������   3 Andrew J. M. Boulton  The Epidemiology of Diabetic Neuropathy ������������������������������������������   5 Christian Stevns Hansen, Laura L. Määttä, Signe Toft Andersen, and Morten H. Charles  Clinical Features of Diabetes Neuropathies������������������������������������������  37 Gordon Sloan, Qi Pan, Ling Gao, Lixin Guo, and Solomon Tesfaye  Neuropathy in Type 1 and Type 2 Diabetes ������������������������������������������  51 Gulcin Akinci, Dustin Nowacek, and Brian Callaghan  Clinical Diagnosis of Diabetic Peripheral Neuropathy������������������������  67 Bruce A. Perkins and Vera Bril  Diagnostic Techniques for Diabetic Peripheral Neuropathy����������������  93 Long Davalos, Amro Stino, and A. Gordon Smith  Sensory Profiles and Diabetic Neuropathy�������������������������������������������� 113 Juliane Sachau, Manon Sendel, and Ralf Baron Neurotrophic Factors in the Pathogenesis and Treatment of Diabetic Neuropathy������������������������������������������������� 127 Nigel A. Calcutt  Treatment Induced Neuropathy of Diabetes ���������������������������������������� 157 Nadia McMillan and Christopher H. Gibbons Asymmetric Diabetic Neuropathy: Radiculoplexus Neuropathies, Mononeuropathies, and Cranial Neuropathies������������ 165 Pariwat Thaisetthawatkul and P. James B. Dyck  Motor Neuropathy in Diabetes �������������������������������������������������������������� 183 Karolina Snopek Khan and Henning Andersen Cardiovascular Autonomic Neuropathy������������������������������������������������ 203 Lynn Ang and Rodica Pop-Busui

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Psychosocial Aspects of Diabetic Neuropathy: From Description to Interventions �������������������������������������������������������� 221 Loretta Vileikyte and Frans Pouwer Part II Pathophysiology  The Genomics of Diabetic Neuropathy�������������������������������������������������� 239 Abirami Veluchamy, Blair H. Smith, and David L. Bennett  Metabolic Mechanisms in Diabetic Neuropathy ���������������������������������� 253 Mark Yorek Mechanisms of Nerve Injury in Diabetes: Dyslipidemia, Bioenergetics, and Oxidative Damage �������������������������� 279 Stephanie A. Eid, Mohamed Noureldein, Masha G. Savelieff, and Eva L. Feldman  Targeting the Mitochondrion in Diabetic Neuropathy ������������������������ 307 Ahmad Hedayat, Krish Chandrasekaran, Lindsay A. Zilliox, and James W. Russell Diabetic Sensory Neurons, Dorsal Root Ganglia, and Neuropathy���������������������������������������������������������������������������������������� 327 Aparna Areti and Douglas W. Zochodne  Microand Macrovascular Disease in Diabetic Neuropathy �������������� 351 Lihong Chen and Aristidis Veves  The Spinal Cord in Diabetic Neuropathy���������������������������������������������� 363 Andrew G. Marshall, Anne Worthington, and Corinne G. Jolivalt  Brain Changes in Diabetes and Cognitive Dysfunction������������������������ 381 Geert Jan Biessels Lifestyle and Dietary Modifications: Relevance in the Management of Diabetic Neuropathy������������������������������������������ 397 Jonathan Enders and Douglas E. Wright  Pathophysiology of Neuropathic Pain���������������������������������������������������� 415 Andreas C. Themistocleous and Miroslav Misha Backonja  Central Nervous System Involvement in Painful Diabetic Neuropathy�������������������������������������������������������������������������������� 427 Dinesh Selvarajah, Joyce Lim, Kevin Teh, Xin Chen, Jing Wu, and Solomon Tesfaye Part III Clinical Consequences and Treatments  Characteristics and Treatment of Painful Diabetic Neuropathy �������� 441 Sandra Sif Gylfadottir and Nanna Brix Finnerup Orthostatic Hypotension and Sudomotor Dysfunction in Diabetes�������������������������������������������������������������������������� 453 Lauren F. Fanty and Christopher H. Gibbons

Contents

Contents

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Gastrointestinal Neuropathy������������������������������������������������������������������ 471 Karen L. Jones, Chinmay S. Marathe, Tongzhi Wu, Christopher K. Rayner, and Michael Horowitz  Diabetic Neuropathy: Clinical Management—Genitourinary Dysfunction in Diabetes�������������������������������������������������������������������������� 491 Vincenza Spallone, Enrico Finazzi Agrò, Roberta Centello, Claudio Lecis, Luca Orecchia, and Andrea M. Isidori Index���������������������������������������������������������������������������������������������������������� 531

Part I Clinical Features and Diagnosis

Introduction Andrew J. M. Boulton

1 Early History of the Diabetic Neuropathies Whereas the first ever records of diabetes appear to be found in ancient Egypt around 1550 BC, the history of the diabetic neuropathies is relatively recent. Indeed, the first references to possible involvement of the nervous system as a complication of diabetes did not appear until the end of the eighteenth century [1]. It was Dr John Rollo, who was a surgeon in the British Royal Artillery, who wrote two texts on diabetes and in one of them described a patient with “burning pains in the palms and hands and the soles of the feet with weakness and complains of painful and gnawing sensations in the leg” [2, 3]. However, as pointed out by Ward [3, 4], reports that such patients with the symptoms as described above, “had a good night’s sleep” this would not be typical of painful diabetic neuropathy. Moreover, Rollo did not

A. J. M. Boulton (*) Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester, UK Manchester Diabetes Centre, Manchester Royal Infirmary, Manchester, UK University of Miami, Miami, FL, USA International Diabetes Federation, Brussels, Belgium e-mail: [email protected]

acknowledge a direct link between diabetes and any nervous system disorder. It was not until 1864 that Marchal de Calvi correctly described the relationship between diabetes and peripheral neuropathies [5]. Indeed, it was the well-known Parisian physician Jean-­ Martin Charcot who acknowledged the importance of the observation by Marchal de Calvi: Charcot also described that in some diabetic cases, there are signs of neurological disorders [5]. It was towards the end of the nineteenth century that Charcot summarised the clinical features of diabetic peripheral neuropathy [6]. Another pivotal observation at the end of the nineteenth century was made by a surgeon in my hometown of Nottingham, UK.  It was Dr T Davies Pryce that described what we now know as neuropathic foot ulcers and stated that these were a consequence of peripheral nerve degeneration [7]. One of the best descriptions of painful neuropathic symptoms was made in 1894 by Pavy, a physician at the Middlesex hospital in London [8], who stated that they were of “of a burning and unremitting character”. Pavy also observed that the pains were generally worse during the night. By the end of the nineteenth century, the neuropathies of diabetes were well recognized: indeed, it was stated that it was rare to meet a case of diabetes without some evidence of nervous disturbance [1].

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 S. Tesfaye et al. (eds.), Diabetic Neuropathy, Contemporary Diabetes, https://doi.org/10.1007/978-3-031-15613-7_1

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A. J. M. Boulton

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2 The Twentieth Century It was RT Williamson, a physician at the Manchester Royal Infirmary, who introduced physiological measurements such as measurement of vibration perception, into the assessment of neuropathy early in the twentieth century [9]. Coincidentally, I joined the same hospital as a physician in 1986—and my group confirmed that loss of vibration sensation was the most reliable predictor of foot ulceration in diabetes [10]. After the discovery of insulin, the understanding of the neuropathies increased, and a series of important publications appeared from US centres. First, Jordan, in a series of patients, observed that neuropathic symptoms did not always match signs in diabetic patients [11]. A decade later Wayne Rundles from the University of Michigan published observations on 125 cases of diabetic neuropathy, and not only proposed an association between glycaemic control and neuropathy, but also described the features of autonomic dysfunction in diabetes [12]. Again coincidentally, the same institution remains active in research into the neuropathies with no fewer than three authors in the book coming from the University of Michigan. It was Sven-Erik Fagerberg, from Gothenburg, who in 1959 published extensive studies on 356 cases of diabetic neuropathy, and in about half, he obtained and studied sections of peripheral nerve, observing substantial abnormalities of the nerve microvasculature [13]. He proposed the potential of a common aetiopathogenesis of neuropathy, retinopathy, and nephropathy. Sadly, the closing years of the twentieth century may well be remembered for numerous clinical trials of putative new therapies that aimed to tackle the underlying pathogenesis of neuropathy, none of which showed clinical efficacy. To end this historical review on a more positive note, the art of clinical medicine remains important in the diagnosis of neuropathy, and it was my mentor and renowned neuropathy researcher John D Ward (1935–2019), who described a clinical sign of autonomic neuropathy in the diabetic foot—distended dorsal foot veins [14].

In conclusion, most of our understanding of the diabetic neuropathies has evolved over the last 250 years. However, much progress has been made in the first 20 years of this century and much of this is covered by the excellent chapters to be found in this up-to-date review of all aspects of the diabetic neuropathies. I know each and every one of the authors and can attest that they are all experts in their own fields and this will provide a most useful volume to update knowledge on the many various conditions that are included under the title of diabetic neuropathies.

References 1. Skljarevski V. Historical aspects of the diabetic neuropathies. In: Veves A, Malik RA, editors. Diabetic neuropathy: clinical management. 2nd ed. Totowa: Humana Press; 2001. p. 1–6. 2. Rollo J. Cases of the diabetes mellitus with the results of the trials of certain acids. London: T.  Gillet for C. Dilly; 1798. 3. Ward JD. A history of diabetic neuropathy in the 19th century. In: Hotta N, Greene DA, Ward JD, et al., editors. Diabetic neuropathy: new concepts and insights. Amsterdam: Elsevier; 1995. p. 89–95. 4. Ward JD.  Historical aspects of diabetic peripheral neuropathy. In: Boulton AJM, editor. Diabetic neuropathy. Bridgewater: Aventis; 2001. p. 6–15. 5. De Calvi M. Recherches sur les accidents diabetiques. Paris: Asselin; 1864. 6. Charcot JM.  Sur un cas de paraplegie diabetique. Arch Neurol. 1890;19:305–35. 7. Pryce TD.  Perforating ulcers of both feet associated with diabetes and ataxic symptoms. Lancet. 1887;2:11–2. 8. Pavy FW. The Croonian lecture on new departures in diabetes. Br Med J. 1894;1:1349–50. 9. Williamson RT.  A clinical lecture on the vibrating sensation in diseases of the nervous system: delivered at the Manchester Royal Infirmary. Br Med J. 1907;2:125–7. 10. Young MJ, Breddy JL, Veves A, Boulton AJM.  The prediction of diabetic neuropathic foot ulceration using vibration perception thresholds: a prospective study. Diabetes Care. 1994;17:557–60. 11. Jordan WR. Neuritic manifestations in diabetes mellitus. Arch Intern Med. 1936;57:307. 12. Rundles RW.  Diabetic neuropathy: general review with report of 125 cases. Medicine. 1945;24:111–60. 13. Fagerberg S-E.  Diabetic neuropathy: a clinical and histological study on the significance of vascular affections. Acta Med Scand. 1959;164(345):1–97. 14. Ward JD, Boulton AJM, Simms JM, et al. Venous distension in the diabetic foot – physical sign of arteriovenous shunting. J R Soc Med. 1983;76:1011–4.

The Epidemiology of Diabetic Neuropathy Christian Stevns Hansen, Laura L. Määttä, Signe Toft Andersen, and Morten H. Charles

1 Introduction Diabetic neuropathy is a common and severe complication of diabetes. It is associated with substantial socioeconomic and personal consequences. The complication encompasses a heterogeneous group of neuropathies, which affect various parts of the nervous system, leading to a wide range of different symptoms and signs of nerve fibre dysfunction. In addition, different types of neuropathy are independent risk factors for various end-organ manifestations. For example, distal symmetrical polyneuropathy (DSPN) is an independent risk factor for peripheral arterial disease and peripheral amputations, while cardiovascular autonomic neuropathy (CAN) is C. S. Hansen Steno Diabetes Center Copenhagen, Herlev, Denmark L. L. Määttä Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark S. T. Andersen Steno Diabetes Center Aarhus, Regional Hospital Gødstrup, Herning, Denmark M. H. Charles (*) Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark Department of Public Health, Aarhus University, Aarhus, Denmark e-mail: [email protected]

independently associated with cardiovascular morbidity and mortality [1]. While the incidence of major diabetic complications, such as cardiovascular disease, renal disease, blindness and amputation, has been decreasing steadily in most countries for the last few decades [2], we do not know if this is true for diabetic neuropathy. Despite its severity, the epidemiological data at hand is not as substantial as for many other diabetic complications. This is linked to a lack of international consensus on the diagnostic criteria for this heterogeneous complication and to the lack of robust, long-term population-­based studies reporting the incidence of different neuropathies. Our epidemiological understanding of diabetic neuropathy is mainly based on cross-­ sectional studies performed at different time points. This allows for point estimates of prevalence. In addition, data from large longitudinal cohort studies and randomised trials have shed light on the natural history of diabetic neuropathy. However, data on indices rate ratios of diabetic neuropathy over time are non-existent. Thus, it cannot be documented if incidence rates are improving. Diabetic neuropathy can be classified into four groups: symmetric polyneuropathy, autonomic neuropathy, polyradiculopathies, and mononeuropathies. In this chapter, we will present an in-­ depth analyses of the epidemiology of the two most prevalent forms of diabetic neuropathy: (1)

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 S. Tesfaye et al. (eds.), Diabetic Neuropathy, Contemporary Diabetes, https://doi.org/10.1007/978-3-031-15613-7_2

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Distal symmetrical polyneuropathy (DSPN) and (2) cardiovascular autonomic neuropathy (CAN). We also provide a short overview of other forms of diabetic neuropathy.

C. S. Hansen et al.

ropathy in both type 1 (T1D) and type 2 diabetes (T2D) constituting approximately 80–90% of diabetic neuropathies [1]. Diabetic DSPN is termed typical diabetic neuropathy while the less common forms are called atypical diabetic neuropathies [3]. In fact, DSPN is the most 1.1 Strategy for Reviewing common form of neuropathy, irrespective of Relevant Literature aetiology [4], and diabetes is the most common cause of DSPN [4]. This chapter is a review of major studies carried Common symptoms of DSPN include neuroout in the past four decades. In addition to report- pathic pain, numbness, tingling, prickling, teming data from landmark studies such as UKPDS, perature insensitivity, and weakness [1, 3]. ACCORD, EURODIAB, ADDITION-Denmark, Symptoms normally start in the toes and feet and the Search Study, DCCT/EDIC, MONICA/ spread proximally, involving the fingers and KORA, and others, we also performed PubMed hands in more severe cases. This typical symmetsearches relating to DSPN and CAN.  However, ric distribution of length-dependent neuropathic the chapter does not have an exhaustive list of symptoms is described as a stocking-and-glove studies in the field of diabetic neuropathy research. pattern [1, 3]. Dysesthesias and pain are comIn addition to a presentation of the prevalence and monly the first symptoms and as DSPN pronatural history of diabetic neuropathy we aim to gresses, motor involvement may appear [1, 3, 5]. elucidate risk factors for the complication. DSPN has a major impact on the life and health For DSPN, relevant literature was obtained of affected people due to invalidating pain, comfrom recent comprehensive reviews on diabetic plicating foot ulcers, falls, and amputations leadneuropathy and on the epidemiology of diabetic ing to a decreased quality of life [1, 6, 7]. neuropathy. We performed additional searches on No single decisive definition of DSPN exists. PubMed using the mesh terms “diabetic neuropa- The American Diabetes Association’s (ADA) thies”, “prevalence”, “incidence”, and “epidemi- definition of DSPN for clinical practice is “the ology” from 2013 and onwards. From the presence of symptoms and/or signs of peripheral prevalence-related search, studies with over 400 nerve dysfunction in people with diabetes after participants were included. the exclusion of other causes” [1]. ADA recomWe performed PubMed CAN searches using mends that the assessment for DSPN should the key words “diabetes”, “autonomic neuropa- include a careful history and assessment of both thy”, “incidence”, and “prevalence”. Studies per- small (temperature or pinprick sensation) and formed prior to 1980 were not assessed and we large fibre function (vibration perception and did not include cohorts with less than 80 partici- 10-g monofilament) [8]. Further evaluation by pants. However, smaller cohorts from non-­ nerve conduction studies (NCS) or skin biopsies western populations were included due to a to assess intraepidermal nerve fibre density paucity of studies reported from these regions. (IENFD) is rarely needed and is primarily reserved for research purposes. The Toronto Consensus Panel criteria for DSPN are widely 2 Diabetic Distal Symmetric accepted as the current gold standard for diagPolyneuropathy nosing DSPN in a research context [3]. The Toronto criteria define hierarchical categories of It is estimated that half of all people with diabe- DSPN graded as possible (symptoms or signs), tes develop neuropathy during their disease [1]. probable (≥2 following: symptoms, signs, abnorHalf of these cases may be asymptomatic [1]. mal ankle reflexes), or definite (symptoms and/or Distal symmetric sensorimotor polyneuropathy signs together with a confirmatory test of DSPN (DSPN) is by far the most common type of neu- (usually NCS, IENFD)) [3, 9].

The Epidemiology of Diabetic Neuropathy

There is emerging evidence that DSPN can be present even prior to the diagnosis of diabetes with a prevalence of 10–30% in people with prediabetes or metabolic syndrome [1, 10–17]. However, such cases of DSPN might not be diagnosed unless small fibre impairment is examined: the natural history of DSPN is hypothesised to start as small fibre damage and proceed towards large fibre damage [1, 5, 18, 19].

2.1 Issues to Consider When Evaluating Epidemiological Studies of DSPN Summarising the prevalence and incidence of DSPN based on existing studies is not straight forward for several reasons [17]. First, the varying pattern of nerve fibre damage can give rise to a heterogeneous presentation of DSPN.  For example, one patient may have decreased vibration perception threshold (VPT) due to large fibre damage, while another patient may have intact VPT but decreased pinprick or temperature sensation due to small fibre dysfunction. Hence, the chosen method for testing DSPN has an impact on prevalence estimates [17, 20]. An example illustrating this issue is the baseline examination of young adults with T1D in the Diabetes Control and Complications Trial (DCCT). The prevalence of DSPN varied from 0.3% (abnormal reflexes, sensory signs, and neuropathic symptoms) to 21.8% (abnormal NCS in at least two nerves) in the standard-care group depending on which test was used to define DSPN [17, 21]. In recognition of this issue, the current clinical guidelines for diagnosing DSPN recommend a combination of tests and symptoms to detect this complication. Second, several available tests for evaluating DSPN are subjective in nature, requiring people to interpret an external stimulus (vibration, hot or cold application, etc.) and can thus be hard to reproduce [17]. Third, the prevalence varies between different study-populations. Hospital-­ based study cohorts can be expected to have a higher prevalence of DSPN compared with primary-­ care or communitybased cohorts [17]. The optimal method for

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estimating the prevalence of DSPN is population-based survey [17]. In general, age and diabetes duration are important factors to consider when comparing the prevalence of DSPN in different studies, irrespective of their setting.

2.2 Prevalence of DSPN The prevalence of neuropathy in the general population is estimated to be 1–8% and approximately half of these cases are due to diabetes [4, 6, 22, 23]. The prevalence of DSPN in T1D and T2D for selected studies and settings is given in Table  1. These studies reveal a varying prevalence of DSPN, from 1.5% [30] to 75.1% [67]. Very similar ranges exist when comparing T1D and T2D (T1D primary care/community-based: 7–62.5% (median 20.8%) and hospital based: 2.6–55.1% (median 22.1%); and T2D primary care/community-based: 1.5–63% (median 27.4%) and hospital based: 18.1–75.1% (median 34.4%). The median values are calculated from the studies included in Table 1 with large variation in age, diabetes duration, diagnostic tests, etc.). Furthermore, it is worth noting that studies defining DSPN by NCS tend to report a higher prevalence of DSPN compared to other diagnostic tests, underpinning the high sensitivity of NCS to detect DSPN [29, 31, 44]. Overall, the prevalence of DSPN increases with diabetes duration and with increasing age despite the setting or testing method. In newly diagnosed diabetes, the prevalence of DSPN tends to be lower [25, 31–34, 41, 45– 47, 65, 68]. A population-based survey of DSPN in Mauritius reported a prevalence as low as 3.6% in newly diagnosed T2D (N = 414) where DSPN was defined using age-specific VPT [34]. Population-based samples from Egypt and India show a prevalence of 14% (N = 125) and 19.5% (N = 338), respectively, in people with newly diagnosed T2D. These studies also used VPT to detect DPSN but did not apply age-specific reference values [33, 41]. The ADDITION-Denmark study, which included individuals with screen-­ detected T2D (N = 1445), reported a prevalence

Study site USA EDC [24]

Italy [25]

Denmark [26]

USA [27]

Scotland [28]

USA [29] Finland [30]

Type 1 (P)

Type 1 (P)

Type 1 (P)

Type 1 (P)

Type 1 (P)

Type 2 (P) Type 2 (P)

13

MNNIq ≥ 4

78 132

5558

NCS (1) Symptoms (2) Knee/ankle reflexes and ≥1 sign (light touch, pinprick, VPT) OR ≥2 signs (3) NCS

11

MNISq ≥ 4

5936

62.5

46.2 (1) 1.5 (2) 2.3 (3) 15.2

28.5

NA 0

20.5

18 (median)

13

NA

DM duration Prevalence (%) (mean, year) 34 19.9

Participants (N) Neuropathy diagnosis 363 ≥2 of the following: symptoms, signs (light touch, pinprick, VPT, proprioception, muscle weakness, gait), knee/ ankle reflexes 379 Symptoms and ≥1 sign OR ≥2 signs (VPT, ankle/knee reflexes, foot ulcers, DB, postural hypotension) 339 VPT

Table 1  Prevalence of DSPN in type 1 and 2 diabetes

62.1 Men 54.9 Women 57.1

44.7

39

20

NA (15–59 year)

Mean age (year) 28.4

Male sex, age, increased albumin excretion rate Age, HbA1c, DM duration, lower socioeconomic status, CVD, smoking, hypertriglyceridemia, BMI, retinopathy, reduced eGFR, Charcot neuroarthropathy, recent severe hypoglycaemia and/or DKA Age, DM duration, waist-to-hip ratio, lipids, HbA1c, smoking, low eGFR, low HDL-c, socioeconomic status, ≥1 other DM complication (nephropathy, retinopathy, CVD, recent severe hypoglycaemia or DKA) NA NA

NA

Risk factors/markers DM duration, HbA1c, smoking status, HDL-c

8 C. S. Hansen et al.

Mauritius [34]

Netherlands [35]

Italy [36]

UK [37] Portugal [38]

Malaysia [39] Bahrain [40]

India [41]

Type 2 (P)

Type 2 (P)

Type 2 (P)

Type 2 (P) Type 2 (P)

Type 2 (P) Type 2 (P)

Type 2 (P)

Type 2 (P)

USA San Luis Valley Diabetes Study [32] Egypt [33]

Type 2 (P)

Type 2 (P)

Study site Finland [31]

1291

134 1477

811 93

347

137

433

384

279

(1) Symptoms (2) VPT (3) Knee/ankle reflexes (4) Temp. sensation ≥2 symptoms and ≥2 of following: “sensation, strength, tendon reflexes” NDS ≥ 6 Knee/ankle reflexes and ≥1 sign (VPT, monofilament, pinprick, temp. sensation, proprioception) NSS and NDS ≥2 of following: symptom score, sign score (“pain”, “touch”, temp. sensation, VPT), VPT VPT

VPT

≥2 of following: Symptoms, ankle reflexes, temp. sensation VPT

Participants (N) Neuropathy diagnosis 132 NCS with or without symptoms

NA

27.8

50.7 36.6

5.9

8.5 9.5

+DSPN 60 –DSPN 47

56.5 57.3

65.4 65.4

NA (≥55 year)

7.5

(1) 18 (2) 53 (3) 62 (4) 63 19

7.4 10.1

68

6.6

12.7

41.6 32.2

NA (over 20 year) 55

NA (20–74 year)

Mean age (year) 56

NA

21.9

DM duration Prevalence (%) (mean, year) Baseline: 8.3 10 10-year follow-up: 41.9 25.8 NA

Age, HbA1c, DM duration (continued)

Age, DM duration Age, DM duration, HbA1c, total cholesterol, smoking, BMI, waist circumference, triglycerides, hypertension

NA Age, DM duration, foot skin changes, MI/ischemia

DM duration, fasting and post-prandial Glc

HbA1c, age, female sex, hypercholesterolemia DM duration, treatment with insulin or oral hypoglycaemic agents, height, fasting Glc, lower 2-h plasma insulin NA

Age, DM duration, male sex, HbA1c

Risk factors/markers Fasting Glc levels, lower insulin levels at fasting and after oral Glc administration

The Epidemiology of Diabetic Neuropathy 9

Taiwan [44]

UK UKPDS [45]

Denmark ADDITION-DK Baseline [46] Denmark ADDITION-DK 6-yr follow-up [47]

Denmark ADDITION-DK 13-yr follow-up [48] Brazil [49]

Australia [50]

Type 2 predominantly (P) Type 2 (P)

Type 2 (P)

Type 2 (P)

Type 2 (P)

Type 2 (P)

Type 2 (P)

Type 1 + 2 (P)

Type 2 (P)

Study site Germany MONICA/KORA [42] Sweden [43]

Table 1 (continued)

MNSIq ≥ 4 (1) Monofilament and/or VPT (2) MNSIq ≥ 7 NCSa and ≥ 1 symptom and/or sign (ankle reflex, VPT, monofilament) (1) NSS = 5–6 OR NSS = 3–4 and NDS = 6–8 (2) Monofilament Pinprick

1445

1161

452

T1 179 T2 904

551

(1) Ankle reflexes (2) VPT

3867

133

T1 8.4 T2 16.8

(1) 6.3 (2) 14.3

(1) INT 30.1; CON 34.8 (2) INT 8.7; CON 9.3 27.0

Baseline: (1) INT 11.8; CON 11.4 12-year follow-up: (1) INT 35; CON 37 (2) INT 30.2; CON 32.8 13.1

29.3

T1 12.6 T2 7.2

10

T1 33.8 T2 63.6

65

70.9

INT 59.6, CON 59.9

6

+DSPN 12.9 –DSPN 12.7

NA (–DPN 60.8)

+DSPN 66.2 –DSPN 54.9 Baseline 53.3

61.7

Mean age (year) 66.8

0

0

+DSPN 3 –DSPN 2

7.0

34

156

VPT and/or monofilament NCS

DM duration Prevalence (%) (mean, year) 28 NA

Participants (N) Neuropathy diagnosis 195 MNSI exam > 2

DM duration, age at DM diagnosis

Baseline HbA1c, steeper increases in HbA1c over time, weight, waist circumference, BMI DM duration

NA

NA

NA

PAD, age, male sex, lower HDL-cholesterol Age, renal insufficiency, HbA1c, fasting Glc, systolic BP

Risk factors/markers Age, waist circumference, PAD

10 C. S. Hansen et al.

USA [53]

UK [54]

USA SEARCH [55]

Europe EURODIAB Baseline [56]

Type 1 + 2 (P)

Type 1 + 2 (P)

Type 1 + 2 (P)

Type 1 (H)

Type 1 + 2 (P)

Study site USA [51]

3250

T1 1734 T2 258

T1 213 T2 864

≥2 of the following: symptoms, ankle/knee reflexes, VPT, HRV and/ or postural hypotension

≥2 of the following: symptoms, light touch, pinprick, ankle reflexes, VPT (only for 2

Participants (N) Neuropathy diagnosis T1 102 ≥2 of following: T2 278 symptoms (NSS [52]), signs (NDS [52]), NCS, VPT, CDT, DB, VAL, with ≥1 being NCS, DB or VAL T1 124 Symptoms T2 2268

28.5

T1 7 T2 22

T1 12.7 T2 17.2

T1 30.2 T2 37.9

14.7

T1 7.2 T2 7.9

NA

T2 +DSPN 12.0 –DSPN 9.6

DM duration Prevalence (%) (mean, year) T1 54 T1 14.5 T2 45 T2 8.1 (median)

32.7

T1 18 T2 22

T2 +DSPN 61.8 –DSPN 61.7 NA

Mean age (year) T1 41 T2 63.2

T1: Age, DM duration, poor glycaemic control, smoking, diastolic BP, obesity, increased LDL-c and triglycerides, lower HDL-c T2: Age, male sex, DM duration, smoking, lower HDL-c Age, DM duration, HbA1c, height, background or proliferative diabetic retinopathy, cigarette smoking, reduced HDL-c, CVD, diastolic BP, severe ketoacidosis, raised fasting triglyceride, microalbuminuria (continued)

T1: height, retinopathy T2: age, height, alcohol, HbA1c, retinopathy

DM duration, hypertension, hyperglycaemia, glycosuria

Risk factors/markers NA

The Epidemiology of Diabetic Neuropathy 11

USA and Canada DCCT/EDIC (Summarising DPN-findings: Albers et al. [58], Martin et al. [59], risk factors [60])

Denmark [61]

USA [62]

Tanzania [63]

Saudi-Arabia [64]

Type 1 (H)

Type 1 (H)

Type 2 (H)

Type 2 (H)

Type 2 (H)

Type 1 (H)

Study site Europe EURODIAB 7.3-year follow-up [57]

Table 1 (continued)

375

153

775

156

1186b

Score based: Several signs (VPT, “sensibility”, hallux flexion, hair loss, foot deformities, dry/cracked skin) OR signs and symptoms (incl. claudication) Pinprick and/or vibration sensation

(1) Confirmed: symptoms or signs (monofilament, VPT, pinprick) and NCSa or ECSc (2) Subclinical: abnormal NCS or ECS Monofilament

NCS and ≥2 of the following: symptoms, signs (light touch, proprioception, temp. sensation, pinprick), ankle reflexes

Participants (N) Neuropathy diagnosis 1172 Same as above

8 (median)

5.2

28

20

11

11.3

Baseline: INT 6; CONV 6 Closeout: INT 12; CONV 12 EDIC year 13/4: INT 26; CONV 26

50

(1) 2.6 (2) 55.1

Baseline: INT 7, CONV 5 Closeout: INT 9; CONV 17 EDIC year 13/4: INT 25; CONV 35

DM duration Prevalence (%) (mean, year) – Cumulative incidence 23.5

50 (median)

44.2

62

Baseline: INT 27; CONV 27 Closeout: INT 34; CONV 33 EDIC year 13/4: INT 48; CONV 47 22

Mean age (year) –

NA

Height, previous foot ulcer, age, HbA1c, alcohol, smoking, albumin level adjusted for serum creatinine NA

None

Risk factors/markers HbA1c, change in HbA1c during follow-up, DM duration, elevated total and LDL-c, elevated triglycerides, higher BMI, higher von Willebrand factor, elevated urinary albumin excretion rate, hypertension, smoking, CVD at baseline Higher mean HbA1c, age, DM duration, height, macroalbuminuria, higher mean pulse rate, β-blocker use, sustained albuminuria

12 C. S. Hansen et al.

Study site Netherlands [65] France [66]

Sweden [64]

Iran [67]

China [68]

Denmark Steno 2 [69]

USA ACCORD [70]

China [71]

Italy [72]

Type 2 (H) Type 2 (H)

Type 2 (H)

Type 2 (H)

Type 2 (H)

Type 2 (H)

Type 2 (H)

Type 2 (H)

Type 1 + 2 (H)

8757

562

10,251

NCS and symptoms and/ or signs (ankle reflex, VPT, monofilament, temp. sensation, pinprick, proprioception ≥2 points: VPT, ankle reflexes, foot ulcer, other foot deformity/dry skin/ infection (1 point per abnormality per side (L/R))

MNSI exam >2

Participants (N) Neuropathy diagnosis 73 VPT 427 Ankle reflexes and/or VPT 79 Pinprick and/or vibration sensation 810 ≥1 of following: pinprick, VPT, light touch, proprioception, ankle reflexes, muscular power 1067 VPT and/or monofilament 160 VPT

32.3

Baseline: INT 43; CON 42 5-year follow-up: INT 55.6; CON 58.6 18.1

Baseline 34.4

56.4

5.6

58.8

62

10

12.1 (data only from records of 1227 participants)

55.1 (40–65)

59.8

52.7

58 (median)

Mean age (year) 65.9 56.9

INT 5.5 CON 6.0

7.2

8.2

75.1

18.3

11.5 (median)

19

DM duration Prevalence (%) (mean, year) 50 6.6 (median) 31.6 10.6

NA

(continued)

Age, DM duration, hypertension, insulin resistance index, HbA1c, HbA1c variability, u-ACR

Retinopathy, HbA1c, DM duration, age NA (INT (targeting hyperglycaemia, risk factors and behaviour) without significant effect on DSPN) INT glycaemic therapy decreased DSPN risk

Age, proteinuria, DM duration, insulin-treatment, retinopathy, IHD

NA

Risk factors/markers NA NA

The Epidemiology of Diabetic Neuropathy 13

UK [74]

Iran [75]

Spain [76]

Type 1 + 2 (H)

Type 1 + 2 (H)

Type 1 + 2 (H)

Type 1 + 2 (H + P)

T1 348 T2 2296

T1 79 T2 521

NDS ≥ 6 OR NDS = 3–5 and NSS ≥ 5

NDS ≥ 6 OR NDS = 3–5 and NSS ≥ 5

Participants (N) Neuropathy diagnosis T1 647 ≥2 of following: T2 524 symptoms, knee/ankle reflexes, VPT T1 2414 NDS ≥ 6 OR NDS = 3–5 T2 3949 and NSS ≥ 5

T1 12.9 T2 24.1

T1 13.8 T2 9.7

DM duration Prevalence (%) (mean, year) T1 17.1 T1 10.3 T2 34.8 T2 9.0 (medians) T1 22.7 T1 13 T2 32.1 T2 6 (medians) T1 21.5 T1 9.5 T2 49.3 T2 9.2

T1 30.5 T2 61.3

Mean age (year) T1 33 T2 54 (medians) T1 45 T2 63 (medians) T1 28.2 T2 57.0 T1: DM duration, education level T:2 history of foot ulcer, age, DM duration, weight, education level, male sex T1: DM duration T2: age, DM duration

Risk factors/markers T1 + T2: Age, retinopathy, macroangiopathy, CAN T1: albuminuria, HbA1c Age, DM duration

BMI body mass index, BP blood pressure, CDT cooling detection threshold, CON conventional treatment, CVD cardiovascular disease, DB deep breathing, DKA diabetic ketoacidosis, DM duration diabetes mellitus duration, DN4 Douleur Neuropathique 4 Questions, ECS electrochemical skin conductance, Glc glucose, H Hospital/out-patient based, HbA1c hemoglobin A1c, HDL/LDL/total-c high density lipoprotein/low density lipoprotein/total chlolesterol, IHD ischemic heart disease, INT intensive treatment, MI myocardial infarction, MNSI examination Michigan neuropathy screening instrument examination, MNSIq Michigan neuropathy screening instrument questionnaire, NCS nerve conduction studies, NNS and NDS Neuropathy symptom score and Neuropathy disability score (Young et al. [74]), P primary care/community-based, PAD peripheral arterial disease, S-LANSS self-report Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) pain scale, u-ACR urin albumin-creatinine ratio, VAL Valsalva’s manoeuvre, VPT vibration perception threshold a NCS measured with handheld DPNCheck©-device b Number of participants at EDIC year 13/14, mean age and DM duration reported for these c ECS measured with Sudoscan©-device

Study site Germany, Austria, Switzerland [73]

Table 1 (continued)

14 C. S. Hansen et al.

The Epidemiology of Diabetic Neuropathy

of 13.1% at the time of diabetes diagnosis using the Michigan Neuropathy Screening Instrument questionnaire (MNSIq) to define DSPN [46]. Similarly, the prevalence of DSPN in the United Kingdom Prospective Diabetes Study (UKPDS) of 3,867 people with newly diagnosed T2D was 11.5%, defined using VPT [45]. Out-patient clinic-based samples show prevalence’s ranging from 6.4% [68] to 39% [65] in people with newly diagnosed T2D.  In summary, estimates of the prevalence of DSPN in newly diagnosed T2D range from 4% and 40%, with lower prevalence (5 and history suggesting neuropathic pain MNSI exam >2 and neuropathic pain (MNSIq) MNSI exam >2 and neuropathic pain (MNSIq) (1) Possible DSPN: MNSIq ≥ 4 (2) Possible P-DSPN: bilateral pain in the feet and DN4 questionnaire ≥3 (1) Possible DSPN: ≥1 of following: symptoms, signs (light touch, pinprick, temp. sensation, VPT), ankle reflexes (2) Probable DSPN: ≥2 of the above 3 (3) Definite DSPN: NCS or IENFD and ≥1 of the above 3 (3) Definite P-DSPN: NCS or IENFD and bilateral pain in feet, signs DSPN: MNSIq ≥ 3 and monofilament OR typical DSPN signs and symptoms evaluated by study physician P-DSPN: DSPN and VAS ≥ 4 last 48 h or use of pain medication for pain in legs and feet or legs and hands DSPN: Monofilament and/or VPT P-DSPN: DSPN and DN4 ≥ 4

Table 2  Prevalence of painful DSPN, and DSPN when stated, in type 1 and 2 diabetes

63.9

10.1

34.5

P-DSPN 57.5 Non-P-­ DSPN 52.6

P-DSPN 63.6 Non-P-­ DSPN 62.5

P-DSPN 13.1 Non-P-­DSPN 11.4

DSPN 33.5 of which 43.1 P-DSPN

P-DSPN 13.6 Non-P-­DSPN 8.2

.

.

(1) 62.2 (2) 43.9 (3) 22.7 (4) 5.4

DSPN 21.3 of which P-DSPN 21.2

64.1

4.6

(1) 18 (2) 10

69

66.8

NA

NA

Mean age (year) 66.7

21

13.3

DM duration Prevalence (%) (mean, year) 26.4 8

(continued)

DSPN: age, insulin treatment, microalbuminuria, overt proteinuria P-DSPN: age, HbA1c, lower HDL-c, overt proteinuria VPT, smoking, obesity, female sex, DM duration

P-DSPN: age, female gender, fasting Glc, hypertension, previous cerebrovascular events

Waist circumference, physical activity, PAD (1) Female sex, age, DM duration, BMI, smoking (2) Smoking NA

Age, weight, PAD

Risk factors/markers NA

The Epidemiology of Diabetic Neuropathy 17

Germany PROTECT study [85]

Belgium [7]

Libya [92]

Type 1 + 2, P-DSPN (P)

Type 1 + 2, P-DSPN (H)

Type 1 + 2, P-DSPN (H)

T1 + T2 450

T1 344 T2 767

S-LANSS ≥ 12

DSPN: Monofilament and/or pinprick Painful-DSPN: DSPN and DN4 >4

DSPN: ≥1 of following: monofilament, temperature sensation, VPT P-DPSN: DSPN and pain/burning in feet

T1 126 T2 943

T1 1338 T2 14,206

Neuropathy diagnosis VPT, NSS, NDS, Pain symptoms score ≥3 and neuropathic pain in legs ≥1 year NSS ≥ 5 and NDS ≥ 3

Participants (N) 350

T1 44.3 of which P-DSPN 54.8 T2 55.3 of which P-DSPN 61.7 T1: DSPN 25.6 P-DSPN 5.8 T2: DSPN 50.8 P-DSPN 17.9 42.2

T1 13.4 T2 21.5 Overall 21

50.6

T1 45.9 T2 63.6

T1 16.5 T2 11.0

15

T1 59.5 T2 70.0

T1 37.6 T2 63.6

Mean age (year) 63

NA

T1 17 T2 4

DM duration Prevalence (%) (mean, year) 16.2 NA

DM duration, smoking (men), obesity, fasting Glc

Nephropathy, obesity, low HDL-c, high triglycerides

Risk for painful symptoms: T2D, female gender, South Asian ethnicity T2 DSPN + P-DSPN: higher and lower BMI

Risk factors/markers NA

BMI body mass index, BP blood pressure, CDT cooling detection threshold, CON conventional treatment, CVD cardiovascular disease, DB deep breathing, DKA diabetic ketoacidosis, DM duration diabetes mellitus duration, DN4 Douleur Neuropathique 4 Questions, ECS electrochemical skin conductance, Glc glucose, H Hospital/out-patient based, HbA1c hemoglobin A1c, HDL/LDL/total-c high density lipoprotein/low density lipoprotein/total chlolesterol, IHD ischemic heart disease, INT intensive treatment, MI myocardial infarction, MNSI examination Michigan neuropathy screening instrument examination, MNSIq Michigan neuropathy screening instrument questionnaire, NCS nerve conduction studies, NNS and NDS Neuropathy symptom score and Neuropathy disability score (Young et al. [74]), P primary care/community-based, PAD peripheral arterial disease, S-LANSS self-report Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) pain scale, u-ACR urin albumin-creatinine ratio, VAL Valsalva’s manoeuvre, VPT vibration perception threshold

England [91]

Type 1 + 2, P-DSPN (P)

Type 1 and 2, P-DSPN (P)

Study site UK [90]

Table 2 (continued)

18 C. S. Hansen et al.

The Epidemiology of Diabetic Neuropathy

Recently, lower P-DSPN prevalences have been reported in the Danish DD2 cohort of recently diagnosed T2D.  Confirmed P-DSPN was estimated to be present in only 5.4% of the cohort of more than 5500 individuals when evaluated clinically in a sub-sample of 389 individuals [89]. By contrast, P-DSPN prevalences from two hospital-based studies in Qatar and Libya report high prevalences of 34.4% and 42.2%, respectively. The latter study was, however, based solely on self-reported and self-evaluated neuropathic pain [84, 92]. However, prevalences similar to the ones reported in community-based samples are also found in out-patient settings [7]. Reports characterising both DSPN and P-DSPN estimate that approximately 20–40% of people with DSPN have neuropathic pain [7, 77, 78, 89]. There is a large disparity between painful symptoms and clinical signs of DSPN and little is known about the natural history of P-DSPN [5, 6, 91, 93, 94]. There are few longitudinal studies of P-DSPN and most are small. These provide conflicting results, indicating both spontaneous pain improvement and remission over time [95, 96] as well as the opposite finding [95, 97]. As recent reviews report the duration and severity of diabetes, and the severity of neuropathy, as risk factors for P-DSPN, pain remission seems unlikely [6, 83]. In conclusion, approximately 15% of people with diabetes have P-DSPN but estimates vary and may be as high as 40%.

19

neurological deterioration is associated with increasing age [17] and the risk factor profile of participants may change over time. Furthermore, nerve fibre dysfunction may be partly reversible [17, 99–101], further complicating interpretation of longitudinal studies of DSPN. A long-term clinic-based study published in the 1970s followed over 4000 people with T1D and T2D for 25 years and found a cumulative DSPN incidence of 50% [102–104]. Even though some aspects of the methodology can be questioned, the size of the study is noteworthy. DSPN incidence has since been evaluated in more recent study cohorts. These are summarised in the following paragraph. In newly diagnosed diabetes, a small Finnish cohort of people with T2D showed an increase from a baseline prevalence of 8.3% to 41.9% over 10 years when defining DSPN using NCS and symptoms [31]. The UKPDS cohort of newly diagnosed T2D evaluated DSPN by VPT and found that the prevalence increased from approximately 11–30% over 12 years, irrespective of treatment arm [45]. In comparison, the ADDITION-Denmark cohort of screen-detected T2D report a cumulative incidence of only 10% over 13 years of follow-up [46]. In contrast, the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial of more than 2,000 people with longstanding T2D and confirmed coronary artery disease, showed a DSPN prevalence of 50% at baseline and a cumulative incidence over 4 years of 66–72% when 2.4 Incidence of DSPN defining DSPN using the MNSI examination [105]. The ACCORD trial similarly defined Although reported prevalences of DSPN in T1D DSPN using the MNSI examination. Although and T2D are similar, the incidence of DSPN is the trial was closed earlier than planned due to estimated to be higher in T2D (6.1 per 100 higher mortality in the intensive treatment arm, person-­years) than in T1D (2.8 per 100 person-­ intensive treatment (INT) decreased the risk of years). This is probably due to differences in the DSPN compared to conventional care (CON). underlying pathophysiology and populations Baseline prevalences of 42% (CON) and 43% characteristics of T1D and T2D [1, 6, 17, 98]. (INT) increased to 59% (CON) and 56% (INT) The slow progression of DSPN complicates after 5 years [70]. Two other smaller longitudinal investigation of incident DSPN and highlights studies of T2D report an annual incidence of the importance of testing methodology. Different 6.1% when evaluating DSPN with both sympnerve fibre populations may be affected at differ- toms and signs [106] and 20% over 2.5 years ent rates and minor changes may be undetected when evaluating DSPN by monofilament [62]. due to low sensitivity of tests. In addition, natural More recently, an Indian study of T2D reported a

20

4-year incidence of 28.4% evaluated using VPT [107]. The landmark studies of DCCT/EDIC provide detailed information on the incidence of DSPN [21]. Incidence of confirmed DSPN was 6% and 14% in the intensive and the conventional treatment arms, respectively, at DCCT closeout after approximately 5 years. The incidence in the EDIC cohort at year 13/14 was 22% (INT) and 28% (CON), respectively, and the prevalence was 25% (INT) and 35% (CON) [58, 59]. Underlying NCS abnormalities were also more prevalent in the CON group and consistently higher than the prevalence of confirmed or clinical DSPN in both the INT and CON groups [59]. The observational Epidemiology of Diabetes Complications (EDC) study of childhood-onset T1D reported a 15% prevalence of DSPN at the 6-year follow-up in participants free from DSPN at baseline, corresponding to an incidence of 2.8 per 100 person-years [108]. At 12 years, the incidence per 100 person-years was 1.2 for people with a T1D duration 100 bpm

Orthostatic Hypotension

Light headedness Weakness Faintness Visual impairment Syncope

Clinical Exam: A reduction of >20 mmHg in the systolic BP or >10 mmHg in diastolic BP within 3 min of standing or upright tilt table testing

Abnormal BP regulation

Non-dipping (lack of nocturnal BP drop)

24-h BP monitoring

Resting Tachycardia

Differential work-up  •  Anemia  •  Hyperthyroidism  •  Fever  •  CVD (atrial fibrillation, flutter, other)  •  Dehydration  •  Adrenal insufficiency  •  Medications   – Sympathomimetic agents (asthma)   – Over-the-counter cold agents containing ephedrine or pseudoephedrine   – Dietary supplements (e.g., ephedra alkaloids)  •  Smoking, alcohol, caffeine  •  Recreational drugs (cocaine, amphetamines, methamphetamine, mephedrone)  •  Adrenal insufficiency  •  Intravascular volume depletion   – Blood loss/Acute anemia   – Dehydration  •  Pregnancy/postpartum  •  CVD    –  Arrhythmias   – Heart failure   – Myocarditis   – Pericarditis    –  Valvular heart disease  •  Alcohol  •  Medications    –  Antiadrenergics    –  Antianginals    –  Antiarrhythmics    –  Anticholinergics   – Diuretics    –  ACEi/ARBs   – Narcotics   – Neuroleptics   – Sedatives

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5.1.2 Clinical Signs of CAN The physiologic HRV is a product of both sympathetic and parasympathetic activity [1, 2]. Patients with subclinical CAN present with a decrease in HRV, usually with deep breathing or change in posture, considered the earliest clinical indicator of CAN [1, 2]. Although HRV testing is largely confined to the research setting, it may be done in the office by either (1) taking an ECG recording as a patient begins to rise from a seated position or (2) taking an ECG recording during 1–2 min of deep breathing with calculation of HRV [1]. However, even these relatively simple methods could be challenging in some clinical settings, highlighting the need for easily accessible diagnostic tools and/or biomarkers for screening and diagnosis of CAN for general clinical care. As CAN progresses, individuals may present with resting tachycardia with fixed heart rate (>100 bpm), exercise intolerance, non-dipping and reverse dipping, and in more advanced cases with orthostatic hypotension (a fall in systolic or diastolic blood pressure by >20 mmHg or >10 mmHg, respectively, upon standing without an appropriate increase in heart rate) [1, 104]. Orthostatic hypotension is usually easy to document in the office by measuring the blood pressure (BP) supine and after standing, keeping also in mind that in most cases of CAN, there is no compensatory increase in the heart rate, despite hypotension [1]. To document non-dipping or reverse dipping, the ambulatory BP monitoring (ABPM), a standard tool in the current hypertension management, allows the assessment of the diurnal BP patterns that is mainly regulated by sleep-awake changes in the autonomic cardiovascular function [1, 104]. However, it is important to note that none of these signs are specific for diabetes related CAN. CAN diagnosis includes documentation of symptoms and signs of CAN (Table  1). In a symptomatic patient with a history of poor glucose control presenting with resting tachycardia or postural hypotension, clinicians may not need to perform additional CAN tests given costs and burden after excluding other potential causes [2]. Importantly, the diagnosis of CAN requires an extensive differential as many other comorbidities, such as cardiovascular disease, adrenal insufficiency, thyroid dysfunction, acute blood loss and anemia, dehydration, and drug effects/interac-

tions may present with symptoms and/or signs mimicking CAN, as illustrated in Table 1 [1, 2]. Key Points • All patients should be assessed for CAN starting 5 years after diagnosis or in the presence of other forms of diabetic neuropathy and/or other diabetic complications with symptoms and signs. • Tests excluding other comorbidities or drug effects/interactions that could mimic CAN should be performed. • Screening for CAN should also be considered in patients with hypoglycemia unawareness and high glucose variability, prior to insulin dose adjustments and/or perioperatively.

5.2 Diagnosis for Clinical Research Several tests are available to diagnose CAN including: CARTs, ideally under paced breathing; HRV studies that derive indices in time and frequency domain using various algorithms; 24-h BP profiles; baroreflex sensitivity testing; and cardiac sympathetic imaging [1, 2]. CARTs remain the gold standard for autonomic testing in both the clinical and research settings [1, 2, 104] and evaluate changes in the heart rate and BP during several physiological maneuvers such as: (1) deep breathing; (2) standing; and (3) a Valsalva maneuver [1, 2]. Several factors may influence the results of CARTs, such as intake of caffeine, tobacco products, food, and some medications like beta blockers. Therefore, these tests should be performed by uniformly trained personalized personnel and using standardized protocols to minimize variability and bias. In addition, given the very large number of recording devices and particularly software ­operating with a “black-box” approach (output of data without reporting the algorithm that calculated the result) have emerged in recent years, it is necessary to carefully select the most transparent and verifiable technologies to use for reliable and reproducible data. In general, it is currently accepted that one abnormal test may indicate early or subclinical CAN, while two or more abnormal tests are recommended for a definite diagnosis of CAN [104].

Cardiovascular Autonomic Neuropathy

Given that age is one of the most important factors affecting HR, age-­related normative are needed for correct classification settings [1, 2, 104]. Indices of HRV are alternative CAN outcome measures that have been used extensively. The HRV can be evaluated either as time domain measures such as: the difference between the longest and shortest RR interval, the standard deviation of 5-min average of normal RR intervals (SDNN), and the root-mean square of the difference of successive R–R intervals (rMSSD), or as frequency domain measures obtained by spectral analysis or other mathematical algorithms such as: low, very low and high frequency power [1, 2, 104]. Although traditionally these indices were initially derived from longer ECG recordings, HRV-derived indices from standard 10-s 12-lead ECG recordings have emerged as more feasible alternative measures of CAN in population studies, and have been shown to independently predict CVD morbidity and mortality in several large cohorts of people with and without diabetes [11, 12, 63, 65] and to define prevalence rates. Until recently, validation studies evaluating the sensitivity and specificity of these ECG-based HRV indices compared to the gold standard CARTs assessment have not been available. However, rigorous assessment of the sensitivity, specificity, and probability of correct classification of CAN using indices of HRV derived from short ECG recordings in predicting CAN compared to the more laborious method using the gold standard CARTs were performed in the DCCT/EDIC cohort that was phenotyped concomitantly with both standardized CARTs and digitized ECGs. The indices of HRV had modest predictive performance comparable with other instruments that have been used successfully to phenotype diabetic peripheral neuropathy in large and diverse cohorts of T1D and T2D [105]. Cardiac sympathetic imaging using I-123 MIBG scintigraphy or 11C-HED PET, 24-h ambulatory blood pressure profiles, baroreflex sensitivity testing to assess cardiac vagal and sympathetic baroreflex function, and microneurography, while valid and useful in some specific research scenarios, require sophisticated infrastructure, highly trained personnel, and are quite expensive and time-consuming widely used in research protocols [1, 2].

213

6 Treatment As it is the case with diabetic peripheral neuropathy, to date no disease modifying agents are available for CAN treatment, likely due to the very complex pathogenic pathways contributing to development of CAN [1, 2]. Thus, the management of CAN includes consideration of glucose control and modification of other risk factors.

6.1 Prevention In individuals with T1D, the conclusive data obtained by the DCCT and later during EDIC study, as well as evidence from several smaller trials strongly support that tight control of blood glucose implemented as early as possible in the disease course is very effective for preventing CAN and slowing its progression in patients with T1D [1–4, 106, 107]. For instance, during over an average of 6.5 years DCCT follow-up, intensive glucose control, with lower hemoglobin A1c levels, reduced the risk of CAN by 45%, a benefit that persisted during EDIC with a 30% reduction in incident CAN over an additional 14  years of follow-up [3, 4, 107]. Similarly, the EURODIAB IDDM Complications Study, found a significant correlation between development of CAN and glycemic control [5]. The evidence for patients with T2D is less conclusive, as in several large cohorts intensive control of blood glucose had no effect on the risk of CAN [108–110] although one could argue that these trials may have not included the most reliable CAN outcomes, and most patients with T2D enrolled had multiple associated comorbidities and other risk factors, such as hypertension, hyperlipidemia, obesity, and require polypharmacy. In contrast, glucose control as part of a multifactorial intervention that targeted besides hyperglycemia, hypertension, dyslipidemia, and lifestyle, demonstrated a 63% reduction in the rate of progression to CAN in a small T2D cohort participating in the STENO-2 trial [111]. Most recently, analyses from the ACCORD trial, reported that after adjusting for multiple other risk factors, intensive glucose treatment significantly reduced CAN risk by 16% compared to standard intervention in a large cohort of more

L. Ang and R. Pop-Busui

214

than 8000 T2D participants in the ACCORD trial over a mean 5 years follow-up [10]. These data confirmed a beneficial effect of intensive glycemic therapy particularly in individuals without cardiovascular disease at baseline. A similar benefit on CAN was found for intensive blood pressure control [10], while intensive treatment of hyperlipidemia with statins and fenofibrate did not. The population-based Coronary Artery Risk Development in Young Adults (CARDIA) study reported benefit of lifestyle interventions in prevention of CAN progression [112]. In the Diabetes Prevention Program (DPP), lifestyle interventions improved measures of HRV over time in participants with prediabetes [113].

6.2 Symptomatic Treatment Management of orthostatic hypotension involves both behavioral and pharmacological interventions

(Table 2). Behavioral supportive measures include: (a) avoiding abrupt changes in body position; (b) avoiding actions that elevate intra-­abdominal and intra-thoracic pressures; (c) avoiding medications that would exacerbate hypotension such as tricyclic antidepressants, phenothiazines and diuretics; (d) raise the head of the bed during sleep; (e) follow a schedule of small and frequent meals to minimize postprandial hypotension; (f) consider physical counter-­pressure maneuvers such as leg crossing and squatting; (g) hydrate with fluids and salt, if not contraindicated [1, 2]. Pharmacological therapy includes midodrine and droxidopa, both of which are FDA approved for the management of orthostatic hypotension and may be considered in patients who fail non-pharmacological interventions. However, it is recommended to proceed with a very slow titration and use the minimally effective dose to avoid undesirable side effects. In selected severe cases low dose fludrocortisone may be also an option [1, 2] (Table 2).

Table 2  Treatment for orthostatic hypotension Simple measures  •  Avoiding sudden changes in body posture to the head-up position  •  Avoiding medications that aggravate hypotension  •  Eating small, frequent meals  •  Avoiding activities that involve straining  •  Raising bed head Pharmacological Dose treatment Initial Effective Midodrine 2.5 mg 2.5–10 mg. p.o, 1–4×/ p.o. day * First dose to be taken before arising

Droxidopa

100 mg p.o 3×/ day

100–600 mg p.o 3×/ day To reduce the potential for supine hypertension, elevate the head of the bed and give the last dose at least 6 h prior to bedtime

Fludrocortisone

0.05 mg po at bedtime

0.1–0.2 mg/day, p.o.

Physical maneuvers  •  Leg crossing  •  Squatting  •  Muscle pumping

Major adverse effects

Notes

 • Supine hypertension  •  Piloerection  •  Pruritus  •  Paresthesias  •  Urinary retention  • Supine hypertension  •  Headache  •  Dizziness  •  Nausea  • Hyperpyrexia and Confusion

–  FDA approved – Activates α-1 receptors on arterioles and veins, increases total peripheral resistance

 • Supine hypertension  •  Hypokalemia  •  Hypomagnesemia  • Congestive heart failure  •  Peripheral edema

– FDA approved for the treatment of neurogenic orthostatic hypotension but not specifically for individuals with orthostatic hypotension due to diabetes –  α/β adrenergic agonist – Effectiveness beyond 2 weeks of treatment has not been established – Not FDA approved for orthostatic hypotension – Synthetic mineralocorticoid – May require up to 1- to 2-week to observe effects

Cardiovascular Autonomic Neuropathy

7 Conclusions CAN is prevalent chronic complication of diabetes with a diverse clinical spectrum of symptoms and signs. The prevalence rates remain high even in contemporary cohorts and under the current standards of care. Prompt recognition of CAN in the clinical setting is crucial, as CAN is an independent predictor of cardiovascular mortality, cardiac arrhythmia, silent myocardial ischemia, major cardiovascular events, and myocardial dysfunction leading to increased morbidity, substantial economic burden, and poor quality of life in patients with diabetes. Despite this knowledge, screening and diagnosis of the disease in its early stages remains elusive, and effective management strategies and interventions to reverse development and progression are missing. The progress in diabetes technologies, combined with big data analyses and integration of the genotype/ phenotype interactions with multiomics-derived biomarkers, are likely to unveil specific increased susceptibilities to or protections against CAN.  This would also lead to identification of modifiable factors and targeted techniques providing the framework for future clinical trials to test novel interventions to either prevent progression or reverse disease in a personalized care approach, ultimately reducing the health care burden and optimizing patients’ quality of life.

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219 retinal sensory neuropathy in persons with type 1 diabetes mellitus. Eye (Lond). 2016;30(6):825–32. 99. Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. N Engl J Med. 2012;366(13):1227–39. 100. Krolewski AS, Barzilay J, Warram JH, Martin BC, Pfeifer M, Rand LI.  Risk of early-onset proliferative retinopathy in IDDM is closely related to cardiovascular autonomic neuropathy. Diabetes. 1992;41(4):430–7. 101. Hotaling JM, Sarma AV, Patel DP, Braffett BH, Cleary PA, Feldman E, Herman WH, Martin CL, Jacobson AM, Wessells H, Pop-Busui R.  Cardiovascular autonomic neuropathy, sexual dysfunction, and urinary incontinence in women with type 1 diabetes. Diabetes Care. 2016;39(9):1587–93. 102. Pop-Busui R, Hotaling J, Braffett BH, Cleary PA, Dunn RL, Martin CL, Jacobson AM, Wessells H, Sarma AV, Group DER.  Cardiovascular autonomic neuropathy, erectile dysfunction and lower urinary tract symptoms in men with type 1 diabetes: findings from the DCCT/EDIC. J Urol. 2015;193(6):2045–51. 103. Lin YK, Fisher SJ, Pop-Busui R.  Hypoglycemia unawareness and autonomic dysfunction in diabetes: lessons learned and roles of diabetes technologies. J Diabetes Investig. 2020;11(6):1388–402. 104. Spallone V, Bellavere F, Scionti L, Maule S, Quadri R, Bax G, Melga P, Viviani GL, Esposito K, Morganti R, Cortelli P, Diabetic Neuropathy Study Group of the Italian Society of D. Recommendations for the use of cardiovascular tests in diagnosing diabetic autonomic neuropathy. Nutr Metab Cardiovasc Dis. 2011;21(1):69–78. 105. Pop-Busui R, Backlund JYC, Bebu I, Braffett BH, Lorenzi G, White NH, Lachin JM, Soliman EZ, Group DER. The utility of using ECG measures of heart rate variability as a measure of cardiovascular autonomic neuropathy in type 1 diabetes. J Diabetes Investig. 2022;13(1):125–33. 106. Margolis KL, O’Connor PJ, Morgan TM, Buse JB, Cohen RM, Cushman WC, Cutler JA, Evans GW, Gerstein HC, Grimm RH Jr, Lipkin EW, Venkat Narayan KM, Riddle MC Jr, Sood A, Goff DC Jr. Outcomes of combined cardiovascular risk factor management strategies in type 2 diabetes: the ACCORD randomized trial. Diabetes Care. 2014;37(6):1721–8. 107. Martin CL, Albers JW, Pop-Busui R.  Neuropathy and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care. 2014;37(1):31–8. 108. Azad N, Emanuele NV, Abraira C, Henderson WG, Colwell J, Levin SR, Nuttall FQ, Comstock JP, Sawin CT, Silbert C, Rubino FA.  The effects of intensive glycemic control on neuropathy in the VA cooperative study on type II diabetes mellitus (VA CSDM). J Diabetes Complicat. 1999;13(5-6):307–13. 109. Charles M, Fleischer J, Witte DR, Ejskjaer N, Borch-­ Johnsen K, Lauritzen T, Sandbaek A. Impact of early detection and treatment of diabetes on the 6-year

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Psychosocial Aspects of Diabetic Neuropathy: From Description to Interventions Loretta Vileikyte and Frans Pouwer

1 Introduction The diabetic neuropathies are a collection of nerve disorders caused by diabetes that affect different parts of the nervous system and present with diverse clinical manifestations of sensorimotor and autonomic dysfunction [1]. Distal symmetric polyneuropathy (DPN) is one of the commonest varieties and is the focus of this chapter. Among the various clinical presentations of DPN, severe unremitting pain is by far the most studied by behavioral scientists. Our chapter, while reflecting on this common tendency, also highlights the importance of other clinical presentations of DPN.  Postural instability, for example, is one of the strongest predictors of poor self-rated health and depression in people with established DPN [2–4]. Numerous neurobiological similarities tie diabetic neuropathies, pain, depression, and anxiety together—these threads include the neuroendocrine system, autonomic system, and the inflamL. Vileikyte (*) Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester, UK Department of Dermatology, University of Miami, Miami, FL, USA e-mail: [email protected] F. Pouwer Department of Psychology, Steno Diabetes Center Odense, University of Southern Denmark, Odense, Denmark

matory cytokine system, and a host of other, interrelated physiological pathways in brain and body, reviewed elsewhere [5, 6]. This chapter focuses exclusively on psychosocial factors associated with DPN. Depression has received the lion’s share of attention from clinical researchers. In people with diabetes, those with co-morbid complications are at increased risk to be depressed or develop depression [7–9]. In two longitudinal studies, people with both diabetes and depression had a higher risk to develop DPN [10, 11]. Longitudinal data from nationwide general practices in Germany showed that individuals with diabetes and DPN had higher levels of incident depression [7]. Besides depression, diabetes distress (the negative affective or emotional experience resulting from living with the demands of diabetes) and anxiety are also common in diabetes [12]. In fact, elevated anxiety symptoms were found to be more prevalent than depressive symptoms, with 32% of people with diabetes reporting elevated symptoms of anxiety and 22% for elevated symptoms of depression, using the Hospital Anxiety and Depression Scale [13]. The observed diabetes and anxiety relationship is consistent with accumulating research linking chronic pain and anxiety; this pattern mirrors but exceeds the pattern examining depression [14]. These observations might be of potential importance to managing painful DPN, as commonly used medi-

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cations are potent mood modulators with distinct class effects on anxiety and depression. Accordingly, we discuss studies that examined the differing contributors to anxiety and depressive symptoms as well as different predictors of analgesic response to duloxetine and pregabalin in persons with painful DPN [15, 16]. Again, we emphasize the importance of distinguishing generalized distress (depression/anxiety) from diabetes/DPN-specific distress, a psychological concept although related to, but not interchangeable with, depression or anxiety [12, 17]. A growing number of researchers studying DPN favor disease-specific over psychiatric definitions of emotional distress. Using a diabetic neuropathy and depression model we illustrate how DPN-­ specific distress mediates the association between DPN severity and depression [2, 3]. Another emerging line of inquiry examines DPN-specific fears such as fear of pain increase and/or fear of falling and their associations with greater disability and reduced quality of life (QoL) in persons with DPN [18, 19]. Pertaining to this, by comparing and contrasting the performance of generic and DPN-specific QoL instruments, we make a case for the need to consider DPN-specific measures when identifying and managing the psychosocial problems surrounding this devastating complication of diabetes, both in clinical care and in clinical research projects. Finally, we provide a critical overview of the paucity of psychosocial interventions conducted in this area and emphasize the need for an integrated, bio-­ psychosocial approach to the management of DPN. This chapter concludes by discussing psychological treatments and interventions that could potentially assist in the management of psychosocial hardships experienced by people with DPN.

2 The Impact of DPN on Physical and Mental Functioning, and QoL Although DPN is a multifaceted complication of diabetes, studies examining the impact of DPN on individuals’ physical and mental functioning

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have traditionally focused on painful DPN. One of the earliest, yet probably most comprehensive assessments to-date of neuropathic pain burden, was conducted by Gore et al. [20]. This community based, cross-sectional self-report survey described pain severity, as measured by the Modified Brief Pain Inventory-DPN [21], its interference with function, as well as prescription medication use and treatment satisfaction among patients with painful DPN.  The burden of pain was reported to be considerable, resulting in a persistent discomfort despite polypharmacy and high resource use, and leading to limitations in daily activities and poor satisfaction with treatments that were often deemed to be inappropriate. Individuals with painful DPN reported significant impairment in physical and mental functioning as compared to the general US population, although the differences in mental functioning were less pronounced than those observed in physical functioning. A qualitative study of persons affected by painful DPN [22] identified four major areas of impact: (1) physical function, i.e. walking, exercise, energy, standing, balance, bending, and mobility; (2) daily life, i.e. productivity, recreational activities, work, enjoyment, focus, and chores; (3) social/psychological, i.e. anxiety, friends/family, irritability, depression, and fear; and (4) sleep, i.e. falling asleep, waking in the night and not feeling rested upon awakening. In a study by Zelman et  al. [23], individuals with painful DPN reported impaired sleep relative to the US population norms and the Medical Outcomes Study (MOS) chronic patient sample on both, the sleep problem index and all six sleep attribute scales. Hierarchical regression indicated that older age, higher average daily pain, and higher levels of anxiety and depression were each significantly associated with, and collectively accounted for, 47% of variance in the MOS sleep problem index. More recently, Naranjo et al. [24] in a cross-sectional study compared sleep characteristics in type 2 diabetes patients with and without painful DPN and investigated the relationship of sensory phenotypes, anxiety, and depression with sleep quality. Persons with painful DPN reported significantly more sleep disturbances

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than the control subjects in all dimensions of the MOS sleep scale. Higher scores in anxiety or depression, greater intensity of pain or a higher score in the paroxysmal pain phenotype were associated with lower sleep quality in individuals with painful DPN. As shown by Tolle et al. [25], inadequate pain control and severe sleep deprivation resulted in over 60% of persons with painful DPN who worked either part or full-time reporting either missing work or decreased work productivity. Worse yet, in this report, pain intensity disrupted substantially employment status, with nearly 20% of persons with painful DPN reporting job loss or early retirement. A subsequent prospective study [26] confirming and expanding upon the literature, showed a significantly worse trajectory of outcomes over time and long-term increased total costs for individuals with painful DPN relative to those without painful DPN and control subjects. The painful DPN group not only reported significantly lower levels of physical functioning, but their physical functioning scores decreased at a significantly faster rate over a 3-year period relative to other groups. In addition, those with painful DPN reported significantly lower work productivity and activity, greater resource use, and higher total 3-year per-­ person costs. Resource use and lost productivity due to health were monetized separately for each year and then totaled for the 3-year period. Although the costs were generally comparable between the diabetes without painful DPN and control groups, those with painful DPN were estimated to have significantly higher direct and total costs than the other groups in each year of the study. The main contributors to increased cost in the painful DPN group were the increased number of physician visits and hospitalizations. The impact of DPN on individuals’ physical and mental function originally reported by US researchers has recently received much attention in other countries. A study of hospital outpatient clinics across Belgium [27] showed that both painless and painful DPN are common, especially in people with type 2 diabetes. Despite its profound negative impact on QoL, painful DPN remains undertreated with only half of individuals receiving analgesic treatment, and only 28%

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of them using anticonvulsants or antidepressants. Similarly, a French study confirmed the notion that persons with painful DPN have poorer QoL and more sleep disturbances, anxiety, and depression than those without pain, with only 39% of the persons receiving appropriate treatment for their painful DPN [28]. Another study conducted in Wales indicated that the severity of painful DPN symptoms predicts poor health-related utility and decreased QoL [29]. Happich et al. [30] described the health-related QoL, using generic and disease-specific questionnaires, the resource utilization, and annual costs associated with DPN in Germany. In this retrospective, observational study of persons with type 1 and type 2 diabetes and DPN, the majority of them were severely impaired with regard to general physical health. Disease-specific QoL decreased continuously with increasing DPN severity. In accordance, costs associated with DPN increased with the progression of DPN, with costs from the societal perspective increasing about 50-fold from the lowest severity stage (those with sensory-motor neuropathy without symptoms) to persons with lower extremity amputation. Canadian researchers [31] have demonstrated that in persons with longstanding type 1 diabetes, compared to other complications, DPN has the greatest association with both diabetes distress and depression independent of clinical and lifestyle confounding variables. A large Danish study estimated the prevalence of painless and painful DPN, important risk factors, and the association with mental health in persons with recently diagnosed type 2 diabetes [32]. The group demonstrated that possible painless and painful DPN were independently and additively associated with lower QoL, poorer sleep, and elevated symptoms of depression and anxiety. These findings are important given that healthcare costs are significantly higher for DPN patients with depression or anxiety relative to those without such comorbid disorders [33]. Several recent systematic reviews [34, 35] of psychosocial factors related to painful DPN have also reaffirmed the results of individual studies indicating that depression, anxiety, sleep quality, and quality of life are the most studied variables

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in relation to pain outcomes and are consistently associated with pain intensity.

3 The Effects of Pain Medication on Psychosocial Outcomes: Sleep and Mental Health Painful DPN is difficult to treat, with treatment regimens often inadequate for pain control and limited by side effects and drug intolerance. Secondary parameters, such as quality of sleep and mood, may also be important for successful painful DPN management. A randomized, placebo-­ controlled trial study by Boyle et  al. compared the analgesic efficacy of pregabalin, amitriptyline, and duloxetine, and their effect on sleep, daytime functioning, and quality of life in patients with painful DPN [36]. All medications reduced pain when compared with placebo, with pain ratings showing 50% improvement, in line with previous studies. However, no treatment was superior to any other. Daytime performance measures showed no evidence of cognitive impairment during treatment. For sleep, pregabalin improved sleep continuity, whereas duloxetine increased wake and reduced total sleep time. The beneficial effects of pregabalin on pain-related sleep interference were documented in a review of clinical trials [37] suggesting that, in addition to its analgesic properties, pregabalin may affect pain perception indirectly, that is, through improving sleep quality. Indeed, a post-hoc analysis of data pooled from placebo-controlled trials of pregabalin in persons with painful DPN using path modeling showed a high degree of association between improvements in sleep and pain relief. Overall, these data suggest that the presence of comorbid sleep disturbance in persons with painful DPN might, in part, predict substantial pain relief in response to pregabalin treatment [38]. The sleep fragmentation with duloxetine, as observed in the study by Boyle et  al. [36], is somewhat concerning. It is widely believed that poor sleep quality may worsen pain, and although duloxetine has good analgesic efficacy, its effectiveness may be limited by this physiological

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effect. Therefore, while there was no significant difference in analgesic efficacy between amitriptyline, duloxetine, and pregabalin, there were significant differences in the secondary parameters, which are of relevance when deciding the optimal treatment for painful DPN.  Somewhat surprisingly, this study [36] found no significant improvements in mental health as assessed by the Short Form (SF)-36 which is unexpected given that all three treatments (pregabalin for generalized anxiety disorder and duloxetine and amitriptyline for depression) are indicated for affective disorders. Moreover, as evident from the studies reviewed in this chapter, painful DPN is associated both with depression and anxiety. Boyle and colleagues therefore proposed that the (SF)-36 measure is not sensitive enough to assess changes in mood and that more specific measures might be more appropriate to detect subtle changes in mood state over time.

4 The Role of Psychosocial Factors in Pain Experience and Response to Treatment While the impact of painful DPN on individuals’ psychosocial functioning is well researched, little is known about the role of psychosocial factors in shaping pain experience and persons’ response to treatment. A study by Otto et al. [39] is one of the earliest reports that examined the impact of individuals’ mental and physical functioning, as measured by the SF-36, on their response to treatment for painful DPN. The researchers demonstrated that individuals’ physical, social and emotional status predicts their response to treatment after controlling for demographic variables, pain duration, and intensity. The authors therefore suggested that psychosocial factors might provide a useful guide in selecting the populations most responsive to treatment for painful DPN. Marchettini et al. [16] using data from the COMBO-DPN study, a multinational clinical trial in painful DPN, investigated whether there are different predictors of analgesic response between duloxetine and pregabalin in painful DPN.  There were no significant interactions

Psychosocial Aspects of Diabetic Neuropathy: From Description to Interventions

between treatment for subgroups by demographic, baseline pain characteristics, glycemic control or presence of comorbidities, and concomitant medication use. The only significant interaction with treatment was observed in the mood symptom subgroups with a larger pain reduction in duloxetine-treated persons having no mood symptoms. Selvarajah et al. [15] examined the contribution of demographic, social, clinical, and psychological factors (Pain Acceptance and Pain Catastrophizing) to anxiety and depressive symptoms in persons with painful DPN. This study found a high prevalence of emotional distress with over 50% of individuals experiencing symptoms of anxiety/depression. Multiple regression analysis showed that catastrophic thinking is an independent contributor to greater symptoms of anxiety and depression. Being young, single, and unemployed significantly contributed to greater anxiety symptoms while pain-related restrictions of quality of life were associated with greater depression symptom scores. The report therefore highlighted the differing independent contributors to anxiety and depressive symptoms which are largely based on an individual’s circumstances and experience. Another study investigated the relationship of pain catastrophizing with disability and QoL in persons with painful DPN [40]. Additionally, the mediating roles of physical activity and/or decline in physical activity were explored. The findings emphasize the role of catastrophic thinking about pain that was associated with an increased disability and decreased QoL as well as with a perceived decline in physical activity, which in turn, mediated the association between catastrophizing and disability and QoL.  Kioskli et  al. [41] investigated whether psychological flexibility is potentially beneficial for people with painful DPN. Psychological flexibility is a model of well-being and performance that includes several related processes: acceptance, committed action, cognitive defusion or ability to separate one’s thoughts from events as they are directly experienced and self-as-context that is not based upon self-evaluations and is separate from one’s thoughts and feelings. In regression analyses, the four variables representing psychological flexi-

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bility accounted for significant variance in painful DPN experience. However, the variance accounted for by psychological variables was less than that accounted for by pain intensity. These results suggest that psychological flexibility may play a smaller role, relative to pain intensity, in the context of painful DPN as compared to the larger populations of chronic, mostly musculoskeletal, pain. A study by Lewko et al. [42] showed that poorer QoL in people with DPN is related to their lower levels of illness acceptance. Among psychosocial factors negatively affecting illness acceptance were feelings of being a burden to their family and friends and the belief that people in their company are made anxious by the person’s illness. Vileikyte and Gonzalez [43] examined the role of psychological variables (generalized distress, personality traits: extroversion, agreeableness, openness, conscientiousness, and neuroticism, and DPN-specific cognitions) and sleep deprivation in generating and sustaining painful DPN. Both cross-sectional and longitudinal models were largely consistent, with depressive and, in particular, anxiety symptoms independently associated with more severe pain over time. Sleep impairment and pain unpredictability cognitions were also predictive of increases in pain. The personality trait “neuroticism” was the only personality characteristic with significant cross-sectional and longitudinal relationships to painful DPN, although its effects were confounded with anxious and depressive symptoms. The results also indicated the substantial chronicity of pain, with baseline pain severity explaining 62% of the variance in painful symptoms at 18 months. Change-based analyses, controlling for baseline pain severity, showed that younger age and higher levels of anxiety were the only significant predictors of increments in pain over time. These data suggest that although DPN pain experience is commonly accompanied by depression, sleep impairment, and negative cognitive appraisals, these factors are unlikely to be causal contributors or symptom amplifiers to pain. The most important predictor of pain over time is baseline pain severity, although anxiety may also play a causal role. These findings once

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again emphasize the intimate linkage between painful DPN and anxiety. The observed painful DPN and anxiety relationship is consistent with accumulating research linking chronic pain and anxiety; this pattern mirrors but exceeds the pattern for research examining depression and chronic pain [14]. More research is still needed, particularly that which uses prospective methods, to delineate the temporal primacy and the mechanisms accounting for the enduring association between painful DPN and anxiety.

5 Pathways Linking DPN and Its Symptoms to Depression and Anxiety Several earlier reports by Vileikyte et  al. examined both cross-sectionally [2] and prospectively [3] the associations between the objective tests of DPN severity and depression symptoms and explored the potential physical and psychosocial mediators of this association. The selection of psychosocial factors was based on existing hypotheses linking physical illness to depression. For example, Williamson [44] postulated that illness-­related functional disability and restrictions in activities of daily living (ADL) can directly contribute to the development of depression. Heidrich et  al. [45] argue that the role of ADL restrictions in generating depression may depend on the extent to which being unable to perform daily activities has a negative impact on sense of self. Furthermore, it has been proposed that shared negative cognitive schemata underlying physical illness and depression may create the possibility of a psychological path linking physical illness to depressive symptoms: both are perceived as chronic, uncontrollable and potentially having serious consequences [46]. The cross-sectional results of the study by Vileikyte et al. [2] demonstrated that DPN severity is significantly associated with higher levels of depression symptoms, with DPN symptoms and DPN-specific psychosocial factors accounting for nearly half of the variance in depression scores. Neuropathic pain, DPN-postural instability and reduced feeling in the feet were each

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independently associated with higher depression symptoms and together accounted for the relationship between the clinical measures of DPN severity and depression scores. The association between DPN symptoms and depression was partially mediated by two sets of DPN-specific psychosocial factors: (1) restrictions in ADL and diminished self-worth (self-perception as a family burden) and (2) illness cognition, or the perceptions of neuropathic pain unpredictability and the lack of treatment control. The longitudinal findings of Vileikyte et al. [3] were largely consistent with their cross-sectional observations and demonstrated that more severe DPN at baseline is associated with worsening depression symptoms over 18-months of follow-up. While neuropathic pain contributed to depression, it was particularly DPN-postural instability and its psychosocial consequences that dominated this relationship over time. DPN-postural instability continued to be a significant predictor of depression symptoms with the hypothesized psychosocial mediators in the equation, thereby suggesting that it is related to depression through mechanisms that are not fully accounted for by these studies. It has been proposed, for example, that perceived postural instability represents not only balance dysfunction but also other domains of vulnerability, such as decreased physiological reserve and psychosocial factors including poor self-efficacy with walking and fear of falling [47]. These are established risk factors for functional decline [48] and might have provided additional linkages of DPN-postural instability to depression symptoms. The emergence of DPN-postural instability as the symptom that is most strongly associated with depression merits attention from clinicians, especially as the preliminary evidence presented in a systematic review [49] suggests that people with type 2 diabetes and DPN can improve their balance and walking following exercise training interventions, such as lower limb strengthening, balance practice, aerobic exercise, walking programs, and Tai Chi. We demonstrated that DPN-­ postural instability is common, with nearly a quarter of DPN patients reporting balance problems as present either most or all the time [50].

Psychosocial Aspects of Diabetic Neuropathy: From Description to Interventions

Unfortunately, balance deficits may be overlooked by clinicians, as patients often do not report balance concerns during medical consultations owing to the perception that these are an indicator of diminishing self-resources-a sign of premature aging rather than illness-related ­disability [50]. Importantly, these patients have a ~20-fold greater risk of falling compared to aged-­ matched controls [51]. The consequences of falling, however, are not only physical but also psychological, such as poor self-efficacy with walking and fear of falling [47]. This highlights the negative spiral between DPN, postural instability, falls, and psychological distress. Although it is acknowledged that psychological factors such as fear of falling can powerfully impact upon individuals’ confidence with walking, resulting in decreased participation in activities of daily living, elevated depression symptoms and diminished overall QoL, no psychological interventions to date have been performed in people with DPN-postural instability. Nonetheless, some positive effects on reducing falls by means of psychological interventions have been achieved in high-risk older adults. One multifactorial intervention that did significantly reduce the risk of falling in at-risk elderly patients utilized a cognitive behavioral skills learning approach [52]. The intervention program aimed to improve self-efficacy for preventing falls, encourage behavior change, and provide education about risk management. Over 14 months of follow-up, intervention group participants experienced a clinically meaningful 31% reduction in falls. Furthermore, those in the intervention group were more confident in their ability to avoid a fall during a variety of functional daily living tasks and used more protective behavioral practices than control participants. Similar methodologies adapted for patients with DPN could be effective and deserve empirical evaluation. Considering this discussion, clinicians should therefore address postural instability as a key symptom when assessing persons with DPN, especially as his/her perception of their postural instability appears to be an adequate indicator of the actual balance impairment [53]. Pending a definitive intervention study, clinicians should

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consider a multifaceted approach to the management of individuals with DPN-postural instability, including a biomechanical component (physical adaptation to postural instability to improve safety) and a psychosocial component (strategies aimed at increasing participation in daily activities and enhanced perceptions of competence in important social roles). The importance of postural instability as a symptom of DPN should receive attention in the education of both persons with DPN and their healthcare providers.

6 Generalized Anxiety Vs. Specific Fears Persons with chronic diseases commonly report fears of illness or symptoms recurring or worsening that have been addressed from several viewpoints: an illness-specific perspective (e.g., fear of hypoglycemia), a generic illness perspective (e.g., fear of progression), and a psychiatric perspective (illness anxiety disorder and somatic symptom disorder) [54]. A growing number of researchers, including those studying DPN, favor disease-specific over psychiatric definitions of illness anxiety. Fear of amputation, for example, is emerging as a predominant emotion in people with diabetic foot ulceration and is a powerful determinant of preventive foot self-care actions [55–57]. Similarly, people with DPN-postural instability experience psychological consequences such as poor self-efficacy with walking and fear of falling [58]. A group of Dutch investigators conducted a qualitative study that identified a series of diabetes-specific fears experienced by people with DPN suffering from pain: fear of hypoglycemia, fear of pain increase, fear of total exhaustion, fear of physical injury, fear of falling, fear of loss of identity, and fear of negative evaluation by others [18]. Subsequently, the same research group subjected their qualitative observations to quantitative examination [19]. In a cross-sectional study of persons with painful DPN, all fears were independently associated both with reduced QoL and with greater disability, after adjusting for appropriate control vari-

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ables. Linear regression models including all fears and confounders showed that pain intensity, pain duration, and fear of falling were significantly associated with reduced QoL while pain intensity, male gender and fear of falling were significantly associated with greater disability. The predominance of fear of falling in persons suffering from painful DPN is an interesting finding that requires further investigation. It is plausible that people with painful DPN are also experiencing postural instability related to their diabetic neuropathy, as it is well-established that DPN-postural instability is associated with fear of falling and reduced physical activity [58]. It could also be possible that medications used to alleviate pain are negatively impacting the peoples’ balance through their recognized effects on the central nervous system [59]. Nonetheless, it is an interesting report confirming that persons with painful DPN suffer from a variety of fears that could be tackled by a carefully designed psycho-­ educational intervention, thereby improving physical and psychosocial well-being of these individuals.

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whether DPN is measured by clinical tests of neurological dysfunction [60] or by patient somatic experience with DPN [36, 61]. For example, Padua et  al. [60] showed that DPN severity, as measured by clinical and neuro-­ physiological tests, correlated with physical but not mental aspects of SF-36. The authors of this paper therefore concluded that DPN is “strictly related to the physical aspects of the patients’ quality of life, and not the mental aspects”. Similarly, a prospective investigation reported a temporal link between the development of painful DPN, foot ulceration and amputations and a subsequent decline in SF-36 physical but not mental function [61]. More recently, in a large cross-sectional study examining the associations between microvascular and macrovascular complications of diabetes and health status, DPN was associated with the greatest reduction in physical but not mental component score as measured by SF-36 [62]. However, the conclusion that DPN and its clinical manifestations do not impact mental function is not necessarily valid, especially as a number of studies reviewed in this chapter reported on a significant association between DPN and elevated levels of both gener7 Measuring QoL in DPN: alized (anxiety/depression) and DPN-specific Generic, DPN-Specific or emotional distress. The alternative explanation Combined Approach? could be that the generic measures of health status are less sensitive and thus do not capture ade7.1 Limitations of the Generic quately neither generalized nor DPN-specific Health status/QoL emotional disturbance. Vileikyte et al. [50] comInstruments pared the performance of the SF-12 and a neuropathy and foot ulcer-specific quality of life The main reason for using a generic measure of questionnaire, the NeuroQoL, providing support health status or QoL is that the potential impact for the latter. This study demonstrated that while of different diseases can be compared. For more the mental functioning scale from the SF-12 was refined assessment of the impact of a certain con- not associated with DPN severity, a DPN-­ dition, validated disease-specific assessment emotional distress scale from the NeuroQoL tools are usually the preferred option. Cross-­ showed a strong association with DPN severity sectional and longitudinal studies in DPN that and was the most important link between DPN employed the generic health status/QoL instru- and diminished QoL.  The results of a comprements, such as the most commonly used, SF-36, hensive review that assessed the impact of neurorevealed a common pattern, that is, that DPN pathic pain on QoL supported these observations. affects health predominantly in the domain of It provided evidence that the impact of neurophysical functioning: the impact of DPN on men- pathic pain varies in part as a function of the QoL tal functioning was non-significant in most of domain being considered, with the condition-­ these reports. This pattern holds regardless specific QoL measures being more sensitive to

Psychosocial Aspects of Diabetic Neuropathy: From Description to Interventions

the effects of neuropathic pain than the generic instruments of physical and especially mental functioning [63]. Taken together, it would seem appropriate to supplement the generic tools of health status with validated anxiety and depression scales when assessing the levels of ­generalized distress while considering conditionspecific questionnaires to study DPN-specific emotional distress. Another inherent limitation of the generic instruments is that their content was imposed by the investigators and did not emerge from interviews with people affected by DPN.  Although the generic measures allow the comparisons between different disease states at the most abstract level, they lack specificity, that is, they do not describe the specific clinical features of DPN and the ways these features impair QoL. Therefore, the findings from these studies leave a gap between DPN as abstractly defined and the person’s experience of DPN that is essential for framing effective interventions. It is also important to note that although appraisals of mental, physical and social functioning are important in QoL decision-making, they are not direct measures of QoL. Individuals can report similar levels of dysfunction and differ in their subjective judgments as to the impact of these functional impairments on their QoL. Therefore, QoL is what it appears to be: “a subjective judgment of quality of one’s life and not a measure of physical or cognitive function, a report of emotional state, or a measure of a patient’s integration into a social network” [64]. Such a definition of QoL necessitates therefore the inclusion of items directly asking respondents to subjectively evaluate their QoL.

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with various peripheral neuropathies including DPN (PN-QOL-97). This instrument consists of 97 items and encompasses several scales with varying specificity of assessment, such as an item on overall health from the generic EuroQoL, the entire SF-36 along with items measuring symptoms specific to peripheral neuropathies and dysfunction. The 47-item Norfolk QoL-DPN, in addition to the generic health status and general information items includes a comprehensive measure of DPN symptoms and the specific ways these symptoms impact on ADL [66]. The important limitation of this instrument is that it does not incorporate DPNspecific emotional distress which is central to DPN experience. The 35-item NeuroQoL [50], derived from the discussions with focus groups of persons with DPN and developed in collaboration neuropathy and psychology experts, is a hierarchically organized scale that assesses an individual’s subjective reports of functioning and QoL in six specific domains. Following the hierarchical model [67], the base of each domain is assessed with items that measure DPNspecific somatic experiences (pain, unsteadiness, and symptoms of reduced feeling in the feet), DPN-specific social and personal dysfunction, and emotional states. The two final items in the scale complete the hierarchical approach by requesting that the patients appraise the impact of DPN on their QoL and provide an overall QoL evaluation. The psychometric analyses that compared the performance of the NeuroQoL to the SF-12 demonstrated that the NeuroQoL was more strongly associated with DPN severity (criterion validity), more fully mediated the relationship of DPN with QoL (construct validity) and significantly increased explained variance in QoL judgment over the 7.2 The Shift from Generic SF-12 (incremental validity) [50]. to DPN-Specific QoL Following the development of DPN-specific Assessments QoL instruments, a number of systematic reviews and DPN expert guidelines subjected In an attempt to overcome the limitations of the these measures to scientific scrutiny. Two sysgeneric instruments, three DPN-specific QoL tematic reviews of patient reported outcomes measures have been developed. The health-­ (PROs) concluded that although the DPNrelated QoL measure by Vickrey et al. [65] was specific tools were better than generic in quantideveloped for the assessment of QoL in persons fying temporal changes in QoL and showed

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greater sensitivity to neuropathy severity, no one measure was identified as a “gold standard” for assessing QoL in DPN.  The authors therefore recommended that the instrument selection should depend on the clinical and social context of the assessment [68, 69]. An international workshop of neurology experts on the selection of outcome measures for clinical trials in peripheral neuropathy recommended the use of PN-QOL-97 and the NeuroQoL [70], while a recent Position Statement by the American Diabetes Association covering diabetic neuropathies proposed the Norfolk QoL-DPN and the NeuroQoL for QoL assessment in DPN [1]. Examination by neurology experts of the content validity of symptom-based measures for diabetic, chemotherapy, and HIV peripheral neuropathies concluded that given significant overlap in symptoms between neuropathy etiology, a measure with content validity for multiple neuropathies with supplemental disease-specific modules could be of great value in the development of disease-modifying treatments for peripheral neuropathies [71]. Therefore, it would appear that in order to advance this complex area, it would seem appropriate that the development and/or refinement of QoL instruments and their critical appraisals were conducted by a team consisting of persons with DPN, experts both in DPN and in developing PRO measures. Additional research on the psychometric characteristics of existing measures is warranted, these future studies should follow rigorous guidelines for reporting on PROs [69].

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position statement regarding psychosocial care for people with diabetes by the American Diabetes Association (ADA) therefore recommended that in general: “…psychosocial care should be integrated with collaborative, patient-­ centered medical care and provided to all people with diabetes, with the goals of optimizing health outcomes and health-related quality of life” [72, 73]. A key element of collaborative, patient-­ centered diabetes care is that levels of diabetes distress, depression, anxiety, and disordered eating are monitored and discussed. This should be done using patient-appropriate validated tools “at the initial visit, at periodic intervals, and when there is a change in disease, treatment, or life circumstance” [72]. In collaborative or stepped care, treatment for depression is intensified if the symptoms still persist [74]. In the ADA position statement [72], a specific paragraph focuses on diabetes complications and functional limitations. People with diabetes complications, including neuropathy, foot ulcers or limb amputation not only experience depression and anxiety, but also have lower overall physical function and impaired QoL.  This can result in reduced autonomy and serious role impairments [72, 75]. It is therefore recommended that in diabetes care settings the levels of chronic pain associated with diabetes complications and the impact of painful DPN or discomfort on QoL are monitored. After a discussion of questionnaire scores, appropriate pain management therapies should be offered, including a consultation with a mental health provider for pain self-management strategies [72]. In their comment on the above ADA position 8 How to Manage statement, Snoek et al. propose that it is key to Psychological Problems emphasize that the absence of a serious mental of Persons with DPN health problem is not the same as emotional in Clinical Care? well-­ being or “a good quality of life” [76]. Another important remark by these authors is As described in this chapter, psychological prob- that the use of screening tools should never lems are common in people with diabetes, espe- become a routine procedure where health care cially in those with diabetes complications, such providers are simply “ticking the box.” The as neuropathy. Diabetes distress, depression, and score(s) on a questionnaire should always be disordered eating can not only seriously impair regarded as a tool that can help to facilitate and quality of life, but also negatively impact self-­ improve the clinical conversation. This is imporcare behaviors and long-term outcomes [8]. A tant, as a questionnaire score that is indicative of

Psychosocial Aspects of Diabetic Neuropathy: From Description to Interventions

a mental health problem does not by definition equal a need for psychiatric or psychological care. Diabetes health care teams should be trained to carefully explore this with an individual with diabetes. If needed, culturally acceptable, affordable evidence-based treatment options should be offered in response to the identified psychosocial needs [76]. Many questionnaires can be used to support clinical diabetes care. In the ADA position statement, several questionnaires are recommended, including the Problem Areas in Diabetes Survey [77] or Diabetes Distress Scale [78] for diabetes distress, Patient Health Questionnaire (PHQ)-9 or Beck Depression Inventory (BDI-II) for depression [79]. The conversation after the assessment can lead to further evaluation or a structured psychiatric diagnostic interview. For the assessment of chronic pain, it is recommended to use the Short-form McGill Pain Questionnaire (SF-MPQ-2) [80]. This tool can also be used to determine in clinical care whether the treatment for painful DPN is effective. It is also important to emphasize that pain is by definition a subjective, personal experience and that emotional difficulties such as loneliness, stress or depression can definitely negatively impact the way people experience and act as symptom amplifiers of pain [81].

9 Psychological Treatment Options for People with Painful DPN Different psychological interventions have been designed to aid people to improve the way they cope with chronic pain by changing: (1) the way they perceive or appraise pain and (2) the way they behave, in order to diminish both distress and disability. A systematic review of 75 studies focused on the effectiveness of psychological treatments in a number of chronic pain conditions, such as chronic low back pain, rheumatoid arthritis, fibromyalgia, and a mixture of persistent pain conditions [82]. The most commonly investigated psychological intervention was cognitive behavioral therapy

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(CBT, 59 studies). The systematic review furthermore has included eight studies that tested behavioral therapy (BT), and five studies that investigated Acceptance and Commitment Therapy (ACT). The results of the systematic review suggest that there is moderate-­quality evidence showing that individuals treated with CBT experience less pain and distress by the end of the treatment and 6–12  months later, compared to those who had received no treatment for their pain, though effect sizes were relatively small. Those in the intervention groups also reported less disability on average (low-quality evidence). Furthermore, moderate-quality evidence showed that CBT reduced pain, disability, and distress in comparison with individuals receiving a non-psychological intervention for their pain, such as an exercise program, or education about how to manage pain, but here too, the effect sizes were relatively small. At 6–12  months follow-up, pain and distress were still significantly lower (moderate-quality evidence), while disability levels did not differ between CBT and non-psychological treatment (low-quality evidence) [82]. Another systematic review with meta-analysis specifically focused on the effectiveness of different psychological interventions on pain and related outcomes in adults with diabetic peripheral neuropathy [83]. In this review, nine trials were included, showing that in the shortterm, psychological therapies had a large positive effect on pain severity, and a small effect on pain interference. In adults with DPN, psychological interventions were concluded to have a moderate effect on depressive symptoms. When the effects on medium-term follow-up assessments were summarized, a large effect on pain severity and on pain interference was observed, while the effect on depressive symptoms was moderate. Furthermore, for long-term follow-up assessments, improvements in pain interference, mood, and self-care behaviors were reported [83]. Three recent randomized controlled trials (RCTs) were not included in the above systematic review. The first small RCT from the USA (n  =  47) by Higgins et  al. compared CBT with

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diabetes education in people with diabetic neuropathic pain [84]. The findings of the study rejected the primary hypothesis that those receiving CBT for painful DPN would experience a larger reduction in pain intensity than those receiving education. The study reported some benefits of CBT relative to education on secondary outcomes, such as, for example, reduction in neuropathic pain intensity in the CBT arm. Therefore, CBT is currently the leading ­psychological treatment for chronic pain, with small to medium effect sizes for CBT relative to controls. One potential new candidate that could help to improve clinical care for people with painful DPN is Acceptance and Commitment Therapy (ACT). ACT is to be considered as a third wave of cognitive behavioral therapies. When ACT is applied to people with chronic pain, the goal is to increase valued action in the presence of pain and also accomplish improvements to functioning. The goal is to increase “psychological flexibility” through six key processes: (1) acceptance, (2) values-based action, (3) contact with the present moment, (4) cognitive defusion, (5) develop an observer self that can change dependent on the context, and (6) committed action in line with important values [85]. ACT was tested in an RCT, where 50 individuals with painful DPN were randomized to (1) medication alone to manage neuropathic pain (2) medication and eight sessions of ACT [85]. The authors reported that ACT increased the level of pain acceptance and reduced pain perception. The third study was a single arm pilot study (n = 30) from the UK [86]. Kioskli et al. [87] were the first to investigate an online ACT for painful DPN (https://www.act4painonline. co.uk), in order to explore whether a larger RCT is warranted. The initial results of this study are promising. Participants who completed the therapy reported clinically meaningful effects at post-treatment for 100% of participants for pain intensity and pain distress, 67% for depressive symptoms, 58% for functional impairment, 42% for cognitive fusion, 67% for committed action, 58% for self-as-context, and 42% for pain acceptance.

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10 Concluding Remarks and Directions for Future Research Distal symmetric polyneuropathy, especially when accompanied by pain, has a profound and wide-reaching impact on the lives of people, with decrements in physical and mental functioning, sleep quality, participation in activities of daily living, employment, and overall quality of life. Unlike painful DPN, postural instability is largely underappreciated clinical manifestation of diabetic neuropathy. Nonetheless, DPN-postural instability is the strongest determinant of depressive symptoms in this population leading to impaired QoL not only through biomechanical difficulties but also through associated psychological distress. There is therefore an unmet need for the development of multifaceted interventions that address both psychological distress and biomechanical challenges experienced by patients with this incapacitating complication of diabetes. The reviewed studies have important implications for the care of people with DPN.  They define several possible psychosocial routes linking DPN to depression/anxiety and impaired QoL thereby providing clinicians with the specific points for interventions to alleviate emotional distress and improve QoL. Notably, these reports identify several aspects of DPN-specific emotional distress, such as diminished self-worth and the perceptions of self as a family burden that are experienced by persons with painful DPN and with DPN-postural instability. Furthermore, a set of specific fears related to DPN experience is also prominent and includes fear of falling and fear of worsening of pain, just to mention a few. It is therefore important to consider not only generalized distress (depression/anxiety) or diabetes distress that is associated with the management of glycemia. Importantly, persons’ emotional responses that are specific to diabetic neuropathy should also be assessed and monitored. Although several DPN-specific instruments capture some of the aspects of neuropathy-related distress [50, 56], more work is needed to further develop and refine these scales. The area that warrants strong

Psychosocial Aspects of Diabetic Neuropathy: From Description to Interventions

support from researchers, funding organizations, and companies is further standardization of PROs that can be used in clinical care and research of people with DPN. The psychometric characteristics of existing tools should be compared and further developed in line with rigorous guidelines [85, 86, 88, 89]. New, more effective drugs with fewer side effects should be developed and tested, and in these trials, the most optimal PROs should be used. Future research should also rigorously test the effectiveness of newer interventions such as ACT and online ACT or Mindfulness-Based Cognitive Therapy [87, 90]. Offering online treatment has several advantages, such as easy access, avoidance of waiting lists, people with painful DPN can participate in their own pace, from their own home and during a time of the day that they prefer. However, it is also known that drop-out rates also tend to be relatively high. Blended care, where online support is offered in combination with a clinical intervention should also be studied. Future research should also investigate how we can become better at preventing the development of painful DPN, and how we can become better at choosing the right intervention for each individual. Precision medicine studies are needed to learn more about how clinicians can quickly find the most successful or most promising intervention for each individual. This applies to both pharmacological and psychological interventions.

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236 75. Argoff CE, Cole BE, Fishbain DA, Irving GA. Diabetic peripheral neuropathic pain: clinical and quality-of-­ life issues. Mayo Clin Proc. 2006;81(Suppl):S3–S11. 76. Snoek FJ, Hermanns N, de Wit M, et al. Psychosocial aspects of Diabetes Study Group of the European Association for the Study of Diabetes. Comment on Young-Hyman et al. Diabetes Care. 2018;41:e31–2. 77. Kenny E, O'Malley R, Roche K, et al. Diabetes distress instruments in adults with type 1 diabetes: a systematic review using the COSMIN ­(COnsensus-­based standards for the selection of health status measurement INstruments) checklist. Diabet Med. 2020;24:e14468. 78. Polonsky WH, Fisher L, Earles J, et  al. Assessing psychosocial distress in diabetes: development of the diabetes distress scale. Diabetes Care. 2005;28(3):626–31. https://doi.org/10.2337/ diacare.28.3.626. 79. van Dijk SEM, Adriaanse MC, van der Zwaan L, et al. Measurement properties of depression questionnaires in patients with diabetes: a systematic review. Qual Life Res. 2018;27:1415–30. 80. Dworkin RH, Turk DC, Revicki DA, et  al. Development and initial validation of an expanded and revised version of the short-form McGill pain questionnaire (SF-MPQ-2). Pain. 2009;144:35–42. 81. Speight J, Holmes-Truscott E, Hendrieckx C, Skovlund S, Cooke D.  Assessing the impact of diabetes on quality of life: what have the past 25 years taught us? Diabet Med. 2020;37:483–92. 82. Williams ACC, Fisher E, Hearn L, Eccleston C.  Psychological therapies for the management of chronic pain (excluding headache) in adults. Cochrane Database Syst Rev. 2020;12(8):CD007407. 83. Racaru S, Sturt J, Celik A. The effects of psychological interventions on diabetic peripheral neuropathy: a systematic review and meta-analysis. Pain Manag Nurs. 2020;S1524-9042(20):30210–1.

L. Vileikyte and F. Pouwer 84. Higgins DM, Heapy AA, Buta E, et  al. A randomized controlled trial of cognitive behavioral therapy compared with diabetes education for diabetic peripheral neuropathic pain. J Health Psychol. 2020;19:1359105320962262. 85. Hughes LS, Clark J, Colclough JA, Dale E, McMillan D.  Acceptance and commitment therapy (ACT) for chronic pain: a systematic review and meta-analyses. Clin J Pain. 2017;33:552–68. 86. Taheri AA, Foroughi AA, Mohammadian Y, et al. The effectiveness of acceptance and commitment therapy on pain acceptance and pain perception in patients with painful diabetic neuropathy: a randomized controlled trial. Diabetes Ther. 2020;11:1695–708. 87. Kioskli K, Scott W, Winkley K, Godfrey E, McCracken LM. Online acceptance and commitment therapy for people with painful diabetic neuropathy in the United Kingdom: a single-arm feasibility trial. Pain Med. 2020;21:2777–88. 88. U.S Department of Health and Human Services Food and Drug Administration (FDA). Guidance for industry: patient reported outcome measures–use in medicinal product development to support labelling claims. 2009. https://www.fda.gov/media/77832/download. Accessed 1 Dec 2018. 89. Frost MH, Reeve BB, Liepa AM, Stauffer JW, Hays RD. Mayo/FDA patient-reported outcomes Consensus meeting group; what is sufficient evidence for the reliability and validity of patient-reported outcome measures? Value Health. 2007;10(Suppl 2):S94–S105. 90. van Laake-Geelen CCM, Smeets RJEM, Quadflieg SPAB, Kleijnen J, Verbunt JA. The effect of exercise therapy combined with psychological therapy on physical activity and quality of life in patients with painful diabetic neuropathy: a systematic review. Scand J Pain. 2019;19:433–9.

Part II Pathophysiology

The Genomics of Diabetic Neuropathy Abirami Veluchamy, Blair H. Smith, and David L. Bennett

1 Introduction For the vast majority of human diseases individual susceptibility is to some degree influenced by genetic variation. Understanding the genetics of common disorders such as diabetes mellitus, heart disease and auto-immune disorders has provided novel insights into disease pathogenesis, identified new drug targets and, through combining multiple genetic risk variants into polygenic risk scores, enabling risk stratification [1]. In this chapter we will discuss how genomics is informing our knowledge of diabetic neuropathy and also key consequences of diabetic neuropathy such as neuropathic pain. Compared to our understanding of the genomics of diabetes per se this field (and indeed the genomics of other diabetes complications such as retinopathy and nephropathy) is still very much in its infancy [2]. The most important reason for this is the fact that large cohorts with detailed harmonised phenotyping of neuropathy and neuropathic pain have not yet been fully developed. As will be apparent from other chapters in this book, the phenotype A. Veluchamy · B. H. Smith Division of Population Health and Genomics, School of Medicine, University of Dundee, Dundee, Scotland, UK D. L. Bennett (*) The Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK e-mail: [email protected]

of neuropathy is ideally captured by a combination of relevant patient reported outcomes, examination findings and investigations such as nerve conduction studies with harmonised definitions. Given the subjective nature of pain, neuropathic pain is arguably an even harder phenotype to capture, and important information such as the duration, quality and localisation of pain and whether this is likely attributable to diabetic neuropathy (e.g., bilateral pain in the feet) is required [3, 4]. These issues are now beginning to be appreciated in large population cohorts such as UK-Biobank, and such cohorts, allied to advances in sequencing technology/analytics and the development of human cellular models, should significantly advance our understanding of the genomics of diabetic neuropathy over the next decade. We will briefly highlight the broad approaches used in human genomics and how they have been applied to diabetes before focusing on the current state of knowledge in diabetic neuropathy.

2 A Brief Introduction to Diabetes Genetics Partly for historical reasons there has been a dichotomy of approach in human genetics into, firstly, the study of rare genetic disorders inherited in a monogenic (Mendelian) fashion, and secondly, common disorders which are polygenic with multiple genes each having a small impact

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 S. Tesfaye et al. (eds.), Diabetic Neuropathy, Contemporary Diabetes, https://doi.org/10.1007/978-3-031-15613-7_14

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on disease risk [1]. In Mendelian disorders the disease allele is absent or extremely rare in the general population and has a large impact on gene function, for instance, through changes in the amino acid sequence or markedly reduced gene expression. A relevant example is neonatal diabetes due to gain of function mutations in subunits of the ATP-sensitive potassium channel, a critical determinant of excitability in pancreatic islet cells [5]. These mutations lead to reduced ATP sensitivity, reduced cellular excitability and impaired insulin secretion. This finding provided a molecular rationale for the use of Sulfonylurea drugs in this disorder, and is an excellent example of how gene identification can enlighten understanding of disease pathophysiology and therapeutics [6]. The second broad approach to human genetics is based on the fact that many common disorders are related to risk determined by multiple genes (also interacting with environmental factors), and this can be revealed by investigating the association of the allele frequency of single nucleotide polymorphisms (SNPs) in individuals with disease phenotype. Such associations can be studied using a candidate gene approach or preferably across the whole genome using a Genome-Wide Association Study (GWAS) approach. Careful attention to bias, appropriate significance thresholds and large sample sizes have generated robust, reproducible findings across a range of common diseases. In this context the SNPs identified each have a small effect size and in most cases are non-coding, and their effect is thought to be mediated through subtle effects on gene expression through altering the function of gene promoters and enhancers. Determining whether and how a variant can impact on gene expression is now greatly facilitated by large datasets being generated by consortia such as ENCODE, which define the elements in DNA and histones that regulate gene expression in multiple cell types [7]. The GWAS approach requires large sample sizes to generate sufficient statistical power. Because diabetes is common and has a large impact on health, diabetes has been at the forefront of advances in genomics. More than 50 genetic loci have been found to be significantly

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associated with type 1 diabetes and more than 200 with type 2 diabetes [8]. These are emphasising important biological pathways such as pancreatic islet cell dysfunction in the case of type 2 diabetes [9]. These advances are likely to continue with increased application of genomics at population level (e.g., UK Biobank [10]) and within national healthcare systems [11]. As we develop larger population cohorts, we are realising that, rather than a dichotomy of monogenic/ Mendelian genetics versus polygenic/common disease genetics, there is a whole spectrum of effect sizes and allele frequencies within the population; gene variants may also have pleiotropic effects influencing multiple phenotypes/disorders. We are also rapidly seeing a transitioning of sequencing technologies (as costs drop) from array sequencing of SNPs and whole exome sequencing to whole genome sequencing. Just as important as these changes in technologies are analysis techniques and availability of very large datasets of genetic variation in adult populations (gnomAD [12]) and in those with clinical disorders (ClinVar [13]).

3 The Genomics of Diabetic Neuropathy in Humans Genomic studies may help us to identify the genetic risk factors which result in 30–50% of patients with diabetes developing neuropathy [14]. This will help in our understanding of the pathogenesis of neuropathy, and any shared genetic architecture with other diabetes complications, implying common pathophysiological pathways. For the past two decades, many genetic association studies have identified potential risk variants for diabetic neuropathy. These indicate that genetics has a significant contribution to its development, though there are currently few studies with heritability estimates. Table 1 presents the known genetic variants associated with neuropathy in people with type 2 diabetes, from 25 human genetic association studies. The diabetic neuropathy phenotype was defined in most of the studies using at least one of the following:

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The Genomics of Diabetic Neuropathy Table 1  Known genetic variants associated with neuropathy in type 2 diabetes patients Study (year) ArredondoGarcía et al. (2019) [15]

Ethnicity Mexican

N (cases/controls) Phenotyping 218(90/128) Monofilament and tuning fork test

Variants rs3025039

Basol et al. (2013) [16] Buraczynska et al. (2017) [17] Chen et al. (2015) [18]

Turkish

468(227/241)

DNS and NDS

Polish

926(406/520)

CNE and EMG

VNTR polymorphism Pro198Leu

Chinese

160(80/80)

Ciccacci et al. (2014) [19]

Italy

130(62/68)

Ciccacci et al. (2018) [20] Gupta and Singh (2017) [21]

Italy

149(69/80)

WHO diagnostic criteria VPT and Neuropathic questionnaire MNSI, VPT

North Indian

650(356/294)

Inanir et al. (2013) [22]a

Turkish

Ji et al. (2015) [23] Kakavand Hamidi et al. (2018) [24]

Effect of association Protective

rs3821799 rs3774261

Gene name Vascular endothelial growth factor (VEGF) Interleukin 4 (IL-4) Glutathione Peroxidase 1 (GPx-1) Adiponectin (ADPN)

rs2910164 rs11888095

MIR146a MIR128a

Protective Risk

rs3746444

MIR499a

Risk

VPT and Monofilament

C106T rs759853

Risk

516(235/281)

NSS and NDS

I/D polymorphism

Chinese

180(90/90)

Iranian

248(141/107)

Clinical assessment UKST score > 2, microfilament

T45G G276T C667T

Kolla et al. (2009) [25]a

Indian

400(198/202)

VPT

+874A/T 1083G/A

Mansoor et al. (2012) [26]

Pakistan

772(276/496)

Clinical assessment

I/D

Marzban et al. (2016) [27]

Iranian

106(49/57)

NSS and NDS

Monastiriotis et al. (2013) [28] Papanas et al. (2007) [29]

Greece

234(54/180)

NDS

HLADQB1*02 and HLADRB1*07 Epsilon 4

Aldo-keto reductase family 1 member B (AKR1B1) Angiotensinconverting enzyme (ACE) Adiponectin (ADPN) Methylenetetrahydrofolate reductase (MTHFR) Interleukin 10 (IL-10) Interferongamma (IFN-G) Angiotensinconverting enzyme (ACE) II Human Leukocyte Antigen (HLA) Apolipoprotein E (APOE)

Risk

Greek

130(70/60)

DN index

I/D

Risk

Han Chinese

787(402/385)

Monofilament test, VPT, Clinical assessment

rs5498

Alpha2B adrenergic receptor (ADRA2B) Intercellular adhesion molecule-1 (ICAM-1)

Ren et al. (2015) [30]

Risk Risk

Risk

Risk

Risk Risk

Risk

Risk

Risk

Risk

(continued)

A. Veluchamy et al.

242 Table 1 (continued) Study (year) Shah et al. (2013) [31]

Ethnicity Asian Indian

N (cases/controls) Phenotyping VPT 495(139/356) 475(133/342) 288(81/207)

Variants T-786C (rs2070744), 27 VNTR Intron 4, G894T (rs1799983) I/D

Stephens et al. (2006) [32]

British

572(173/399)

Clinical assessment

Stoian et al. (2014) [33]a

Spanish

174(84/90)

Clinical assessment

I/D

Sun et al. (2018) [34]

Chinese

281(143/138)

WHO diagnostic Criteria

rs2248069 rs16030 rs216008 rs2239050 rs3794619 rs7191246

Tang et al. (2012) [35]

British

773(211/558)

CNE

rs1050450

Tang et al. (2019) [36]b

American/ 5168(4384/784) Canadian

MNSI >2.0

rs13417783

Ukinc et al. (2009) [37]

Turkish

52(37/15)

Neurological assessment and symptoms

C677T

Wang et al. (2012) [38]

Chinese

251(101/150)

C667T

Yigit et al. (2013) [22]

Turkish

512(230/282)

Toronto Diabetic Neuropathy Consensus NSS and NDS

C667T

Gene name Endothelialderived nitric oxide synthase (eNOS)

Angiotensinconverting enzyme (ACE) Vascular Endothelial Growth Factor (VEGF) Calcium Voltage-Gated Channel Subunit Alpha1 A (CACNA1A) Calcium Voltage-Gated Channel Subunit Alpha1 C (CACNA1C) Calcium Voltage-Gated Channel Subunit Alpha1 H (CACNA1H) Glutathione peroxidase-1 (GPx-1) Sodium Voltage-Gated Channel Alpha Subunit 2 (SCN2A) Methylenetetrahydrofolate reductase (MTHFR) Methylenetetrahydrofolate reductase (MTHFR) Methylenetetrahydrofolate reductase (MTHFR)

Effect of association Risk

Risk

Risk

Risk

Risk

Risk

Risk

Risk

Risk

ACCORD action to control cardiovascular risk in diabetes, BARI 2D bypass angioplasty revascularization investigation in type 2 diabetes, CNE clinical neurological examination, DN diabetic neuropathy, CNE clinical neurological examination, EMG electromyography, MNSI Michigan neuropathy screening instrument, MPQ McGill pain questionnaire, NDS neuropathy disability score, NSS neuropathy symptom score, UKST the United Kingdom screening test, VPT vibration perception threshold, WHO World Health Organisation a DN vs healthy controls b Genome-wide association studies

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243

monofilament test, vibration perception thresh- ined in four cohorts [22, 24, 37, 38]. The MTHFR old, Toronto Diabetic Neuropathy Expert C677T polymorphism was found to be signifiConsensus, the United Kingdom screening test, cantly associated with diabetic neuropathy in a Michigan neuropathy screening instrument meta-analysis of these cohorts (OR, 1.43; (MNSI), neuropathy symptom score (NSS) and/ P = 0.014) [42]. Although the exact role of this or neuropathy disability score (NDS). Most of gene in diabetic neuropathy is not yet known, the candidate gene association studies investi- in vitro studies showed that hyper homocysteingated the association of genetic variants with dia- aemia affects nerve function. betic neuropathy using cohorts of type 2 diabetes A recent meta-analysis [41], the GPx-1 varipatients with and without neuropathy. Very few ant (rs1050450) showed a significant association compared diabetic neuropathy cases only with with diabetic neuropathy (OR = 1.43, P   D and MTHFR DQB1, HLA-DRB1-DQB1, IL-4, IFN-G, ICAM-­ 1298A/C variants were significantly associated 1 and eNOS represent the immune response with increased risk of diabetic neuropathy [42]. pathway. The other genes (APOE, ADPN and The DD genotype of ACE was shown to increase AKR1B1) are relevant to cell signalling and the risk of developing diabetic peripheral neu- metabolism. Notably, two studies implicated speropathy in Caucasian, South Asian, Turkish and cific microRNAs (rs2910164, rs11888095 and Egyptian cohorts, with an odds ratio of 1.43  in rs3746444) involved in the regulation of inflamthe meta-analysis (P  =  0.004) [42]. The ACE mation [19, 20]. None of these findings have yet gene has been the most frequently studied in dia- been replicated in large cohorts. betic neuropathy. It encodes angiotensin-­ Some candidate genes have been found to converting enzyme which induces oxidative be associated with neuropathy in type 1 diabestress, inflammation and vascular changes. ACE tes cohorts in Russia. These include the inhibitors were shown to be effective in treating −262 T > C polymorphism of the catalase gene diabetic neuropathy in experimental studies [43]. (CAT) [45, 46], the Ala(−9)Val SNP of superA recent study examined the efficacy of ACE oxide dismutase 2 (SOD) [47] and the inhibitors for 2  years on 63 patients with auto- Arg213Gly polymorphism of superoxide disnomic and/or peripheral diabetic neuropathy and mutase 3 (SOD3) [48, 49]. All three genes found that they improved cardiovascular auto- (CAT, SOD2 and SOD3) protect the body nomic diabetic neuropathy but did not improve against oxidative stress. A genetic variant peripheral neuropathy [44]. More studies are (rs1001179) in CAT was shown to decrease the therefore needed to elucidate the role of ACE risk of developing neuropathy in type 1 diabeinhibitors in diabetic neuropathy. The MTHFR tes (OR, 0.68; CI, 0.53–0.86; P  β1 increased the percent of cleaved caspase-3 compared to high glucose alone, and TGF-β neutralizing antibody inhibited the increase. TGF-β isoforms applied directly to DRG neurons reduced neurite outgrowth, and this effect was partially reversed by TGF-β neutralizing antibody. These findings implicated upregulation of TGF-beta in experimental diabetic peripheral neuropathy and suggested a potential new target for the treatment of diabetic peripheral neuropathy. Patients with T2DM and clinically detectable serum TGF-β1 showed a positive correlation with nerve conduction velocities, suggesting that this cytokine might be used as a biomarker for diabetic peripheral neuropathy [81]. TGF-β increases Smad3 signaling, thereby affecting metabolism and energy homeostasis and reducing inflammation and ROS production [82].

2.6 Metabotropic Glutamate Receptors, Oxidative Injury, and DN Metabotropic glutamate receptors (mGluRs) are a subfamily of glutamate receptors that are G-protein-coupled and linked to second messenger systems [83]. Glutamate is the principal neurotransmitter in the CNS that is transported to the axon terminals [84]. The mechanism for production, paracrine release, and recycling of gluta-

Targeting the Mitochondrion in Diabetic Neuropathy

315

mate happens in sensory ganglia and contains the enzymes amidohydrolase, glutaminase [85, 86], glutamate aspartate transporter (GLAST), glutamate transporter 1 (GLT1) [87], as well as the recycling enzyme glutamine synthetase [85, 88]. The Glutamate carboxypeptidase II (GCP II) inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA), which activates mGluR2/3, protects against glucose-induced programmed cell death (PCD) and neurite degeneration in DRG neurons in a cell culture model of DN [83]. Preclinical data indicate that GCPII inhibitors ameliorate DN in animal models. Direct or indirect activation of mGluR2/3 protects against development

of DN in animal models [89]. mGluR2/3 agonists prevent glucose-induced neuronal injury in DRG neuronal cultures by increasing glutathione and maintaining mitochondrial function only in the presence of Schwann/SGC cells [83, 90, 91]. Treatment with a mGluR2/3 agonist normalizes levels of glutathione and oxidized proteins, while increasing levels of superoxide dismutase 2 (SOD2), SIRT1, PGC-1alpha, TFAM, glutamate transporter proteins, and glutamine synthetase in DRG neurons. Thus, mGluR3 agonists have the ability to protect against cellular injury by regulating oxidative stress in models of DN (Fig. 3).

Fig. 3  Glutamate transporters GLT-1 and GLAST are present in Satellite Glial Cells (SGC) cells to transport extracellular glutamate into the SGC where glutamine synthetase (GS) converts it to glutamine, which is eventually recycled to the neuron for conversion into glutamate. In diabetes, hyperglycemia-induced oxidative stress affects glutamate transport proteins, increasing extracel-

lular glutamate. LY379268 treatment promotes glutamate uptake, and it likely decreases extracellular glutamate. In addition, mGluR 2/3 receptors present in DRG neurons decrease extracellular glutamate. Thus, activation of mGluR2/3 receptor by an agonist can likely constrain sensory transmission and importantly reduce nociceptive transmission

316

2.7 Mitophagy, the Inflammasome, and Innate Immune Pathways in DN Recent results suggest that mitochondrial impairment contributes to inflammasome formation and activation of the innate immune system. Maintaining functional mitochondria is essential to generate energy (ATP) for maintaining resting potentials, action potentials, and neurotransmission at both the pre- and post-synaptic sites in the neuron [92, 93]. Mitochondria, therefore, need to be repaired and replaced [94]. Mitochondrial biogenesis, axonal transport, and mitochondrial fission and fusion contribute to this rejuvenation [95]. Mitochondrial stress has been proposed as a major mediator of diabetic complications such as neuropathy in humans and animal models [7, 43, 96]. Therefore, in order to maintain a healthy mitochondrial population, damaged proteins and organelles must be cleared. Mitochondria undergo a process of regeneration and autophagy (clearance), termed mitophagy. Impaired mitochondrial quality control can cause disease, for example, mitofusin 2 mutations in Charcot-Marie Tooth disease type 2A [97, 98] and Opa1 mutations in autosomal-dominant optic atrophy [99– 101]. In addition, impairment of mitochondrial quality control has been demonstrated to activate innate immune pathways, including inflammasome (NLRP3)-mediated signaling and the antiviral cyclic GMPAMP synthase (cGAS)/ stimulator of interferon genes (STING)–regulated interferon response [reviewed in [95]]. Innate immune-signaling pathways have evolved in complex multicellular eukaryotes to recognize invasive pathogens, including bacteria, viruses, fungi, and protists. Damage-associated mitochondrial protein (DAMP) is recognized by the cell’s immune-recognition pathways as foreign due to the resemblance to ancient prokaryotes [102]. Sensing of these DAMPs by NOD-, LRR-, and pyrin domain–containing proteins (NLRPs) has been shown to activate inflammatory immune responses [103]. Like the problems posed by mitochondria’s resemblance to ancient prokaryotes, the presence of a second nonnuclear com-

A. Hedayat et al.

plement of DNA in the mitochondria presents a range of challenges to the host immune system [104]. Release of mtDNA has been shown to trigger DNA-sensing antiviral pathways [104]. Activation of the innate immune system occurs in peripheral neuropathy and is of importance. For example, vincristine-induced peripheral neuropathy is driven by activation of the NLRP3 inflammasome and subsequent release of interleukin-1β from macrophages. However, if inflammation is reduced by treatment with the NLRP3 inhibitor MCC950, or if there is knockout of NLRP3  in mice, then there is a significant reduction in mechanical allodynia and gait impairment [105, 106]. Similarly, paclitaxel can induce high-level expression of NLRP3 inflammasomes in the infiltrated macrophages within DRG and sciatic nerve. This in turn promotes IL-1β production and mechanical allodynia in a chemotherapy-­ induced neuropathic pain model [107]. The NF-kappaB pathway is part of the central machinery initiating and propagating inflammatory responses, and this is true also for DN. The NF-kappaB inflammatory cascade may be inhibited by BAY 11-7082, an IkappaB phosphorylation inhibitor [108]. BAY 11-7082 (1 and 3 mg/ kg) was administered to STZ diabetic rats for 14 days starting from the end of the 6th weeks post diabetic induction. Diabetic rats developed altered nociceptive parameters and deficits in nerve functions and also demonstrated elevated expression of NF-kappaB (p65), IkappaB, and p-IkappaB along with elevated levels of IL-6 and TNF-alpha and inducible enzymes (COX-2 and iNOS). In addition, DN was associated with a surge in oxidative stress, a reduction in Nrf2/ HO-1 expression, and an amelioration in GSH levels. BAY 11-7082 improved abnormal sensory responses and deficits. BAY 11-7082 also facilitated the surge in the expression of NF-kappaB, IkappaB, and p-IkappaB. BAY 11-7082 restrained the levels of IL-6, TNF-alpha, COX-2, and iNOS in the sciatic nerve. Thus, it can be concluded that NF-kappaB expression and downstream expression of proinflammatory mediators are significant features of nerve damage resulting in inflammation and oxidative stress. Furthermore, BAY 11-7082 is able to improve experimental DN by

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modifying neuroinflammation and improving antioxidant protection.

3 Current Treatment Approaches That Target Mitochondrial Function in DN 3.1 Lifestyle Modification and Improvement in Mitochondrial Function in DN There are currently no disease-modifying treatments that have been definitively shown, in ­randomized clinical trials, to reduce or reverse diabetic sensory polyneuropathy. However, individuals with impaired glucose regulation and neuropathy may benefit from aggressive diabetic control and lifestyle interventions. These interventions can postpone the onset of diabetes and may reverse small fiber neuropathy associated with early diabetes mellitus. Exercise not only increases insulin sensitivity and glucose control, but also increases end organ perfusion, reduces lipid and protein oxidation, inhibits adipocyte production of free fatty acids and deleterious adipokines, and reduces humoral inflammation [1, 9, 109–111]. The mechanisms by which lifestyle changes can affect mitochondrial function have previously been described [109]. Although dietary and lifestyle interventions are likely to affect multiple pathways, there is evidence that improved mitochondrial function in muscle might exert a remote effect. AMP-activated protein kinase (AMPK) and the protein deacetylase, sirtuin 1 (SIRT1), are fuel sensing molecules. During energy deprivation, AMPK activation restores energy balance by increasing levels of ATP, for example by increasing fatty acid oxidation, and reducing processes that consume ATP.  AMP-activated protein kinase has been shown to circulate in the blood after release from muscle [112]. This could explain why exercise, which improves muscle function, can also have remote effects on somatic and autonomic nerve fibers. Furthermore, in exercised muscle, nutrient

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deprivation leads to an increase in NAD+ and a decrease in nicotinamide (NAM), which in turn leads to activation of SIRT1 and 35 kDa peroxisome proliferator-activated receptor-gamma co-activator-1α (PGC1-α) in the mitochondrion, resulting in an increase in oxidative phosphorylation and fatty acid metabolism [2, 39, 109, 113]. NAM and NADH act as inhibitors of SIRT1. NAM phosphoribosyltransferase (Nampt) is important in the conversion of NAM to NAD+. Exercise increases Nampt activity in muscle but also circulates outside the muscle to increase insulin sensitivity. Nampt then decreases NAM and increases NAD+ resulting in further activation of the SIRT1-PGC1-α pathway and increasing mitochondrial function. AMP-activated protein kinase (AMPK) also likely regulates SIRT1 by acting as an energy sensor and activates Nampt. Thus, the net effect of nutritional restriction and exercise is to increase NAD+ and drive the SIRT1-PGC1-α pathway toward improved mitochondrial function. In addition, changes in fatty acid metabolism likely affect mitochondrial function in the muscle. Translational research indicates that high-fat diets can result in neuropathy in diabetes and that withdrawing or otherwise manipulating a high fat diet can reduce neuropathy [114–116]. In humans, a nutritional intervention study that was targeted to improve essential fatty acid dysmetabolism in type 1 diabetes mellitus examined supplementation with seal oil omega-3 polyunsaturated fatty acids in individuals with type 1 diabetes mellitus and neuropathy. After 12 months of supplementation, there was an increase in corneal nerve fiber length [117]. There was no progression of clinical disease symptoms, and there were no declines in small and large fiber sensory and functional measures. However, there was no improvement detected in nerve conduction studies or sensory function.

3.2 Improved Glycemic Control and DN As discussed above, improved glycemic control will reduce mitochondrial dysfunction and oxida-

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tive or nitrosative stress, consequently reducing protein and lipid oxidation, neuroinflammation, and neuronal and Schwann cell injury signaling. Early hyperglycemic insult can lead to permanent, cumulative damage. Mitochondrial injury takes place after just 1 h of hyperglycemic exposure due to an increase in mitochondrial membrane potential likely caused by a decrease in the cells’ NAD+/NADH ratio [118]. The Diabetes Control and Complications Trial (DCCT) determined a clear link between impaired glycemic control, neuropathy, and retinopathy. This DCCT prospectively followed 1441 participants with T1DM for a mean of 6.5 years to study the effect of intensive insulin on the development of diabetic complications [reviewed in [111]]. The study divided participants into a primary (prevention) and a secondary (intervention) group and treated them with intensive or conventional insulin therapy. In the secondary-intervention cohort, intensive insulin therapy reduced clinical neuropathy’s appearance by 60% at the 5-year follow-­up. If patients had neither retinopathy nor significant albuminuria at the start of the study (primary-prevention cohort), then the results were even more impressive: intensive therapy reduced the appearance of neuropathy by 69% compared to only 10% with conventional therapy and showed that early optimal glycemic control could prevent the development of neuropathy before patients developed microvascular injury and retinopathy. Although studies show clear improvement in diabetic and somatic neuropathy outcomes for T1DM, the data for T2DM is less clear [119]. Despite these reservations, improvement in T2DM was observed in the UK Prospective Diabetes Study (UKPDS) study. In this study, 3867 patients with newly diagnosed T2DM were randomly assigned to intensive therapy with a sulfonylurea (chlorpropamide, glibenclamide, or glipizide), with insulin, or conventional diet therapy. After 10 years, risk of microvascular endpoints was reduced by 25% (p = 0.0099) [120]. Thus, intensive blood glucose control by either sulfonylureas or insulin substantially decreased the risk of microvascular complications in patients with T2DM; however, there was a higher

rate of hypoglycemic complications, particularly in the insulin treatment group [120]. Other studies have shown a less definitive change in neuropathy in T2DM with improved glycemic control. For example, the VA Diabetes Trial randomized 1791 military veterans with T2DM to either intensive or standard glucose control. The development of neuropathy was determined based upon self-report. While the study did not find any difference in the rate of new microvascular complications, such as neuropathy, there was a non-significant 5% reduction in the incidence of neuropathy [121]. Not all studies have shown that aggressive glucose control reduces the development or progression of neuropathy in T2DM. The VA cooperative study on type II diabetes mellitus (VA-CSDM) compared standard insulin treatment to an intensive therapy group in men with T2DM who required insulin. The enrolled men had poorly controlled T2DM with an average duration 7.8 ± 4 years and about half had neuropathy at baseline. Intensive insulin therapy did result in an improvement in HgBA1c after 6 months, but no difference was found in the prevalence of DN between the intensive vs. standard arms (64% intensive vs 69% standard) after 2 years [122]. Importantly, improved glycemic control has been shown to have a sustained benefit on diabetes and its complications. The NeuroEDIC study found a reduced prevalence of neuropathy in a group of type 1 diabetics that received intensive treatment compared to the standard treatment group during the DCCT study. However, although intensive glycemic control reduced the severity of neuropathy, 34% of subjects in the former intensive treatment group and 41% of those in the former conventional treatment group still developed clinical neuropathy [123].

3.3 Diet and Lifestyle Interventions in DN Glucose-modifying drug therapy is typically not appropriate in patients with impaired glucose regulation due to cost and potential for serious side effects such as hypoglycemia. A more suit-

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able approach for these patients would be a lifestyle intervention that could arrest the underlying process that leads to neuropathy and its associated functional disability. At present there is no evidence from a randomized study that a lifestyle intervention would reverse somatic neuropathy. However, there is evidence that a lifestyle intervention can be more effective than a drug intervention in preventing conversion from IGT to diabetes. The Diabetes Prevention Program (DPP) study was designed to determine if a more intensive dietary and exercise intervention or metformin treatment effectively prevented or delayed the onset of T2DM in people with IGT or impaired fasting glucose (IFG). The DPP demonstrated that lifestyle changes reduced the risk of developing T2DM by 58% in adults with IFG or IGT who were at high risk of developing diabetes [124]. Metformin drug therapy did also reduce the risk of developing T2DM, but was less effective than weight loss and increased physical activity [124]. To prevent one case of diabetes in 3 years, only 6.9 persons would have to participate in the lifestyle intervention program, whereas 13.9 would have to receive metformin [124], which clearly showed that the lifestyle intervention was almost twice as effective as drug therapy. Examining the 10-year cost-­effectiveness of the DPP interventions, lifestyle was found to be cost-effective, and metformin was marginally cost-saving compared to placebo [125]. Optimally, lifestyle changes should be introduced in patients with IGT, who are early in the course of developing neuropathy. The Impaired Glucose Tolerance Causes Neuropathy Study (IGTN) was a natural history study that gave general dietary and physical activity advice (similar to those in the DPP “lifestyle intervention” group) to participants with IGT or IFG and mild neuropathy. In the IGTN study, weight loss and/ or an increase in physical activity was associated with slower progression of neuropathy based on the intraepidermal nerve fiber density and with the ability to re-grow epidermal nerve fibers [110, 126]. More recent studies have underscored the importance of intervention during the earliest stages of impaired glucose regulation, and a lifestyle intervention can be more effective than a

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drug intervention in preventing conversion from IGT to diabetes [124]. Furthermore, studies have shown that an exercise intervention can prevent the development of neuropathy in subjects who have T2DM but do not have neuropathy [127– 129], may affect pain and symptom outcomes in subjects with neuropathy, and is safe [130, 131].

3.4 Alpha-Lipoic Acid and DN Alpha-lipoic acid (ALA) is biosynthesized in small amounts from octanoic acid in the mitochondrion, where it is used as a cofactor for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase complexes [132, 133]. ALA is a strong antioxidant that functions by removing already formed free radicals [134]. ALA has a disease modifying effect, and in several studies, it has been shown to improve DN symptoms. However, the evidence to support its use is not strong because clinical trials with ALA have been completed using a variety of study designs, routes of administration, and sample sizes [135–138]. In the multicenter, randomized, double-blind, placebo-­controlled ALADIN III trial, there was a small but significant improvement in the Neuropathy Impairment Score (NIS) in ALA-­ treated patients, but no significant improvement in the Total Symptom Score (TSS) [136]. In the Deutsche Kardiale Autonome Neuropathie (DEKAN) Study, there were small improvements in the cardiac autonomic spectral analysis in ALA treated patients [139]. In the SYDNEY2 trial, 181 diabetic patients were treated for 5 weeks after a 1-week placebo run-in period with the following daily oral doses of ALA: 600 mg (n = 45) (ALA600), 1200 mg (n = 47) (ALA1200), and 1800 mg (n = 46) (ALA1800) or placebo (n = 43) [137]. The change from the baseline TSS was the primary outcome measure. The Neuropathy Symptoms and Change (NSC) score and the NIS were secondary end points. The mean TSS decreased by 51% in ALA600, 48% in ALA1200, and 52% in ALA1800 compared with 32% in the placebo group (P < 0.05 vs. placebo). The NSC significantly improved in all three ALA groups, and the NIS was numerically reduced.

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Thus, oral treatment with ALA for 5 weeks improved neuropathy measures in patients with DN. The optimum risk-to-benefit ratio occurred with 600 mg alpha-lipoic acid once daily [137]. Further support for ALA therapy is provided by a meta-analysis of four trials (ALADIN I, ALADIN III, SYDNEY, NATHAN II) comprising 1258 patients (ALA n = 716; placebo n = 542) [140]. In the Nathan I study [138], 460 diabetic patients with mild-to-moderate diabetic sensory polyneuropathy were assigned randomly to oral treatment with 600 mg ALA once daily (n = 233) or placebo (n = 227) for 4 years. A composite score of the NIS-LL and seven neurophysiologic tests was the primary end point. The NIS, NIS-LL, nerve conduction, and quantitative sensory tests (QSTs) were included as secondary outcome measures. There was no significant difference between treatment groups for the change in primary end point from baseline to 4 years (P = 0.105). When sub-scores of the composite score were measured independently, the change from baseline was significantly better for ALA compared to placebo for: NIS (P = 0.028), NIS-LL (P = 0.05), and the NIS-LL muscular weakness sub-­ score (P = 0.045). With ALA compared to placebo, more patients showed a clinically meaningful improvement, and fewer showed progression in NIS (P = 0.013) and NIS-LL (P = 0.025). Part of the reason that the primary study endpoint failed to detect a difference was that nerve conduction and QST results did not significantly worsen in the placebo group. Global assessment of treatment tolerability did not differ between the groups. The ALA studies’ overall results indicate that chronic treatment with ALA at an optimal dose of at least 600 mg/day is safe and improves some neuropathic deficits in patients with DN. However, limitations in end point measures have precluded a definitive conclusion about whether ALA reverses or prevents DPN. In the analysis of the NATHAN 1 trial, improvement and prevention of progression of NIS-LL with ALA vs. placebo after 4 years was predicted by lower BMI, higher age, male sex, history of cardiovascular disease (CVD), normal blood pressure, insulin treatment, longer duration of diabetes and neuropathy, and

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higher neuropathy stage. A more recent study used a combination therapy with superoxide dismutase, ALA, acetyl L-carnitine, and vitamin B12  in a prospective, double-blind, placebo-­ controlled study, randomized study in 85 patients with T2DM over 12 months [141]. In this study, the Michigan Neuropathy Screening Instrument Questionnaire, vibration perception threshold, sural nerve conduction velocity and amplitude, pain, and quality of life questionnaires were measured endpoints and showed statistically significant improvement after 12 months compared to the placebo group. The cardiovascular autonomic reflex tests and Michigan Neuropathy Screening Instrument Examination did not significantly change. However, similar results were obtained with normalization of just B12 levels [142] suggesting that the main active component in the combination tablet was B12.

3.5 Benfotiamine and DN Mitochondria take up and use thiamine pyrophosphate, the active form of thiamine. In diabetic tissues, only about 10% of a cell’s thiamine is in the cytosol, available to transketolase, while the remainder is inside the mitochondrion [118]. Thiamine plays a crucial role in the metabolism of energy. Benfotiamine is a synthetic derivative of thiamine. It elevates the levels of thiamine diphosphate in the cell, a cofactor necessary for the activation of transketolase, resulting in the reduction of tissue levels of AGEs. The anti-AGE effect of benfotiamine makes it effective for DN treatment [143]. Benfotiamine is able to reduce the accumulation of triosephosphates in diabetes. Excess triosephosphates can be removed via the reductive pentosephosphate pathway. However, this pathway is impaired in diabetes by mild thiamine deficiency. The activity and expression of the thiamine-dependent enzyme, transketolase, are consequently decreased in the pentosephosphate pathway. Benfotiamine therapy in experimental diabetes restores disposal of triosephosphates by the reductive pentosephosphate pathway in hyperglycemia. This prevents activation of mul-

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tiple biochemical pathways that cause injury in diabetes: PKC, hexosamine, glycation and oxidative stress pathways [144]. High-dose thiamine also corrects dyslipidemia in experimental diabetes, in part by normalizing cholesterol and triglycerides. IGT is observed with thiamine deficiency, and thus dietary thiamine may help prevent T2DM. Benfotiamine has been assessed as a clinical therapy in a double-blind, placebo-controlled, phase-III study [145]. A total of 165 patients with DPN were randomized to one of three treatment groups: benfotiamine 600 mg/day, benfotiamine 300 mg/day, or placebo. After 6 weeks of treatment, the primary outcome parameter, the Neuropathy Symptom Score, differed ­significantly between the treatment groups in the per-­protocol but not in the intention to treat population (p = 0.055). The Total Symptom Score showed no significant differences after 6 weeks of treatment. The improvement was more noticeable at the higher benfotiamine dose and increased with treatment duration. In the TSS, “pain” showed the best response to treatment. Treatment was well tolerated in all groups.

4 Conclusion Many lines of evidence indicate that aberrant mitochondrial structure and function contribute to cellular dysfunction, cell death, and disease pathology including diabetic neuropathy. In general, disease may occur within several levels of mitochondrial dysfunction. These include impaired oxidative phosphorylation, lipid metabolism, imbalanced mitochondrial dynamics, fragmented mitochondrial networks, impaired mitochondrial signaling, neuroinflammation, and mutations in the mitochondrial or nuclear genome. Exploration of some of the mitochondrial directed mechanisms for diabetic neuropathy reveals targets for treatment of disease. If these targets are promising in preclinical studies, they may be utilized in human clinical trials. Dietary and exercise interventions are not only effective but have significant effects on mitochondrial function

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and signaling, although it remains to be seen whether these effects can be sustained. As with all interventions, therapeutics targeting mitochondria will face problems with delivery, and specificity challenges to ameliorate pathological symptoms without inducing negative side effects. Acknowledgments Supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health 1R01DK107007-01A1, Office of Research Development, Department of Veterans Affairs (Biomedical and Laboratory Research Service and Rehabilitation Research and Development, 101RX001030), Diabetes Action Research and Education Foundation, University of Maryland Institute for Clinical & Translational Research (ICTR), and the Baltimore GRECC (JWR), 1K2RX001651 (LAZ).

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325 111. Russell JW, Kaminsky AJ. Oxidative injury in diabetic neuropathy. In: Opara E, editor. Nutrition and diabetes: pathophysiology and management. Boca Raton: Taylor & Francis; 2005. p. 381–97. 112. Kobilo T, Guerrieri D, Zhang Y, Collica SC, Becker KG, van Praag H. AMPK agonist AICAR improves cognition and motor coordination in young and aged mice. Learn Mem. 2014;21(2):119–26. 113. Chandrasekaran K, Choi J, Arvas MI, Salimian M, Singh S, Xu S, et  al. Nicotinamide mononucleotide administration prevents experimental diabetes-induced cognitive impairment and loss of hippocampal neurons. Int J Mol Sci. 2020;21(11):3756. 114. Hinder LM, O’Brien PD, Hayes JM, Backus C, Solway AP, Sims-Robinson C, et al. Dietary reversal of neuropathy in a murine model of prediabetes and metabolic syndrome. Dis Model Mech. 2017;10(6):717–25. 115. Cooper MA, Menta BW, Perez-Sanchez C, Jack MM, Khan ZW, Ryals JM, et  al. A ketogenic diet reduces metabolic syndrome-induced allodynia and promotes peripheral nerve growth in mice. Exp Neurol. 2018;306:149–57. 116. Coppey L, Davidson E, Shevalye H, Torres ME, Yorek MA.  Effect of dietary oils on peripheral neuropathy-related endpoints in dietary obese rats. Diabetes Metab Syndr Obes. 2018;11:117–27. 117. Lewis EJH, Perkins BA, Lovblom LE, Bazinet RP, Wolever TMS, Bril V. Effect of omega-3 supplementation on neuropathy in type 1 diabetes: a 12-month pilot trial. Neurology. 2017;88(24):2294–301. 118. Teodoro JS, Gomes AP, Varela AT, Duarte FV, Rolo AP, Palmeira CM. Uncovering the beginning of diabetes: the cellular redox status and oxidative stress as starting players in hyperglycemic damage. Mol Cell Biochem. 2013;376(1-2):103–10. 119. Ang L, Jaiswal M, Martin C, Pop-Busui R. Glucose control and diabetic neuropathy: lessons from recent large clinical trials. Curr Diab Rep. 2014;14(9):528. 120. UK Prospective Diabetes Study (UKPDS). Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837–53. 121. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360(2):129–39. 122. Azad N, Emanuele NV, Abraira C, Henderson WG, Colwell J, Levin SR, et al. The effects of intensive glycemic control on neuropathy in the VA cooperative study on type II diabetes mellitus (VA CSDM). J Diabetes Complicat. 1999;13:307–13. 123. Albers JW, Herman WH, Pop-Busui R, Feldman EL, Martin CL, Cleary PA, et al. Effect of prior intensive insulin treatment during the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathy in type 1 diabetes during the Epidemiology of

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Diabetic Sensory Neurons, Dorsal Root Ganglia, and Neuropathy Aparna Areti and Douglas W. Zochodne

1 Introduction Worldwide, there are few more compelling clinical problems than burgeoning diabetes mellitus (DM) and its irreversible complications, particularly neurological. Diabetic polyneuropathy (DPN) is not only the most common DM complication, but it is also the most common form of damage to the peripheral nervous system and its prevalence dwarfs that of many other neurological disorders. Over 6% of Canadians have DM, and the WHO estimates that 366 million people worldwide will develop it within 10 years, with diabetic polyneuropathy (DPN) in over 50% [1, 2]. It is a progressive irreversible neurological problem that begins with foot numbness and pain. Investigators of this unfortunate disorder recognize the urgency of finding new solutions, none successful to date, to prevent DPN’s major clinical burdens: loss of sensation, insensitivity

to injury, risk of falls, intractable neuropathic pain, and foot ulceration leading to amputation [3–10]. From a neurosciences perspective, there is also exquisite neurobiology, not well understood, that dictates how this condition, a unique form of sensory predominant axon neurodegeneration, develops. DPN speaks to the singular behavior of sensory axon terminals in the epidermis that possess a dynamic plasticity required to maintain their investment of skin and its turnover of epidermal keratinocytes [11]. In DPN, this plasticity is abnormal and sensory axons change their phenotype, retract, and disappear. Human DPN is described as “stocking and glove” because the distal terminals of sensory axons that innervate the skin of the toes and fingers are retracted first (see our reviews [12–16]). Essential features of DPN are slowing of conduction velocity, altered sensory behavior, and prominent loss of dermal and epidermal skin axons [17–20].

A. Areti · D. W. Zochodne (*) Peripheral Nerve Research Laboratory, Division of Neurology, Department of Medicine and the Neurosciences and Mental Health Institute, University of Alberta, Edmonton, AB, Canada e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 S. Tesfaye et al. (eds.), Diabetic Neuropathy, Contemporary Diabetes, https://doi.org/10.1007/978-3-031-15613-7_18

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The material in this chapter overlaps with a number of papers and reviews from our laboratory alone or collaboratively including some published recently, which the reader is referred to for greater depth [7, 14, 16, 21–27]. These related reviews cover similar material but are updated in this chapter with several nuances in their interpretation. Some of the materials on molecular alterations in diabetic neurons are not replicated in this review. In discussing how DM targets the nervous system, we begin with dorsal root ganglia, critical but understudied sites that house the cell bodies of peripheral sensory neurons.

2 Structure and Physiology of Dorsal Root Ganglia Dorsal root ganglia (DRGs) are paired paraspinal collections of peripheral neurons, cell bodies (perikarya) of sensory axons that supply sensation to the head, trunk, and limbs. Identified within or adjacent to spinal foramina, they are susceptible to mechanical compression by disc material or osteophytes, an outcome that may be important in common symptoms such as back or neck discomfort. DRGs have a vascular supply subserved by segmental radicular branches that supply nerve roots and by anastomoses from the spinal artery [28]. They are unique structures, not often studied in humans or animals because of their relative inaccessibility to dissection. Covered by a capsule, within is a subjacent layer of neurons of varying sizes and molecular makeup with their processes directed inward toward the center of the ganglion. The capsule is a derivative of the perineurium of the nerve trunk and has a slightly different structure and properties when it surrounds DRG versus exiting nerve root axons [29]. Neuron DRG are also placed at varying depths within the ganglia interspersed among the exiting axons. While less studied, it is inferred that peripheral trigeminal ganglia share characteristics of paraspinal DRGs. While we are aware of few studies on quantitative measures of blood flow in DRGs, the findings have suggested interesting characteristics [30]. Blood flow of rat

A. Areti and D. W. Zochodne

DRGs is higher than that of the endoneurium of peripheral nerve trunks, almost double in a range of 35–40  mL/100g/min compared to 15–17 mL/100g/min in the endoneurium respectively. Moreover, there is evidence of partial “autoregulation” of flow, with relative stability down to mean arterial pressures of 60  mmHg. This differs from the nerve trunk endoneurium where a gradual curvilinear relationship between mean arterial pressure and blood flow is observed. It is also different than CNS, where flows are more tightly preserved at low mean arterial blood pressures. Mean oxygen tensions directly measured in DRGs were comparable to the endoneurium but lower than brain. While speculative, these unique characteristics of DRG physiology may render them susceptible to microangiopathy in DM.  A second important characteristic of DRGs is that their barrier characteristics to ingress of blood-borne molecules are less robust than both the blood nerve and blood brain barriers [31]. This is important translational information given that yet undeveloped therapies of DPN might be capable of accessing DRG neurons through a “leaky” barrier following systemic administration. Dorsal root ganglia house populations of large, medium, and smaller sensory neurons, the perikaryal size of which determines the caliber of their axons. These neurons are classified as “pseudo-unipolar” because one perikaryal branch forms into a central branch that enters the spinal cord and a peripheral branch joins with motor and autonomic axons to form mixed spinal nerve roots that blend into peripheral nerve trunks. The central branches of large, neurofilament rich expressing neurons join the dorsal columns of the spinal cord where they travel upward to the brainstem. In DM, this anatomy is important because detailed MR images of the spinal cord have identified dorsal column atrophy, suggesting degeneration of the central branches of large afferent sensory fibers [32]. Further resolution in these studies will be required to determine whether column atrophy relates to increased fiber packing, myelin thinning, axon loss, or axonal atrophy. Early images of DM DRGs have also been captured by MR

Diabetic Sensory Neurons, Dorsal Root Ganglia, and Neuropathy

but have not had the resolution yet to clarify their changes beyond gross volume alterations [33]. Large caliber neurons give rise to large myelinated “Aα” axons that subserve discriminative touch, vibration, proprioception, and hair movement. Their peripheral branches, also myelinated, innervate sensory organs such as Pacinian corpuscles, Meissner’s corpuscles, and hair follicles transmitting rapidly adapting mechanical sensation. The central branches of alternative, small neurofilament poor neurons synapse within the dorsal horn of the spinal cord. All sensory neurons express neurofilaments, but the content of this scaffold protein varies with neuronal size, in turn influencing its signal in studies using immunohistochemical labeling, hence the inaccurate terminology of “neurofilament negative” small neurons. Small neurons send unmyelinated axons to the skin and other target organs. In the skin, the axons invade and innervate the epidermis, sensing pain, mechanical damage, and probably chemosensitivity. The detailed physiology and innervation of sensory neurons in the skin are reviewed elsewhere [34, 35]. Unmyelinated afferent sensory axons, so-­called C fibers that innervate the epidermis as free nerve endings, are divided into two categories, peptidergic and nonpeptidergic. Peptidergic axons and neurons express substance P (SP) and CGRP (calcitonin gene-related peptide) and ­terminate in deeper layers of the skin known as the stratum basale. Nonpeptidergic axons are also called Mrgprs (Mas-related g protein-coupled receptors) or IB4 (named for lectin binding that labels these neurons) [36]. This is of interest because in DM, peptidergic and nonpeptidergic central axons entering the dorsal horn of the spinal cord may be targeted differentially [37]. Medium caliber neurons contain CGRP and through intermediate caliber myelinated axons (Aβ and γ) transmit mechanical sensitivity and pain. While the normal differential protein content of DRG sensory neurons has expanded, not reviewed here, other common classifications include their expression of neurotrophin family receptors [38–40]. TrkA (Tropomyosin receptor kinase A), the high affinity NGF receptor, is expressed

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on small peptidergic axons. TrkB is the receptor for BDNF and NT4/5, and it is expressed on medium sized neurons, whereas TrkC, the receptor for NT3, is found on larger caliber sensory neurons. IB4 neurons are responsive to GDNF and express its receptor, GFRα1.

3 DRG Responses to Injury DRG neurons sense injury to their distal axon branches by developing a series of structural and molecular changes known as the “axotomy” response or axon reaction [41]. Structural changes include a change in the histological appearance called central “chromatolysis,” attributed to displacement of ribosomes to the periphery of the perikarya. Nuclei similarly are shifted to the periphery of the cell. More important are a series of molecular changes initially described by Richardson, Hokfelt, Verge, and others [40, 42, 43] known as “RAGs” or regeneration-associated genes. Prominent and early characterized RAGs were downregulation of neurofilament proteins, Trk receptors and upregulation of tubulin, GAP43,c-Jun, and others. More recent RNA sequencing data has identified an extensive list of upregulated and downregulated sensory neuron transcripts [44]. In turn, the trigger for RAG development is likely a retrograde signal from the injured axon, initially an electrical and calcium wave, then retrogradely transported signals including importins α and β and pErk [45]. The major conceptual idea behind altered gene regulation after axotomy is that it represents a major shift in sensory axons from a stable maintenance role to a growth and regenerative state. Both upregulation and downregulation of neuron mRNAs may be important in facilitating a growth response. It is also a characteristic of the CNS that similar retrograde RAG induction is attenuated, in concert with a dramatically diminished regenerative potential. An important reason for addressing RAGs in this review is the remarkable absence of RAG development in experimental diabetes despite an “axotomy-like” loss of their distal terminals. Missing in particular are the upregulation of

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growth-related proteins such as tubulin and GAP43 [19]. The general downturn in gene expression has suggested a degenerative phenotype and the possibility that mRNA generation and protein translation are impaired. There are other remarkable features of DRGs, but of unknown significance in DM, given the paucity of studies of both human and chronic animal models. DRG neurons are intimately surrounded by a special class of glial cell known as the perineuronal satellite cells. These are placed in close circumferential relationship to DRG sensory neurons and have the curious property of enlarging and proliferating in response to distal axotomy. This is despite the lack of a direct cellular connection to the injured neuron. These glial cells thereby “sense” distal neuronal injury albeit by unclear mechanisms. Despite the lack of an overt physical connection, perineuronal satellite cells have direct molecular communication with their neuron partners. For example, administration of a fluorochrome dye to distal axon branches not only is retrogradely transported to their parent neuron perikarya, but over time, the perineuronal glial cells also express the fluorochrome, having been transferred from neurons. Perineuronal satellite cells are more dynamic than their neuron partners and exhibit ongoing turnover-cell death and proliferation, even in the absence of injury. They also have close relationships with intrinsic resident macrophages within DRGs. The latter are a newly recognized constituent of DRGs, broadly classified as among DRCCs (dorsal root ganglia resident cycling cells) [46]. DRCCs are populations of self-­renewing cells that include resident macrophages as well as satellite glial cells that colabel with Sox2, indicating cells with stemlike characteristics. Moreover, the close physical relationships of these cells with adult DRG neurons suggest an ongoing role in the spatial and temporal arrangements of the DRG.  Interestingly, despite prior assumptions that DRG macrophages are largely blood borne, the populations that proliferate within DRGs are local. For example, their ongoing replication stimulated by local CSF1 (colony-­stimulating factor 1) signaling can be identified in explant

A. Areti and D. W. Zochodne

cultures without a connection to the systemic circulation. Macrophages are important sources of growth factors, of relevance if their endogenous function within DRGs were impaired by DM.  Schwann cell (SC) dysfunction, not discussed in this review, is a well-established feature of DPN, making it highly likely that related perineuronal satellite cells are similarly targeted [47–49]. The Sox2 expressing cell populations in DRG likely overlap with progenitor cells in spheroids isolated from DRGs [50] and are interesting in that they may offer avenues to replenish DRG sensory neurons when lost. However at present, there is insufficient evidence that this would be required in DPN.  Overall, the extent and potential role of altered DRG cellular dynamics and signaling have not been explored in DM. One important outcome of DM may be DNA damage, either nuclear or mitochondrial. BRCA1 (Breast Cancer 1) is a DNA repair molecule that repairs double-strand DNA breaks but also has transcriptional activity, acts as a ubiquitin ligase, and has heterochromatin-related gene silencing activities [51, 52]. Surprising new findings indicate that axotomy alone is sufficient to trigger a DNA damage response in DRG sensory neurons and that its repair is important for viable regrowth. Along these lines, axotomized DRG sensory neurons had a substantial rise in γH2A.X (H2A histone family member X; >60% of neurons) expression, a marker of DNA damage, a change that indicates a dramatic rise in the extent of DNA damage after injury. Whether DNA damage can account for alterations in gene expression in DPN is speculative and has not been examined. Nuclear BRCA1 colocalizes in neurons with γHSA.X expression where it may offer a repair and stabilizing action that allows neurons to recover and regenerate. For example, elimination of BRCA1 in knockdown experiments impaired neurite growth of adult sensory neurons in vitro and peripheral nerve regeneration in vivo. Further work is required to discover whether DNA damage may be important in DM, whether it is properly repaired by BRCA, and whether it could also account for diabetic mitochondriopathy [53, 54].

Diabetic Sensory Neurons, Dorsal Root Ganglia, and Neuropathy

4 Dorsal Root Ganglia and Diabetes Mellitus Beyond DM-related declines in overall DRG volume by MR analysis [33], neither gross structural alterations of ganglia nor intra-ganglion axonal damage have been described in diabetic DRGs. In a chronic model of mouse DM type 1, perikaryal area and nuclear area were reduced [55]. Careful nonbiased counting of DRG neurons in a long-term models of diabetes in rats has not identified evidence of sensory neuron loss [19]: absence of loss in rats of 12 months diabetes duration and a maximum of 10% loss in mice of 9 months diabetes duration [18]. This finding has argued against reports of short-term DRG neuron apoptosis in cell culture models, a finding not substantiated and potentially linked to high and nonphysiological acute glucose exposure [56]. Relative preservation of neuron numbers and axon counts during these long-term chronic models indicate that neuron drop out is unlikely to contribute to the phenotype. Despite the absence of significant neuron dropout, an important and positive finding, DRGs and sensory neurons are nonetheless targeted by chronic DM.  While our group failed to identify declines in nerve blood flow in an extensive series of DM models, we did identify significant declines in DRG blood flow in chronic models of DM in rats. This was noted in 17- to 23-week diabetic BBW rats, a model of type 2 DM [57] and 16-week diabetic type 1 STZ diabetic rats [58]. These changes, interestingly, developed in the absence of declines of DRG oxygen tensions. While reductions in DRG blood flow might contribute to neuronal stress, they may also arise from declines in oxygen demand, with lesser oxygen extraction. In an anatomical study of vascular architecture in rats (examined in the absence of fixation and harvested under anesthesia prior to euthanasia), numbers of perfused microvessels were elevated in the endoneurium but not DRG of diabetics [59]. The findings suggest that gan-

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glia and nerves may adapt to microvascular abnormalities in DM, maintaining essential perfusion through angiogenesis perhaps triggered by hypoxia. Recent work has also suggested the possibility of altered capillary dynamics in chronic DM, but it is uncertain whether these are sufficient to cause neurodegeneration [60] (Table 1). Endothelin-1 (ET-1) is a highly potent vasoconstrictor peptide that when topically applied over the epineurial vascular plexus induced temporary ischemic conduction block in nondiabetic nerves. In this model of ischemia, intense vasoconstriction of the epineurial circulation impaired downstream blood flow within the endoneurial compartment. In models of DM however, the impact had more significant consequences [62– 64]. ET-1 generated endoneurial infarction and axonal degeneration in diabetics but not control nondiabetic rats. DM microvascular dysfunction in arterial and arteriolar preparations has been linked to potentiated microvascular vasoconstriction, in turn attributed to attenuated vasodilatation [65, 66]. These physiological alterations develop in the absence of overt structural microangiopathy but nonetheless may render ischemic damage to diabetic neurons. Selective DRG ischemia was studied using topical ET-1-induced vasoconstriction of capsular and radicular ganglia feeding vessels. In DM, ET-1 generated intense vasoconstriction of the feeding vessels of ganglia with large and prolonged declines in local ganglion blood flow, exceeding the changes observed in nondiabetics [67]. Sensory neuron damage was manifest as loss of neurofilaments, dissolution of neurons, nuclear TUNEL labeling (indicating apoptosis), “nests of Nageotte,” replacing lost neurons, and chromatolytic changes such as displacement of nuclei to the periphery of neuron cell bodies. Intraganglionic axons and downstream sural sensory axons developed degeneration. These findings provided evidence that DRGs are indeed sensitive to ischemia secondary to diabetic-­ related changes in microvascular physiology.

C57B6/L mice STZ

CD-1 male mice STZ C57BL/6 mice STZ

ES studies, regeneration HSP27 overexpression

CD-1 mice STZ

Male Female RAGE−/− male RAGE−/− CD-1 mice

C57B6/L mice

dbdb

Model SW mice Type 1 STZ

Spliceosome

DM, PTEN KD regeneration Epigenetic studies

Intranasal Insulin, RAGE−/−

Title GLP-1

24 weeks

4 or 8 weeks

Intraplantar CWC siRNAx4; 28d endpoint None

IN miRNA 3 doses/2 weeks Let-7i MiR-341

12–16 weeks

12 weeks

None

IN insulin None

Treatment 4 weeks, insulin pellets, exendin Exendin-4 Low dose insulin High dose insulin Exendin-4 Low dose insulin High dose insulin Intranasal Insulin for 8 weeks IN insulin IN insulin

20 weeks

10 weeks

8 weeks

8 weeks

DM duration (pretreatment) 8 weeks

Table 1  Phenotype and interventions in chronic diabetic models, Zochodne Laboratory

+

−

Y

Y

Y

+ Y

+ Y

±

+

Y

+ Y

+

Y

± Y

+ + +

+ − − − − − Y

+ − − + − − Y

+ + +

SCV slowing Y

MCV slowing Y

− Loss

− Loss

Loss

Loss

+

+ Loss

+

Elevated

Loss

−

− Loss

+

Loss

− − +

− + −

Loss

+ + − + − − M loss

Mechanical sensation Loss

+ + − + − − F gain

Thermal sensation Loss

Loss

+

Loss

− − − − − −

Footpad axons ±

[61]

[158]

[55]

[73]

[163]

[134]

Citation [148]

332 A. Areti and D. W. Zochodne

Indomethacin

BBW model

Near nerve insulin

Chronic DM

Spontaneous regression Neurofilament−/− DM Chronic DM

Intrathecal

ZDF model

Plantar insulin

Title

Female BBW rats SD male rats STZ

16 weeks

20 weeks

4 weeks

26 weeks

52 weeks

SD rat STZ

SD male rats STZ SD male rats STZ

None

8 weeks

Indomethacin± Guanethidine 8 weeks

Y

Y ±

+

0.1 IU 3×/week for 4 weeks

Y

Y

Y (incl Nf−/−) Y

+

+

+ + Loss

+

Footpad axons − Loss

− + + ±

+ Loss

Mechanical sensation + Loss (CD-1 only)

Loss

− No loss

Thermal sensation + No change

Y

Y

SCV slowing +

Different nerve Y

Y

Y

Y (incl Nf−/−) Y

+ + + +

Y

Y

MCV slowing −

Near nerve insulin

None

None

None

IT insulin or IGF-1- 4 weeks

None

Treatment HSP overexpression Paw insulin

SW mice STZ B6C3 mice

8 weeks

16 weeks

8–12 weeks

DM duration (pretreatment)

0.1 IU insulin 0.2 IU insulin IGF-1 36 weeks

C57BL/6J STZ dbdb CD-1 STZ ZDF rats Type 2 SD male rats STZ

Model

(continued)

[211]

[57]

[131]

[19, 209, 210] [17]

[116, 133]

[208]

[132]

Citation

Diabetic Sensory Neurons, Dorsal Root Ganglia, and Neuropathy 333

SD male rats STZ

Sulindac

12 weeks 16 weeks

DM duration (pretreatment) Treatment Indomethacin Guanethidine Indo+Guaneth Sulindac onset Sulindac later Insulin 1.0 IU Sulindac onset 16 weeks Sulindac later 1 month Insulin

SCV slowing + − worsens − Y

+ ± +

MCV slowing + − − Y

− ± −

Thermal sensation

Mechanical sensation

Footpad axons

[58, 212]

Citation

Bolded entries are findings in the models, with specific interventionsm; (unbolded) from each study listed below; Y = yes; ‘Loss’ refers to an impairment in the listed modality. For interventions, +indicates that the intervention did improve this parameter, – had no improvement. Nf -/- are neurofilament lacking animals

Model

Title

Table 1 (continued)

334 A. Areti and D. W. Zochodne

Diabetic Sensory Neurons, Dorsal Root Ganglia, and Neuropathy

5 Sensory Neurons in Diabetes

335

contribute to the disease and might be amenable to intervention. Peptide loss may explain the As discussed above, there is very little direct evi- alterations in vascular reflexes that accompany dence for significant sensory neuron loss or drop- DPN [72], and shifts in sodium channel expresout in chronic DM despite their susceptibility to sion may contribute to neuropathic pain, triggeracute ischemia and their vulnerability to short-­ ing anion overload and degeneration in diabetic term exposure to high glucose levels. Neither neurons. Finally, heightened expression of PARP, scenario is informative about their fate during NFκB, and activated caspase-3 demonstrate neulong-term diabetes. Human studies of diabetic rons under duress, despite their capacity to surDRGs are limited. An older report by Greenbaum, vive. PARP is an energy-consuming DNA repair lacking immunohistochemical or newer histo- molecule. However, in light of all of these logical stains, studied six patients at postmortem changes, the finding that most sensory neurons in [68]. Only three patients with clinical diabetic chronic DM survive remains important news. polyneuropathy had evidence of mild neuron loss Restoring function and growth to surviving and with nests of Nageotte, axon retraction bulbs, and existing neurons is an easier task than replenishvacuolation of sensory neurons. Vacuolation ing them. however may have been a processing artifact More recent RNA microarray analyses of [69]. In a later and separate report using EM, mRNAs in experimental diabetes have added Schmidt identified degenerative changes in new targets and information [73, 74]. While relaDRGs from both chronic DM and aging includ- tively few of these assays have been carried out, ing dystrophic proximal axons that accumulated it is likely the lists will vary with the choice of the neurofilament [70]. DM model and its sex and the duration of hyperA previous review from our laboratory catego- glycemia. Moreover, unexplored factors such as rized known molecular changes in experimental the gut microbiome of housed study rodents may DM [71] including loss of structural proteins alter findings. Cheng et al. [73] identified a series such as neurofilament subunits, tubulin, of up- and downregulated mRNAs in chronic CGRP,SP,PACAP, and other neuropeptides, type 1 DM mice (streptozotocin [STZ] induced) sodium channel Nav1.8, neurotrophin receptors, of duration 5 months. Prolonged models are preGAP43 and NFκB among others. Upregulated ferred given that chronic human disease requires molecules included activated caspase-3, Poly a significant exposure to DM, not addressed by (ADP-ribose) polymerase (PARP), sodium chan- short duration studies of 1–2 months. In the long nels Nav1.3,1.6,1.9 and subunit β3, Heat shock duration STZ model, theoretical concerns raised protein HSP27, MAPK second messengers over STZ toxicity are obviated. The list of altered (ERKs, JNKs, P38), and the insulin receptor. mRNAs in the Cheng model was accompanied This original list, now expanded, remains incom- by two additional features: (1) upregulation of plete but has identified a range of molecular alter- GW bodies, cytoplasmic sites of RNA processing ations associated with chronic DM. The loss of within DRGs; and (2) a concurrent list of differneurofilament structural protein mRNA in DRGs entially altered miRNAs, the short RNA supraparalleled loss of neurofilament investment in regulatory system of epigenetic RNA control distal axons and their associated atrophy [17]. (discussed further below). Both the findings offer Despite this loss, mice lacking neurofilaments additional and alternative explanations for the nonetheless develop conduction slowing and altered molecular architecture of DM sensory accelerated changes of DPN, indicating that this neuron-altered mRNA handling by GW bodies protein is probably not part of the pathogenesis of and shifted supraregulatory control by miRNAs. the disease [20]. The loss of growth-related These mechanisms contributing to altered protein GAP43 and changes in MAPK signaling mole- synthesis may be additive to other disruptions cules are important in providing impetus to sub- such as altered DNA repair considered above. sequent ideas that attenuated growth programs However, the findings have added yet another

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neurodegenerative mechanism, that of altered spliceosomes, considered below. Among the differentially regulated mRNA “hits” in chronic diabetic DRGs, only a few members have been examined in depth to date. Price and Tomlinson identified evidence for a role of Txnip (thioredoxin interacting protein) in experimental DM [75], upregulation also confirmed in our work [73]. The significance of this finding is that the protein may be a mediator of oxidative stress in sensory neurons but also act as a tumor suppressor, potentially limiting growth. From our array list, we have also focused on two lesser understood upregulated proteins, DUSPs (dual specificity phosphatases) and CWC22, a spliceosome protein. CWC22, an upregulated protein involved in the spliceosome, has proved interesting and relevant to DM and DPN in different ways [55]. CWC22 is largely expressed in sensory neuron nuclei, and its knockdown enhanced neurite outgrowth of adult sensory neurons in dissociated cultures. This finding suggested that the protein was a “brake” on neuron growth and plasticity. In a chronic model of DPN in mice, unilateral hindpaw dosing of CWC siRNA designed to knockdown CWC improved ipsilateral sensory conduction and thermal sensation. The contralateral paw treated with scrambled control siRNA retained neuropathic abnormalities, indicating a pathogenic role for CWC22 upregulation in DPN. Aberrant CWC action may disrupt the spliceosome with which it is associated, a nuclear complex that determines the fate of transcribed mRNAs. Additional spliceosome abnormalities in chronic DPN mice included upregulated numbers of Cajal bodies, sites of RNA splicing in nuclei, altered localization of survival motor neuron (SMN) protein, and abnormal nuclear foci of small nuclear ribonucleoprotein particles (snRNPs), also parts of the spliceosome. Dysregulated motor neuron SMN is linked to the development of spinal muscular atrophy. DUSPs (dual specificity phosphatases; MAP kinase phosphatases, MKPs), proteins that interact with the MAPK signaling pathway, are a separate group of proteins we discovered in our chronic DM mRNA array to be upregulated in

A. Areti and D. W. Zochodne

DRGs. Similarly understudied, DUSPs have proven of interest in unexpected ways, albeit not yet in the context of DPN [76]. Sensory neurons, both injured and noninjured, express isoforms DUSP1 and 4 in both perikarya and axons. Their knockdown (KD) in sensory neurons, unlike CWC22, suppresses neurite outgrowth, suggesting a role by DUSPs in supporting normal axonal “plasticity” of adult neurons. Along these lines, DUSP KD or inhibition intensified axonal damage in the setting of capsaicin neurotoxicity, indicating a protective role by DUSPs for axons. Moreover, in vivo, DUSP knockdown or inhibition accelerated axonal degeneration following axon transection-loss of axon excitability, neurofilament dissolution, and morphological features of axon breakdown. DUSPs are part of the recently and partly untangled process of active axonal degeneration, for which several member proteins have been identified. A protein known as SARM1 (sterile alpha and TIR motif containing 1) appears central to axonal degeneration. Along these lines, accelerated axonal degeneration secondary to DUSP inhibition or KD was rescued by concurrent SARM1 KD. In DM, DUSP upregulation within sensory neurons might provide a compensatory response to incipient axon damage. There is also early evidence that SARM1 KD may protect against DPN [77]. The cascade of axonal degeneration, not reviewed here, likely involves mechanisms shared by many neuropathies; its unraveling has offered several new targets for axonal protection, including SARM1 [78]. Downstream of SARM1, further proteins also participate in axon breakdown including calpains and caspase-6, the latter identified in early degenerating skin axon profiles [79]. Overall, there are close connections between the repertoire of proteins also found mainly in perikarya that nonetheless have major impacts on downstream axon survival. A full understanding of how DM might impact the full complex of axonal degeneration related proteins requires further work, but may offer opportunities to intervene. Understanding the roles of supraregulatory miRNAs in rendering diabetic neuron dysfunction has only just begun. Their role might relate to the problem of fitting together diverse pieces

Diabetic Sensory Neurons, Dorsal Root Ganglia, and Neuropathy

of the DPN phenotype into a single molecular trigger. These pieces include, for example, electrophysiological slowing of motor and sensory conduction, distal loss of sensory axons in the skin and other targets, axon, perikaryal atrophy, and the generation of neuropathic pain despite fiber loss. Moreover, the range of mRNA changes discussed above is difficult to link together beyond a generalized down run of cellular machinery. miRNAs characteristically have many mRNA targets and could be important in wide “down tuning” of neurons or alternatively in supporting inappropriate upregulation, as in the case for CWC22. Cheng et  al. [73] identified a series of differentially regulated miRNAs in the same 5-month-old type 1 cohort of diabetic mice that underwent mRNA analysis described above. These mice had well-characterized phenotypic features of DPN. One of the most prominent differentially expressed miRNAs was mmu-Let7i, reduced by 39% in diabetic DRGs. mmu-Let 7i has a large range of mRNA targets (>900) that include IGF-1 and its receptor among 84 other growth pathway mRNAs, contrasted to 21 metabolism and diabetes pathway mRNAs. Exogenous application of a mmu-Let 7i mimic had a trophic impact on adult sensory neurons, encouraging both neurite outgrowth and branching. Moreover, intranasal administration of a mmu-Let 7i mimic improved thermal and mechanical sensation, motor and sensory conduction velocity and epidermal innervation in a model of chronic type 1 DM.  In the same work, intranasal treatment of anti-miR to instead tune down an alternative upregulated miRNA, mmu-miR-341, improved thermal sensation, and conduction velocities. The overall findings lent support to the idea that miRNA manipulation may influence the DPN phenotype and to the idea that intranasal nucleotides, may have promise in DPN or other disorders, not unlike that offered by intranasal insulin. Several findings described above emphasize the role of growth and plasticity molecules that may have impaired actions in DPN. Although the term “plasticity” has wide use, here we apply it to the capacity of neurons to extend processes and grow or regenerate. This property may provide

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critical capacity for sensory axons to maintain their investment in endorgans like skin. In keeping with this theme, we next discuss several new examples of strategies to enhance neuron growth in the setting of damage or disease.

6 Regrowth Strategies for Sensory Neurons Diabetic neurons targeted by diverse metabolic impacts from DM on sensory neurons may withstand damage through strategies that support their overall growth properties. In several instances, these approaches, largely not yet tested in humans, have remarkable impacts on experimental DPN. Proposed mechanisms of DPN are not reviewed here in depth. A key tenet however is “neurotoxic stress,” arising from glucotoxicity, increased polyol flux, free radical toxicity, nitrergic damage, mitochondrial abnormalities, lipid toxicity, and deficits in growth factors [80–102]. In many putative therapies for DPN, alleviation of the impact of one or more of these mechanisms has been highlighted. An important example has been the long history of aldose reductase inhibitors (ARIs) to eliminate polyol flux. While ARIs have had some impact on human disease, interest in their use has waned and none have been fully accepted therapeutically [103, 104]. Growth Factors and Insulin  The limited impact of traditional growth factors in experimental and human DPN has been reviewed elsewhere [15, 23]. In the cases of neurotrophins, lack of enthusiasm has stemmed from negative clinical trials, uncertain dosing, downregulation of their receptor expression in models, and their capability to support only subsets of neurons [105]. Hepatic growth factor has recently been trialed, albeit with limited published pretrial preclinical data as to its mechanism, with results suggesting an impact on human pain [106]. We have previously made the case for exploiting the neurotrophic properties of insulin. Almost 50  years ago, Frazier et  al. in “Nerve Growth Factor and Insulin,” published by Science,

338

emphasized the evolutionary structural similarities between NGF and insulin [107]. Unlike the neurotrophins, of which NGF is a member, insulin receptors (IRs) are widely expressed on peripheral neurons and are upregulated in diabetic models. IRs share downstream transduction cascades with other growth factors [108–117] and on ligation they undergo autophosphorylation, exhibit tyrosine kinase activity, and utilize downstream activators known as IRS-1 and 2 (IRS=insulin receptor substrate) [118, 119]. There is eventual activation of the p85 subunit of PI3K, a central growth signal for neurons [119– 127]. Insulin is associated with increased neurite outgrowth from adult neurons studied in  vitro [128]. It also improves nerve regeneration in nondiabetic injury models, a property that may be appropriate for addressing DPN [129, 117]. Either loss of insulin in type 1 DM or resistance to its actions in type 2 DM may have a role in the development of peripheral neuron dysfunction. Finally, the neuronal actions of insulin as a growth factor are separate from its impact on glycemia. The preclinical data suggesting a role for insulin signaling in DPN are several: low insulin doses (that do not alter blood glucose levels) applied near nerve, within the skin, or intrathecally to access DRGs all improve DPN [130– 133]. Intranasal insulin, a route that accesses DRG through the CSF, improved experimental DPN [134, 135]. Local corneal insulin restored innervation as assessed using corneal confocal microscopy [136]. Insulin-like Growth Factors (IGFs), family members, use similar downstream signaling pathways [137–139]. While the range of impacts of insulin in preclinical work is impressive, there are potential barriers to its translational success. Insulin resistance is a central deficit in most type 2 DM patients characterized by normal or high systemic insulin levels in relationship to failed insulin-­ mediated glucose uptake by muscle and adipose tissue [140–143]. We described evidence for insulin “resistance” in neurons, referring to a deficit in its ability to display trophic actions following high dose or prolonged insulin exposure [144, 145]. These findings were confirmed by others [146, 147]. Whereas several mechanisms

A. Areti and D. W. Zochodne

may account for neuronal insulin resistance, it is possible that combined use with insulin sensitizers may overcome this limitation. Glucagon-like peptide 1 (GLP-1) operates by enhancing systemic insulin sensitivity in type 2 DM, but its receptors are also expressed on adult sensory neurons, and upregulated in a model of DM type 2 [148]. Moreover, a GLP-1 agonist, exendin-4 has trophic actions on adult sensory neurons in vitro, associated with increased neurite outgrowth. In the setting of only a mild impact on glycemia, subcutaneous exendin-4 given over 8 weeks in mice with DM of 2 months duration was examined for its impact on DPN. In contrast to partial impacts of either low- or high-­ dose insulin, exendin-4 improved motor and sensory conduction velocity in type 1 DM mice and reversed thermal and mechanical sensory loss. Similar benefits, excepting sensory conduction velocity, were noted in type 2 DM mice. There were no significant impacts on epidermal innervation but the shorter model durations limited this endpoint. The overall findings paralleled similar results in two other laboratories [149, 150] and provide preclinical support for human studies of GLP-1 agonism in DPN. Human trials focused on GLP-1 or its analogs in DPN have not yet been reported. Supporting Intrinsic Neuronal Growth Properties  That sensory neurons require an ongoing level of “plasticity” or growth in the absence of injury is supported by newer findings. For example, changes in epidermal and hair follicle innervation may readjust at short notice from noninvasive stimuli, such as hair shaving [11]. In DM models, short-term local hindpaw injections of low-dose insulin, signaling dermal axon insulin receptors, can rapidly restore axon numbers to nondiabetic values [132]. Finally, human skin biopsies of normal subjects display markers of growth and plasticity on epidermal axons, indicating evidence of ongoing growth. These included GAP43, Shh, SCG10, and others [151]. Overall, it may be that sensory axons require ongoing growth and plasticity simply to deal with the wear and tear of skin and routine shedding of superficial skin keratinocytes.

Diabetic Sensory Neurons, Dorsal Root Ganglia, and Neuropathy

Removing intrinsic “brakes” on neuron growth as a novel strategy to enhance plasticity allows consideration of several targets. The idea has been to unleash the growth potential of stable and regeneration reluctant adult sensory neurons temporarily and locally. Several “brakes” are “tumor suppressor” molecules and pathways identified as being gatekeepers to uncontrolled tumor cell growth. Moreover, some “brakes” are not among injury-related “RAGs” described above, indicating that their expression is ongoing, and stable irrespective of injury. Others however are tuned down after injury to foster regrowth. “Preconditioning” refers to a heightened regenerative response of peripheral neurons that have been subjected to an axon injury (axotomy) within the previous 5–7 days; it ramps up early RAG expression, allowing a more robust response to a subsequent injury [152]. While the mechanism of preconditioning is unconfirmed, rises in BDNF neurotrophic signaling have been considered. In vitro preparations of adult neurons (see below) demonstrate a dramatic rise in outgrowth if their axons are subjected to an axotomy prior to their harvesting and growth in culture. How dissociated cultured adult neurons respond to interventions in vitro is an important investigative screening step as a robust predictor of in vivo regeneration. “Neurites” are axon-like outgrowths from neurons in  vitro and their growth along with overall neuron survival, neurite initiation, branching, and directional conduct are all important deliverables from in vitro analysis. Replicating the molecular reprogramming generated by preconditioning might encourage better regrowth of peripheral sensory neurons. While the triggers for preconditioning are debated, axon injuries generate a retrograde directed injury discharge and a calcium wave. On the supposition that exogenous electrical stimulation (ES) might mimic or augment this signal, Gordon, Brushart, and colleagues identified that a specific ES paradigm, delivered immediately after axotomy to the intact proximal stump was associated with improved motor axon regeneration and preferential motor branch reinnervation of muscles [153, 154]. Follow on work confirmed a similar benefit from a 1 h epoch of 20 Hz stimu-

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lation on sensory axon regrowth [155–157]. Additional findings were that ES indeed evoked a calcium transient, as occurs during preconditioning, and that it increased induction of specific RAG mRNAs including GAP43 and tubulin while reversing the changes in ATF3, an injury marker [158]. In vitro ES enhanced the transcription of BDNF mRNA, indicating a close connection between ES and preconditioning [156, 159]. It also lowered PTEN levels (see below) and was sensitive to PI3K inhibition. Superimposed axon injury in the setting of DPN offers insights into the regenerative potential of neurons, not unlike those gained by preconditioning. In the peripheral nervous system, DM is associated with a “double hit” comprised of degenerative neuropathy as well as a specific failure in regeneration. This topic has been reviewed in detail separately [160]. Nonetheless, ES, as a surrogate for preconditioning, was associated with improved regeneration from a superimposed sciatic nerve injury in chronic diabetic mice [158]. Yet to be tested is whether ES reverses overall features of DPN, but since this is a focal strategy, thought will be required as how best to exploit it for generalized nerve dysfunction in DM. PTEN (phosphatase and tensin homolog deleted on chromosome 10) was among the first tumor suppressor molecules examined in peripheral neurons [161]. Mutations in PTEN are associated with Cowden’s syndrome, a condition that predisposes persons to oncogenesis with solid tumors. PTEN is expressed in adult DRG neurons, but more prominently in small caliber nonpeptidergic IB4 or Mpgprs neurons that have slower regrowth properties [162]. We noted that PTEN pharmacological inhibition or knockdown by siRNA was associated with dramatic rises in neurite outgrowth from dissociated adult neurons in vitro. PTEN knockdown or inhibition was an important example of the impact of removing a key “brake” on neuron plasticity, demonstrating robust enhanced outgrowth of their neurites. Moreover, this impact was striking irrespective of whether the neurons were previously uninjured (intact) or already preconditioned. Preconditioning has been assumed to generate

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the peak regenerative response that neurons are capable of. However, both the ES work, superimposing stimulation on an injury, and PTEN inhibition have indicated that it is possible to drive neuron regenerative plasticity significantly higher than achieved with preconditioning alone. Indeed, in the case of PTEN inhibition or knockdown, heightened neurite outgrowth was yet more pronounced if superimposed on an injury state. Thus, this was the first example we were aware of in which neuron outgrowth could be ramped up substantially by a single molecular trigger beyond the preconditioning level. In vivo PTEN knockdown or inhibition increased axon outgrowth from transected sciatic nerves. In both type 1 and type 2 DM mice, PTEN was upregulated in DRG sensory neurons and its knockdown enhanced their neurite outgrowth in vitro. Finally, we confirmed that PTEN knockdown in  vivo could repair the regenerative deficit of mice with type 1 DM and others confirmed similar findings in a type 2 DM model in vivo [163, 164]. Taken together these findings indicate that diabetic neurons are responsive to strategies that improve their plasticity, an important property to exploit in treatment. The next “tumor suppressor” analyzed was chosen for its central role in transcriptional regulation, Rb1(retinoblastoma 1), known to be mutated in childhood retinoblastoma tumors. Rb1 is expressed in the cytoplasm and nuclei of adult DRG primary sensory neurons [165], but unlike PTEN, its expression appears to involve most sensory neuron subtypes, including those from mice with chronic DM. In its nonphosphorylated state Rb1 binds to a divergent transcription factor E2F1 and prevents its activation [166]. While E2F1 signaling is best established in facilitating S phase mitotic DNA replication stage entry, its actions are less well understood in growth [167, 168]. Following phosphorylation by cyclin-CDKs Rb1 releases E2F1 to permit its signaling. Like PTEN, Rb1 is not among the known RAGs indicating a constitutive “braking” role independent of injury or axotomy [44, 165, 169]. Rb1 knockdown also does not activate PI3k-pAkt [161, 170, 171], but its knockdown enhanced adult neuron outgrowth, branching and initiation

A. Areti and D. W. Zochodne

in  vitro, in part through increased levels of PPARϒ [Peroxisome proliferator-activated receptor gamma]. PPARϒ, in turn, was expressed in sensory neuron nuclei and cytoplasm, and it enhanced in vitro neurite growth. In addition to being a mediator of Rb1 knockdown’s impact on neurons, PPARϒ is a known insulin sensitizing agent [172, 173], recognized to promote insulin signaling at several levels: IRS-1 and IRS-2 [174, 175], the p85 subunit of PI3K [176] and elsewhere [177, 178]. Given this series of findings, Rb1 knockdown, E2F1 activation, and PPARγ may allow neurons to overcome insulin resistance and respond to insulin especially in more common type 2 DM. This role has yet to be confirmed. However, preliminary evidence indicates that Rb1 knockdown has synergistic impacts on neuronal growth with insulin and that it improves chronic experimental DPN (unpublished data). There are additional, less well-explored molecules and pathways that may offer roles in restoring neuron plasticity. Adenomatous polyposis coli (APC) is mutated in colorectal carcinomas [179] and suppresses tumorigenesis by forming a destruction protein complex with β-catenin, also a divergent transcription factor. APC thereby blocks β-catenin signaling to suppress growth. APC expression rises in DRG neurons after axotomy injury, and it is expressed in the sensory neuron cytoplasm, axons, and SCs. Like PTEN, APC is prominent within nonpeptidergic IB4 neurons that have attenuated growth behavior. APC knockdown facilitated β-catenin translocation to the neuron nucleus and enhanced neurite outgrowth in vitro and nerve regeneration in  vivo. The analysis of its impact on nerve regrowth involved local application of siRNA at a nerve injury site and ipsilateral knockdown of its mRNA in the DRG and sciatic nerve. As in several siRNA studies to date, the findings speak to the mobility of small nucleotides exploiting retrograde transport to knockdown and obviating the need for viral vector directed therapies [180]. Sonic hedgehog protein (Shh) is a morphogen that directs developmental motor pathway formation. It is expressed in adult DRG sensory neurons, axons, and Schwann cells. Unlike the tumor suppressor molecules, constitutive Shh may act

Diabetic Sensory Neurons, Dorsal Root Ganglia, and Neuropathy

to support regeneration, as its knockdown attenuates growth. Shh has been identified within epidermal axons from normal human subjects, supporting ideas that these axons are normally in a state of ongoing growth [151]. Finally, but not discussed here are a range of SC mitogens and signals that may support axon regrowth indirectly through the close partnership of axons and SCs during regrowth [181, 182]. Topical Manipulation of Sensory Axons  While this review has focused on overall strategies to improve the growth and plasticity of sensory neurons, manipulating their distal terminals may be of interest. For example, a substantial number of mRNAs are transported from perikarya (cell bodies) distally to axon terminals and their growth cones where they undergo local translation [183, 184]. CGRP is an interesting example of a local axon synthesized peptide that signals to SCs and microvessels [185, 186]. Several growth factor receptors, including the insulin receptor, are also expressed on skin axons and discussed above. Local intracutaneous insulin restored epidermal innervation in type 1 and 2 DM models of mice [132]. Beyond these findings, growth cones also express a number of intrinsic proteins, not reviewed here, that determine whether they advance and grow or collapse and retract. An important example is RhoA, a GTPase that activates ROCK (Rho kinase) to collapse growth cones exposed to inhibitor cues such as myelin or chondroitin sulfate proteoglycans. RhoA or ROCK inhibition increases growth of adult sensory neurons in  vitro and outgrowth of axons from a nerve injury [187]. A novel and exciting approach to directly support regrowth of skin axons has emerged from work by Fernyhough and Calcutt exploiting axonal muscarinic acetylcholine type 1 receptors (M1Rs) [188–190]. Mice lacking the receptors had enhanced neurite outgrowth in vitro and were protected from DPN.  Moreover, M1R-specific antagonists reversed mitochondrial dysfunction in diabetes and features of neuropathy by mechanisms operating in part through activation of CAMKKβ, AMPK, and PGC-1α. In female dia-

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betic mice, the M1R antagonist, pirenzepine applied at 2% to the paw improved tactile allodynia, thermal sensory loss, and loss of epidermal axons. Interestingly pirenzepine does not cross the blood brain barrier and has already been used extensively as a therapy in the clinic for reflux and other clinical conditions. A clinical trial of pirenzepine topical in patients with type 2 DM is underway.

7 Sensory Neurons and Pain This topic is reviewed in detail elsewhere [15, 191, 192]. The pain phenotype of DPN is of complex origin involving alterations within DRGs, axons, and their ion channels together with altered pain pathway signaling. Within DRG neurons, the generation of pacemaker ectopic discharges, reflecting inappropriate excitability has been recognized for several decades as contributing to pain [193]. Both peripherally generated and perikaryal originating discharges may underlie the positive sensory symptoms that contribute to painful DPN.  Current ideas have particularly focused on the roles of sodium channels and T-type calcium channels. Mutated SCN9A Nav1.7 sodium channel α subunits that are associated with a gain of function and hyperexcitability have been identified by Faber, Merkies, and Waxman in painful idiopathic sensory polyneuropathies [194]. Nav1.7 channels are localized to DRG neurons and axon terminals [195]. Alternative sodium channel α subunits designated Nav1.8 are expressed on DRG cell bodies and terminals and have activation properties linked to Nav1.7. Both have been described in diabetic models linked to methylglyoxal, a metabolic byproduct of DM [195, 196]. β-Subunits of the sodium channel that modulate channel opening have also been implicated [197] and a specific mutation, associated with neuron hyperexcitability, has recently been described in a diabetic patient [198]. Similarly, hyperexcitability of DRG neurons may develop from T-type voltage-gated calcium channels (Cav3.2) that are found in small- and medium-sized neurons. These channels may also

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contribute toward ectopic painful discharges in DM [199, 200]. Their upregulated currents have been described in both types 1 and 2 DM models [201, 202]. Abnormalities in other channels have also been described in DPN including HCN (hyperpolarization-­ activated cyclin nucleotide-­ gated) channels [203] and potassium ion channels, specifically Kv1.2 [204]. Related changes in the function of TRP channels including TRPV1 and TRPA1 have also been described in relation to pain from DPN [205, 206]. Taken together, the evidence for several forms of ion channelopathy in DM that contribute to pain is substantial. It is unclear whether axon ectopic discharges, DRG neuron pacemaking, or remodeling of upstream CNS pain pathways are primarily responsible for DM pain syndromes. It is recognized that peripherally originating discharges are capable of widespread secondary remodeling of ascending nociceptive pathways. Additional questions one might ask are how specific ion channel abnormalities develop in overall DPN degeneration and what mechanisms generate these changes: transcriptional, translational, or epigenetic? Since not all DPN phenotypes have pain, it seems difficult to attribute neurodegeneration to pain-associated cation overload within axons or perikarya. In DPN models, some mouse strains routinely develop thermal and mechanical sensory loss, even early in their course, whereas others are characterized by hyperalgesia. In patients, there may be an important interaction between genotype and the likelihood to develop the painful subtype of DPN.

8 Conclusions The interaction between sensory neurons and chronic DM remains complex and not neatly categorized. Sensory neurons develop a range of morphological (axon retraction), gene expression and protein changes that are difficult to link into a unifying mechanism. Only briefly mentioned here are primary targeting of mitochondria, reviewed elsewhere [207] and dysfunction of Schwann cells, the critical neuron glial partner. Important is the rec-

ognition that DPN is a unique neurodegenerative disorder with sensory, but also autonomic and later motor neuron targeting. Despite an onslaught of multiple mechanisms that generate neurotoxic “stress” with efforts to mitigate them, this review instead emphasizes the promise of enhancing the overall plasticity of the sensory neuron, enabling it to withstand diabetes and thrive. Acknowledgments  The effort devoted to this chapter was supported by current operating grants from the Canadian Institutes of Health Research (FRN148675 and 168929). The authors acknowledge the experimental work cited here and contributions by colleagues and trainees in the Zochodne laboratory. Work described has been supported since 1989 by the Canadian Institutes of Health Research, Canadian Diabetes Association, the Alberta Heritage Foundation for Medical Research, Muscular Dystrophy Association of Canada, University of Alberta Hospital Foundation, Department of Medicine and Division of Neurology, University of Alberta, NIDDK Complications Consortium, and the Juvenile Diabetes Foundation.

Disclosures  None.

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Micro- and Macrovascular Disease in Diabetic Neuropathy Lihong Chen and Aristidis Veves

1 Introduction Diabetes is often defined a “vascular disease” because of the early and extensive involvement of the vascular tree observed in diabetic patients and, even, in those at risk of developing diabetes. Both the micro- and macrocirculation are affected, though the pathophysiology, histology, clinical history, and clinical sequelae at the two vascular levels appear to be quite different. Historically, there have been two competing hypotheses regarding the origins of diabetic neuropathy. According to the first one, diabetic neuropathy is secondary to the impairment of nerve and Schwann cells, while the second one stated that diabetic neuropathy is mostly ascribed to microvascular disease. However, it is currently realized that nerve and microvascular injury are both among the factors that contribute to nerve dysfunction.

Chronic diabetic complications are the result of small vessel disease. Diabetic microangiopathy has been considered the main anatomic alteration leading to the development of retinopathy, nephropathy, and neuropathy. Nevertheless, macroangiopathy, i.e., atherosclerosis of peripheral arteries, is also a prominent feature of long-­ lasting diabetes and is characterized as involving predominantly distal arteries. The possible links between diabetic micro- and macrovascular alterations and nerve damage will be the focus of this chapter.

2 Microvascular Disease: Overview and Anatomic Changes Lesions specific for diabetes have been observed in the arterioles and capillaries of the foot and other organs that are the typical targets of dia-

L. Chen Division of Endocrinology, West China Hospital, Sichuan University, Chengdu, China A. Veves (*) Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 S. Tesfaye et al. (eds.), Diabetic Neuropathy, Contemporary Diabetes, https://doi.org/10.1007/978-3-031-15613-7_19

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betic chronic complications. A nowadays-­ ity of the vessels further limiting their ability to historical retrospective histological study dilate in response to different stimuli [12]. demonstrated the presence of PAS-positive mateIn the kidney, nonenzymatic glycosylation rial in the arterioles of amputated limb specimens reduces the charge on the basement membrane, from diabetic patients [1]. Though it was believed which may account for transudation of albumin, for several years that the anatomic changes an expanded mesangium, and albuminuria [13]. described were occlusive in nature, in 1984 Similar increases in vascular permeability occur LoGerfo and Coffmann recognized that, in dia- in the eye and probably contribute to macular betic patients, there is no evidence of an occlu- exudate formation and retinopathy [14]. In simsive microvascular disease [2]. Subsequent plest terms, microvascular structural alterations prospective anatomic staining and arterial casting in diabetes result in an increased vascular permestudies have demonstrated the absence of an arte- ability and impaired autoregulation of blood flow riolar occlusive lesion, thus dispelling the hope- and vascular tone. less notion of diabetic “occlusive small vessel Previous studies have shown a correlation disease” [3, 4]. between the development of diabetic chronic While there is no occlusive lesion in the dia- complication and metabolic control with perhaps betic microcirculation, other structural changes the strongest evidence coming from the Diabetes do exist. Arteriolar hyalinization, corresponding Control and Complications Trial (DCCT), which to the thickening of walls of arterioles, was enrolled type 1 diabetic patients, and the United observed in patients with diabetes, regardless of Kingdom Prospective Diabetes Study (UKPDS), hypertension [5]. These abnormalities are char- which enrolled type 2 diabetic patients [15, 16]. acterized by hypertrophic remodeling and are The results from both clinical trials clearly associated with impaired endothelium-depen- showed a delay in the development and progresdent vasodilation in  vitro. Furthermore, endo- sion of retinopathy, nephropathy, and neuropathy neurial capillary density was also found to be with intensive glycemic control, thus supporting increased in patients with diabetes, suggesting the direct causal relationship between hyperglythat ­capillary density may respond to diabetes- cemia and microcirculation impairment. In coninduced nerve ischemia [6]. The thickening of trast, there was less evident for macrovascular the capillary basement membrane, which is disease, which was assessed only in the UKPDS. accompanied by pericyte degeneration and It should be emphasized hyperglycemia alone endothelial cell hyperplasia, is the dominant is not sufficient to trigger generalized diabetic structural change in diabetic neuropathy. The microvascular pathologies. The Joslin Diabetes composition of basement membrane in diabetes Center 50-year Medalist Study has shown that suggested that accumulation of glycosylated 30–35% patients with type 1 diabetes did not have and cross-linked proteins contributed to the significant microvascular complications [17]. expanded membrane structure and impaired This suggests that there may be unidentified function. This can affect endothelial cell and genetic or other endogenous protective factors extracellular matrix interactions and represents that diminish the adverse microvascular effects of a response to the metabolic changes related to hyperglycemia. It has been shown that multiple diabetes and hyperglycemia [7–9]. Furthermore, mechanisms are involved in the adverse effects of the thickness of basement membrane of skin hyperglycemia with vascular complications, and nerve correlates with the extent of neuropa- including nonenzymatic glycation and the formathy in diabetes [10]. However, this alteration tion of advanced glycation end products (AGEs); does not lead to occlusion of the capillary enhanced reactive oxygen production and actions; lumen, and arteriolar blood flow may be normal endoplasmic reticulum (ER) stress; and the actior even increased despite these changes [11]. vation of the polyol pathway, the diacylglycerol On the contrary, it might act as a barrier to the (DAG)–protein kinase C (PKC) pathway [5], Src exchange of nutrients and/or increase the rigid- homology-2 domain-containing phosphatase-1

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Hyperglycemia Genetic and epigenetic modulators

LocaI tissue responses

Increase intracellular glucose metabolism Cell signaling dysfunction (Activation of PKC, MAP kinase, SHP-1, and phosphatases)

Toxic metabolites (AGE, oxidants, methylglyoxal

Altered osmols and redox potentiaI (polyol pathway)

Oxidative stress, ER stress, Inflammatory cytokines Loss of insulin actions Kallikrein-bradykinin activation Vascular and specific tissue cells dysfunction and abnormal turnover Nephropathy

Retinopathy

Neuropathy

Fig. 1  Schema of hyperglycemia’s induced pathways to microvascular complications. MAP, mitogen-activated protein

(SHP-1), and the reninangiotensin system (RAS) and kallikrein-bradykinin (BK) systems (Fig. 1). Although the structural alterations observed in diabetic capillaries do not affect the basal blood flow, some functional abnormalities of the microvascular circulation, which may eventually result in a relative ischemia, have been extensively documented. This aspect will be deeply discussed in the next section.

3 Pathophysiology of Microvascular Disease and Endothelial Dysfunction in Diabetes 3.1 Functional Changes Diabetes mellitus, even in the absence of complications, impairs the vascular reactivity, that

is the endothelium dependent and independent vasodilation, in the skin microcirculation [18]. Many glucose-related metabolic pathways can determine endothelium dysfunction: increased aldose reductase activity leading to the imbalance in nicotinamide adenine dinucleotide phosphate (NADP)/nicotinamide adenine dinucleotide phosphate, reduced form (NADPH); auto-­oxidation of glucose leading to the formation of reactive oxygen species (ROS); “advanced glycation end-products” (AGEs) produced by nonenzymatic glycation of proteins; abnormal n6-fatty acid metabolism and inappropriate activation of protein kinase C. All these different pathways lead to an increase of oxidative stress which is responsible for a reduced availability of nitric oxide and, in turn, for a functional tissue hypoxia and the development of diabetic chronic complications [19] (Fig. 2).

L. Chen and A. Veves

354 DIABETES

Hyperglycemia

DAG

Triglycerides LDL

Impaired n-6 fatty acid metabolism

Polyol pathway

Sugar autoxidation

Advanced glycation

PKC

OXIDATIVE STRESS

ENDOTHELIAL DYSFUNCTION

Capillary blood flow

endoneurial hypoxia

NERVE DYSFUNCTION

NCV,

Regeneration, Structural

Fig. 2  New concepts in the pathogenesis of diabetic neuropathy

3.2 Microvascular Dysfunction and Diabetic Neuropathy Microvascular reactivity is further reduced at the foot level in the presence of peripheral diabetic neuropathy. Endothelial nitric oxide synthase (eNOS) is a key regulator of vascular nitric oxide production. Immunostaining of foot skin biopsies in our unit, with antiserum to human eNOS, glucose transporter I (GLUT I), which is a functional marker of the endothelium and von Willebrand factor, an anatomical marker, showed no difference among diabetic patients with or without peripheral neuropathy in the staining of GLUT I and von Willebrand factor, while the staining for the eNOS was reduced in neuropathic patients (Fig.  3) [20]. Another study documented increased levels of iNOS and reduced eNOS lev-

els in skin from the foot of diabetic patients with severe neuropathy and foot ulceration [21]. Differences in the microcirculation between the foot and forearm levels have also been investigated, the main hypothesis being that increased hydrostatic pressure in distal microcirculatory beds, related to the orthostatic posture, affects the foot microcirculation more than at the forearm level. The endothelium-dependent and -independent vasodilation is, in fact, lower at the foot level when compared to the forearm in healthy subjects and both non-neuropathic and neuropathic diabetic patients [22]. This forearm–foot gradient exists despite a similar baseline blood flow at the foot and forearm level. Therefore, it is reasonable to believe that erect posture may be a contributing factor for the early development of the nerve damage at the foot, compared to the forearm.

Micro- and Macrovascular Disease in Diabetic Neuropathy Fig. 3  Expression of eNOS in patients with diabetic neuropathy (black columns), patients with both diabetic neuropathy and peripheral vascular disease (hatched columns) and healthy subjects (white columns). The expression of eNOS was reduced in both the diabetic groups compared to the healthy subjects

355

80

60

40

20

0

absent

Endoneurial microangiopathy was related to the severity of neuropathy, suggesting that there might be a causal relationship between impaired microvasculature and diabetic neuropathy [6, 23]. In a large observational study, it was found that endothelial function was a strong independent predictor of DPN [24]. Experimental data also showed that endothelium impairment could cause neuropathy through involvement of the Desert Hedgehog pathway [25].

3.2.1 Endothelium Dysfunction Previous studies have suggested that endothelium-­ dependent vasodilation is impaired in diabetes, regardless of the presence of long-term complications [26–28]. It has also been shown that endothelium dysfunction precedes the development of macro- and microvascular diabetic complications, indicating that endothelial impairment could be a critical factor toward the development of diabetic vascular complications [29]. However, these changes mainly involve the ability of microcirculation under stress, such as foot injury while they do not affect the baseline blood flow [20]. This feature, combined with the arteriovenous shunt that is present at the foot level due to autonomic neuropathy, can account for observations in clinical practice, in which, diabetic neuropathy with or without ulceration presents with a warm limb with distended veins and palpable

reduced

normal

pulses. The final result is that despite no reduction in the total lower extremity blood flow, there is functional ischemia that promoted injury and impairs wound healing.

3.3 Autonomic Denervation Autonomic nerve fibers take part in the modulation of blood circulation. At rest, noradrenergic sympathetic nerves are tonically active in normothermic environments and increase their activity during cold exposure, releasing both norepinephrine and co-transmitters to decrease skin blood flow [30]. Autonomic neuropathy can compromise the diabetic microcirculation because of the development of arterio-venous shunting due to sympathetic denervation. The opening of these shunts leads to a maldistribution of blood between the nutritional capillaries and subpapillary vessels, and consequent aggravation of microvascular ischemia. Studies employing sural nerve photography and fluorescein angiography as well as other elegant techniques seem to support this concept [31, 32]. In addition to the above, these changes also result in impaired thermoregulation [33]. A loss of sympathetic tone is also responsible for an increased capillary permeability in diabetic patients with neuropathy [34, 35]. This might

L. Chen and A. Veves

356 Fig. 4  The nerve axon reflex-related vasodilation or neurovascular response: stimulation of the c-nociceptive nerve fibers by acetylcholine or other noxious stimuli leads to antidromic stimulation of the adjacent c-fibers, which secrete Calcitonin Gene-Related Peptide (CGRP) that causes vasodilation and increased local blood flow

NERVE AXON REFLEX Acetylcholine

Nerve cell

Vasodilation

CGRP

cause endoneurial edema, as demonstrated by employing magnetic resonance spectroscopy, which can in turn represent another mechanism leading to a reduction of endoneurial perfusion and a worsening of the nerve damage [35]. The increased lower extremity capillary pressure upon assuming the erect posture, due to early loss of postural vasoconstriction (mediated by the sympathetic fibers), might amplify this edematous effect.

% 300

Diabetic somatic neuropathy can further affect the skin microcirculation by the impairment of the axon reflex-related vasodilatation (Lewis’ flare). Under normal conditions, the stimulus of the c-nociceptive nerve fibers not only travels in the normal direction, centrally toward the spinal cord, but also peripherally (“antidromic conduction”) to local cutaneous blood vessels, causing a vasodilatation by the release of vasoactive substances, such as calcitonin gene-related peptide (CGRP), Neuropeptide Y, substance P, and bradykinin by the c fibers initiate neurogenic inflammation (Fig. 4). This short circuit, or nerve axon reflex, is responsible for the Lewis’ triple flare response to injury and plays an important role in increasing local blood flow when it is mostly needed, i.e., in condition of stress.

268

200

100 29* 0

3.4 Nerve Axon Reflex

286

DN

41* DA

25* DV

DC

C

Fig. 5  The neurovascular response (expressed as percentage of blood flow increase over the baseline blood flow) is significantly reduced at the foot level of diabetic patients with peripheral somatic neuropathy (DN), autonomic neuropathy (DA), and peripheral artery disease (DV) compared to diabetic patients without complications (DC) and healthy controls (C) *p 65 years where lower doses are required because of risk of sedation, falls, and sudden cardiac death [72, 73]. SNRIs also target the serotonin noradrenergic system by inhibiting presynaptic reuptake of serotonin and noradrenalin, augmenting descending inhibitory pathways. Examples are duloxetine and venlafaxine. Most common adverse effects are nausea, somnolence, dizziness, constipation, and dry mouth; these side effects are often mild and transient. Recommended daily doses are 60–120 mg/day for duloxetine and 150–225 mg/ day for venlafaxine. The NNT for 50% pain reduction for SNRIs is 6.4 (95% CI 5.2–8.4) [20, 59].

Characteristics and Treatment of Painful Diabetic Neuropathy

The group of antidepressants should be tried for some time for pain relief before switching to another drug because lack of effect [69]. In patients with concomitant depression TCAs and SNRIs may have some effect on depressive symptoms [41]. Gabapentin and pregabalin have similar modes of action and bind to the α2δ subunit of the presynaptic voltage-gated calcium channels and thereby reduce Ca2+ influx resulting in decreased neurotransmitter release [20, 67]. The site of action can be peripheral, spinal, and supraspinal. The NNT for pregabalin is 7.7 (6.5; 9.4) and for gabapentin 7.2 (5.9; 9.1) [59]. Common side effects are dizziness, somnolence, peripheral edema, headache, and weight gain. Daily doses for gabapentin are 900–3600  mg daily in three doses starting with 300  mg/day and for pregabalin 300–600  mg in two doses starting with 75  mg/day. There are increasing concerns and evidence for misuse of gabapentin and pregabalin [74]. Topical treatment with capsaicin 8% and lidocaine 5% patches can be beneficial in a selected group of patients. Capsaicin binds to the transient receptor potential vanilloid 1 (TRPV1) on nociceptors desensitizing them for 12  weeks. Normally one to four patches are applied in the painful area for 30–60  min every 3  months. Lidocaine inhibits ectopic nerve activity by blocking voltage-gated sodium channels [20]. One to three lidocaine 5% patches are applied in the painful area for up to 12 h.

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[76, 78]. Tramadol, which is a centrally acting synthetic opioid working on both opioid and monoaminergic pathways, may be considered for flares of pain. A range of drugs have inconclusive evidence based on conflicting results from randomized trials, including lamotrigine, oxcarbazepine, topiramate, and selective serotonin-reuptake inhibitors, and thus there is no evidence to support their use for P-DPN, and further studies are needed to support their use, e.g. in specific subtypes of patients [59]. One study found oxcarbamazepine to be effective in a subgroup of patients with painful polyneuropathy and a sensory phenotype with preserved small-fiber sensation (cold and warm sensation and sensory hypersensitivity compared to those without), but these results have not been confirmed [79]. Recent systematic reviews find no evidence for the use of cannabinoids, cannabis, and cannabis-based medicines in chronic pain [80, 81]. The NeuPSIG guidelines have a weak recommendation against the use of cannabis-based medicines in neuropathic pain because of lack of effect in clinical trials, potential misuse, diversion, and long-term mental health risks [59].

3.6 Emerging Treatment Possibilities

Several drug classes are currently in clinical development for neuropathic pain, although to date, we have seen a failure in developing new drug classes for neuropathic pain [82, 83]. A 3.5 Other Pharmacological peripherally acting drug EMA401, which is a Treatment Options competitive antagonist to angiotensin II type 2 receptor, showed promising effects in peripheral Tramadol and strong opioids have also shown neuropathic pain [84], but recently phase 2 trials some effect in randomized controlled trials of have been terminated due to safety reasons. short duration, but are generally not recom- Antibodies targeting the activity of human nerve mended for the treatment of chronic non-­ growth factors are also in development for pain. malignant pain because of long-term Recombinant human nerve growth factor had no consequences, risk of abuse and dependence, effect on diabetic polyneuropathy in a large trial and lack of effect on functional status [75–78]. but showed some effect on pain in the legs, which If opioids are indicated for medium-term use, a was one of many secondary outcomes [85]. low dose in a monitored setting following local Tanezumab, a humanized monoclonal antibody opioid prescribing guidelines is recommended against nerve growth factor was found to reduce

448

P-DPN despite early study termination due to a partial clinical hold by the US Food and Drug Administration (FDA) due to joint-related safety [86], but currently the drug is only being developed for osteoarthritis and other pain types. Subtype-selective sodium channel inhibitors, in particular Nav1.7 blockers, are also being investigated for neuropathic pain.

4 Nonpharmacological Treatment The first treatment of neuropathic pain offered to patients is most often pharmacological, but it is also important to consider nonpharmacological treatment options, either as the only treatment or as an addition to medical treatment. With a general agreement of having P-DPN being associated with worse mental health, there are paradoxically few studies that have examined the effect of psychological treatment in P-DPN [39, 87]. Psychological therapy for chronic pain may consist of cognitive behavioral therapy (CBT), a traditional therapy form that helps patients to identify, change, and provide coping strategies for negative thoughts or behavior associated with pain. Another therapy form derived from CBT also used in the treatment of pain is acceptance and commitment therapy (ACT) which integrates acceptance, cognitive defusion, and mindfulness to produce more psychological flexibility [88]. In a recently published single arm primarily feasibility trial with online ACT treatment in patients with P-DPN the clinical outcomes showed beneficial effect on psychological functions and pain intensity, although the study has limitations due to design [89]. In a newly updated systematic review of the effect of psychological therapies on the broad spectrum of chronic pain, compared to standard treatment or waiting list, there was only very small to small beneficial effect of CBT in pain reduction, disability, and stress [90]. In separate studies of neuropathic pain and P-DPN the evidence was too sparse and insufficient to make any conclusions on the effect of psychological treatment in pain relief [39, 87]. Therefore psychological treatment

S. S. Gylfadottir and N. B. Finnerup

may have a place in the treatment of painful DPN although the evidence is sparse. Physiotherapy treatment options can be aimed at pain reduction, preserve function level, and prevent immobilization or it can consist of therapeutic exercise [91]. In a qualitative study, patients with P-DPN described walking difficulties and other impacts of pain on physical functions [92]. A review of physical therapy in chemotherapy induced neuropathy showed that there was possible a symptom effect, although with limited evidence [93]. In general, physical activity in adjutancy to other treatments or alone could have positive effects on P-DPN, although the evidence is limited with a high risk of bias [94, 95]. Yoga, mindfulness, and meditation are gaining increased popularity as a treatment option in various conditions, often for the improvement of mental health and quality of life, but data on the efficacy for pain relief are few or missing in the treatment of neuropathic pain, the same is for acupuncture [95–97]. Neurostimulation has been used as a treatment option in P-DPN. Examples are spinal cord stimulation (SCS) and transcutaneous electrical stimulation (TENS). According to the newly published guidelines from the European Academy of Neurology (EAN), there is weak evidence for adding spinal cord stimulation (SCS) to the pharmacological treatment in P-DPN compared with pharmacological treatment alone [98] and a recent meta-analysis including randomized controlled trials concluded that SCS was effective for pain relief compared to standard care [99]. A Cochrane review of TENS treatment for neuropathic pain could not conclude whether the treatment was effective compared to sham therapy or not, because of the size and quality of the included studies, neither were side effects nor adverse events adequately addressed in the studies [100].

5 Conclusion Painful neuropathy is a common and often disabling consequence of diabetes. It is a neuropathic pain and is caused by the lesion of the

Characteristics and Treatment of Painful Diabetic Neuropathy

peripheral nerves. The pharmacological treatment is challenging and often provides only partial pain relief at best. Therefore both nonpharmacological and pharmacological treatments are recommended.

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of pregabalin and gabapentin: a systematic review update. Drugs. 2020;81:125. 75. Franklin GM.  Opioids for chronic noncancer pain: a position paper of the American Academy of Neurology. Neurology. 2014;83:1277–84. 76. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain--United States, 2016. JAMA. 2016;315:1624–45. 77. Hoffman EM, Watson JC, St Sauver J, Staff NP, Klein CJ. Association of Long-term Opioid Therapy With Functional Status, adverse outcomes, and mortality among patients with polyneuropathy. JAMA Neurol. 2017;74:773–9. 78. Ballantyne JCBS, Blyth F, Cordosa M, Finley A, Furlan A, et  al. https://www.iasp-­pain.org/ Advocacy/OpioidPositionStatement.2018. Accessed 19 Jan 2021. 79. Demant DT, Lund K, Vollert J, et  al. The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: a randomised, double-­ blind, placebo-controlled phenotype-stratified study. Pain. 2014;155:2263–73. 80. Fisher E, Moore RA, Fogarty AE, et al. Cannabinoids, cannabis, and cannabis-based medicine for pain management: a systematic review of randomised controlled trials. Pain. 2020;162:S45. 81. Moore RA, Fisher E, Finn DP, et al. Cannabinoids, cannabis, and cannabis-based medicines for pain management: an overview of systematic reviews. Pain. 2020;162:S67. 82. Attal N, Bouhassira D.  Translational neuropathic pain research. Pain. 2019;160(Suppl 1):S23–s28. 83. Yekkirala AS, Roberson DP, Bean BP, Woolf CJ. Breaking barriers to novel analgesic drug development. Nat Rev Drug Discov. 2017;16:545–64. 84. Rice ASC, Dworkin RH, McCarthy TD, et  al. EMA401, an orally administered highly selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic neuralgia: a randomised, double-blind, placebo-controlled phase 2 clinical trial. Lancet. 2014;383:1637–47. 85. Apfel SC, Schwartz S, Adornato BT, et al. Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy: a randomized controlled trial. rhNGF Clinical Investigator Group. JAMA. 2000;284:2215–21. 86. Bramson C, Herrmann DN, Carey W, et  al. Exploring the role of tanezumab as a novel treatment for the relief of neuropathic pain. Pain Med. 2015;16:1163–76. 87. Eccleston C, Hearn L, Williams AC. Psychological therapies for the management of chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2015;2015:CD011259. 88. Hayes SC, Luoma JB, Bond FW, Masuda A, Lillis J. Acceptance and commitment therapy: model, processes and outcomes. Behav Res Ther. 2006;44:1–25. 89. Kioskli K, Scott W, Winkley K, Godfrey E, McCracken LM. Online acceptance and commitment therapy for people with painful diabetic neuropathy

452 in the United Kingdom: a single-arm feasibility trial. Pain Med. 2020;21:2777–88. 90. Williams ACC, Fisher E, Hearn L, Eccleston C.  Psychological therapies for the management of chronic pain (excluding headache) in adults. Cochrane Database Syst Rev. 2020;8:CD007407. 91. Akyuz G, Kenis O.  Physical therapy modalities and rehabilitation techniques in the management of neuropathic pain. Am J Phys Med Rehabil. 2014;93:253–9. 92. Brod M, Pohlman B, Blum SI, Ramasamy A, Carson R.  Burden of illness of diabetic peripheral neuropathic pain: a qualitative study. Patient. 2015;8:339–48. 93. Jesson T, Runge N, Schmid AB. Physiotherapy for people with painful peripheral neuropathies: a narrative review of its efficacy and safety. Pain Rep. 2020;5:1–e834. 94. Singleton JR, Smith AG, Marcus RL.  Exercise as therapy for diabetic and prediabetic neuropathy. Curr Diab Rep. 2015;15:120. 95. Davies B, Cramp F, Gauntlett-Gilbert J, Wynick D, McCabe CS. The role of physical activity and psychological coping strategies in the management of

S. S. Gylfadottir and N. B. Finnerup painful diabetic neuropathy--a systematic review of the literature. Physiotherapy. 2015;101:319–26. 96. Baute V, Zelnik D, Curtis J, Sadeghifar F.  Complementary and alternative medicine for painful peripheral neuropathy. Curr Treat Options Neurol. 2019;21:44. 97. van Laake-Geelen CCM, Smeets R, Quadflieg S, Kleijnen J, Verbunt JA. The effect of exercise therapy combined with psychological therapy on physical activity and quality of life in patients with painful diabetic neuropathy: a systematic review. Scand J Pain. 2019;19:433–9. 98. Cruccu G, Garcia-Larrea L, Hansson P, et al. EAN guidelines on central neurostimulation therapy in chronic pain conditions. Eur J Neurol. 2016;23:1489. 99. Amato Nesbit S, Sharma R, Waldfogel JM, et  al. Non-pharmacologic treatments for symptoms of diabetic peripheral neuropathy: a systematic review. Curr Med Res Opin. 2019;35:15–25. 100. Gibson W, Wand BM, O’Connell NE. Transcutaneous electrical nerve stimulation (TENS) for neuropathic pain in adults. Cochrane Database Syst Rev. 2017;9:CD011976.

Orthostatic Hypotension and Sudomotor Dysfunction in Diabetes Lauren F. Fanty and Christopher H. Gibbons

1 Introduction Diabetic autonomic neuropathy (DAN) is the leading cause of autonomic neuropathy in the USA. There are multiple mechanisms underlying the pathophysiology of diabetic neuropathy including neurovascular insufficiency, metabolic insult to nerve fibers, neurohormonal growth factor insufficiency, and bioenergy failure [1]. Generalized DAN typically is gradual in onset and leads to progressive autonomic impairment to vasomotor (vascular), visceromotor (gastrointestinal), parasympathetic, sympathetic adrenergic, and sympathetic cholinergic autonomic fibers [2–4]. Clinical features are broad, as DAN affects the cardiovascular, gastrointestinal, pupillomotor, thermoregulatory, sudomotor, and urogenital systems. Many large epidemiologic studies have established the increased morbidity, mortality, and sudden death in patients with diabetic autonomic neuropathy [4–9]. The prevalence of diabetic autonomic neuropathy varies depending on diagnostic criteria, patient cohort, and testing modality with esti-

mates ranging from 7% to 90% [10]. Prevalence of autonomic impairment also varies between the types of diabetes, with an estimated prevalence of 54% and 73% in type 1 and type 2 diabetes, respectively [10]. Cardiac autonomic neuropathy (CAN) is the most life-threatening form of diabetic autonomic neuropathy with a 56% 10-year mortality [5, 10, 11]. In CAN, Vagus nerve denervation leads to reduced heart rate variability and presents initially as a resting tachycardia [6]. With continued disease progression, sympathetic cardiac denervation leads to orthostatic hypotension and chronotropic incompetence [6, 12, 13]. Sudomotor (sweating) dysfunction is often comorbid with CAN and one of the earliest signs of DAN. Sudomotor dysfunction typically occurs in a length-dependent fashion, often in parallel with sensory neuropathy. In DAN, orthostatic hypotension is due to sympathetic adrenergic failure, while sudomotor dysfunction function is due to sympathetic cholinergic failure [6]. This chapter will focus on the pathophysiology, clinical presentation, diagnosis, and treatment of orthostatic hypotension and sudomotor dysfunction in patients with diabetes.

L. F. Fanty Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

2 Orthostatic Hypotension

C. H. Gibbons (*) Beth Israel Deaconess Medical Center, Boston, MA, USA e-mail: [email protected]

Orthostatic hypotension, OH, is defined as a fall in systolic blood pressure (SBP) of 20 mmHg or fall in diastolic blood pressure (DBP) of 10 mmHg

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 S. Tesfaye et al. (eds.), Diabetic Neuropathy, Contemporary Diabetes, https://doi.org/10.1007/978-3-031-15613-7_26

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within 3  min of standing or a head-up tilt to at least 60° on a tilt table [14]. It is one of the most incapacitating manifestations of autonomic failure [6]. Orthostatic hypotension in isolation may be a clinical sign indicating a variety of medical conditions such as severe anemia, intravascular volume depletion, physical deconditioning, antihypertensive medication use, or impairment of peripheral vasoconstriction [15, 16]. Neurogenic orthostatic hypotension, nOH, is a subset of OH that occurs when the autonomic nervous system fails to provide sufficient autonomic postural response via sympathetic vasoconstriction and fails to increase heart rate to maintain blood pressure [15]. In diabetes, there is degeneration of sympathetic pre- and postganglionic fibers leading to failure in both the vagal and adrenergic limbs of the baroreflex resulting in nOH [6]. In a normal response to moving to the upright position, there is an increase in plasma norepinephrine as well as increased cardiac output and peripheral vasoconstriction. In nOH, there is impaired release of peripheral norepinephrine with impaired peripheral vasoconstriction and impaired cardiac acceleration in response to a fall in blood pressure [17, 18]. Inadequate blood pressure response is most often attributable to decreased norepinephrine released from postganglionic sympathetic nerves leading to pooling of blood in the splanchnic region, pelvis, and dependent areas [15]. Compensatory increase in heart rate when standing from a seated position is augmented by norepinephrine and sympathetic nerve endings, which may also be impaired with sympathetic dysfunction [6, 19]. The Rochester Diabetic Study, which evaluated a cohort of 83 Type I diabetics and 148 Type II diabetics, found that of the approximately 50% of patient with clinical manifestations of neuropathy, about 10% additionally had clinical evidence of autonomic neuropathy [20, 21]. Orthostatic hypotension was present in 8.4% of type 1 diabetics and 7.4% of type 2 diabetics [2, 20, 21]. Other estimates report the prevalence of orthostatic hypotension to be as high as 20–25% in patients with long term diabetes [2]. A symptom that is sometimes associated with nOH is worsening of orthostatic tolerance after eating secondary to a drop in blood pressure,

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known as postprandial hypotension. Postprandial hypotension is defined as a fall of at least 10 mmHg within 2 h of eating [22]. This is caused by degeneration of the fibers supplying the splanchnic mesenteric bed, a large vascular bed that increases in volume by 200–300% after a carbohydrate heavy meal, resulting in orthostatic stress from venous pooling [22]. Normally, this increase in volume is compensated for by an increase in sympathetic response leading to splanchnic vasoconstriction [19]. However, this compensatory mechanism is deficient in patients with nOH. Supine hypertension is another common complication detected in an estimated 50% of patients with nOH [15]. Supine hypertension is defined as a supine SBP  ≧  150 or DBP  ≧  90 [15, 16]. In patients with supine hypertension, a reduction in SBP of 30 mmHg or DBP of 15 mmHg may be a more appropriate criterion for nOH [15]. Supine hypertension is a product of both impaired baroreflex function and chronically increased activation of the renin–angiotensin system from orthostatic hypotension [15, 19]. nOH and supine hypertension are associated conditions with the same underlying pathophysiology but create a challenge to effectively treat both conditions simultaneously [15, 19]. While our focus of discussion will be on nOH secondary to disruption of peripheral sympathetically mediated reflex vasoconstriction attributed to diabetic neuropathy, it is important to note that other neuropathies, neurodegenerative disorders, and high spinal cord lesions also affect peripheral sympathetic neurons [19]. Some neurodegenerative disorders, such as multiple systems atrophy, affect central sympathetic neurons resulting in nOH from central autonomic dysfunction, which will not be a focus of this chapter [15].

3 Clinical Presentation and Initial Evaluation The prevalence of orthostatic hypotension in diabetes is estimated to range from 6% to 30% and increases with age, disease duration, and disease control [2, 6, 23]. It is more common in institutionalized than community dwelling elderly and is

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normally a late manifestation of cardiovascular autonomic neuropathy [10]. Neurogenic OH can be either symptomatic or asymptomatic, thus ­creating a barrier to both recognition and treatment [24]. It is the recommendation of the American Autonomic Society that patients with peripheral neuropathies known to be associated with autonomic dysfunction, such as diabetes, be screened for nOH [15]. At minimum, patients should be asked if they have symptoms, they commonly experience within 3–5 min of standing that resolve when sitting or lying down. There are additionally different variants of OH, and while some occur within the first 15  s of standing (initial OH), delayed OH occurs after 3 min of standing [15]. Please see Table 1 for a full list of recommended screening questions in patients with suspect nOH.

3.1 Symptoms Orthostatic hypotension is thought to be one of the most incapacitating manifestations of autonomic failure [6]. Symptoms are limited to standing and resolve when sitting or lying down. Inadequate perfusion of the brain may cause dizziness, lightheadedness, cognitive slowing, blurry or dimmed vision, “coat hanger” pain in Table 1  Screening questions for patients with suspect orthostatic hypotension 1. Have you fainted/blacked out recently? 2. Do you feel dizzy or lightheaded upon standing? 3. Do you have vision disturbances when standing? 4. Do you have difficulty breathing when standing? 5. Do you have leg buckling or leg weakness when standing? 6. Do you ever experience neck pain or aching when standing? 7. Do the above symptoms improve or disappear when you sit or lay down? 8. Are the above symptoms worse in the morning or after meals? 9. Have you experienced a fall recently? 10. Are there any other symptoms you commonly experience when you stand up or within 3–5 min of standing and get better when you sit or lay down? Any of the questions that are answered “yes” should prompt measurement of orthostatic vital signs Adapted from Gibbons et al. 2017 [15]

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the upper body, fatigue, dyspnea, chest pain, and syncope [16]. Patients may also report worsening of symptoms during exercise, within 2 h of eating, or that symptoms are exacerbated by large, carbohydrate rich meals and alcohol [16]. Symptoms may show diurnal variability (worse in the morning) and are influenced by hydration and ambient temperature [14, 15].

3.2 Initial Steps If any of the screening questions for OH are positive, orthostatic vitals should be obtained in the clinic. If possible, have patients track their orthostatic vital signs at home upon awakening, when symptomatic, and prior to bedtime for around a week to aid in accurate clinical assessment of the condition [15]. In addition to recording changes in blood pressure, orthostatic changes to heart rate should be evaluated. A change in heart rate of 0.5  beats/min/mmHg is suggestive of non-­ neurogenic cause of orthostatic hypotension [25]. The relevance of the heart rate ratio was evaluated in a prospective study of 423 patients and neurogenic OH was reliably distinguished from other causes of OH when the ΔHR/ΔSBP ratio at 3  min of tilt was 80% of cases of severe gastroparesis resistant to conventional therapy, which are, not surprisingly, heterogeneous. The dominant abnormalities, in addition to changes in vagal innervation, are loss or damage to the Interstitial Cells of Cajal (ICC), which are integral to the function of the gastric ‘pacemaker’ [58], an immune infiltrate in the myenteric plexus, a reduction in intrinsic nerves and loss of inhibitory neurons expressing nitric oxide synthase (nNOS) (Fig. 2). The basal lamina a

around smooth muscle cells and nerves has been noted to be characteristically thickened [58]. The cause of the loss of ICCs, which is now regarded as the ‘dominant’ abnormality in diabetic gastroparesis, remains uncertain but may be secondary to changes in immune function with a shift from protective M2 to, activated, M1 macrophages, reductions in insulin or IGF-1 signalling and the production of stem cell factor [54], and impaired regulation of heme-oxygenase-1, resulting in increased oxidative stress [60, 61]. The expression of the Ano-1 gene, expressed in the ICCs and which encodes a calcium-activated chloride channel, may also be abnormal [62]. Abnormal duodenal mucosal mitochondrial gene expression has recently been reported to be associated with a delay in gastric emptying [63], suggesting that mitochondrial function may be important. While it should be appreciated that the studies of the Gastroparesis Clinical Research Consortium relate primarily to patients with severe gastroparesis, the heterogeneous nature of the abnormalities demonstrated has substantial implications for effective management. b

Fig. 2  Haematoxylin and eosin staining of the inter-­ myenteric plexus (original magnification 340) in a patient myenteric plexus from patients with gastroparesis. (a) with severe diabetic gastroparesis [59]. (Figure courtesy Normal ganglia and nerve fibres (original magnification of Prof H Parkman) 340). (b) Moderate lymphocytic infiltrate in the inter-­

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4.3 Effects of the Glycaemic Environment on Gastric Emptying

but significant, effect to slow gastric emptying of both solids and liquids in longstanding type 1 diabetes, measured using scintigraphy in 1990 [65] and, subsequently, elevations in blood gluAcute changes in the blood glucose concentra- cose within the normal postprandial range were tion represent a reversible determinant of the rate shown to delay gastric emptying modestly in of gastric emptying in diabetes [64–66], so that uncomplicated type 1 diabetes [64]. Acute elevagastric emptying is slowed by hyperglycaemia tions in blood glucose were also shown to attenuand accelerated by insulin-induced hypoglycae- ate the effects of drugs which accelerate [70], mia [24]. Accordingly, the relationship of gastric potentiate the effects of drugs that delay, gastric emptying with glycaemia is bidirectional (Fig. 3). emptying [71], and affect both gastro-­ Guidelines for measurement of gastric emptying pyloroduodenal motility [72] and gastric electristate that blood glucose concentrations should be cal activity, in health. Prostaglandins [73] and 1.4–1.6 ng/mL. Specialist evaluation and prostate cancer screening, assessment of sexual function, and proper counseling on the possible impact on sexual function are advisable in patients with diabetes prior to prescription [63]. When indicated, surgery can be performed, taking into account in preoperative counseling that diabetes is associated with some persistence of LUTS and voiding dysfunction at 3 months after surgery [64]. 2.6.3 Treatment of Urgency, Detrusor Overactivity, and Urgency Incontinence Muscarinic receptor antagonists (antimuscarinics) are the cornerstone of treatment of storage symptoms in the general population and can be also offered to patients with diabetes. All available formulations have similar clinical efficacy

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[65]. M3 selective inhibitor darifenacin has shown similar efficacy in patients with overactive bladder and diabetes vs. those without comorbidities, and a similar class effect for all antimuscarinics might be suggested [65]. Patients’ counseling on side effects like xerostomia, constipation, dizziness, blurred vision, nasopharyngitis, and occasionally tachycardia is advisable, as well as on the possible worsening effect on post-void residual, which requires regular voiding symptoms monitoring and 1-month re-­evaluation and represents a contraindication if ≥150 mL. Combination therapy of antimuscarinics with α1-blockers can be effective in men with moderate-severe LUTS not responding to a single first-line drug, taking into account the safety profile of both. Mirabegron is the only licensed oral β-3 adrenoceptor agonist with efficacy in treating voiding frequency, urgency, and urgency incontinence in the general population. A pooled analysis of trials showed a better tolerability profile compared to antimuscarinics in elderly patients [66], with less xerostomia and constipation. However, hypertension, headache, and nasopharyngitis are drug specific adverse effects, while severe uncontrolled hypertension is a contraindication. Evidence on combination therapy with mirabegron is lacking. Electrical neuromodulation is a therapeutic option in patients with an overactive bladder. Tibial nerve stimulation (TNS), via a percutaneous or transcutaneous approach, delivers electrical stimuli to the sacral micturition center via the S2-S4 sacral nerve plexus through a fine gauge needle or a patch positioned above the medial malleolus. Treatment is performed in an outpatient setting in cycles of 10–12 onceweekly stimulations of 30 min. TNS was effective and comparable to the antimuscarinic drug tolterodine in females with urgency urinary incontinence [67, 68] and also effective in those not benefiting from antimuscarinics. TNS is a minimally invasive and safe option available as a second therapeutic line or in combination with oral treatment. However, data on the long-

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term durability of treatment [69] and on the efficacy in patients with diabetes are needed. Implantation of a permanent sacral neuromodulator (SNM) seems to modulate spinal cord reflexes and brain networks by peripheral afferents. It was similarly effective in patients with diabetes as in those without in a 29-month follow-up study, with ­success rates of 69.2% for urgency urinary incontinence and 85.7% for urgency-frequency [70]. The finding of a higher number of explants due to infection in patients with diabetes in this study (16.7% vs. 4.3%) [70] was not however confirmed in another study (3.1% vs. 6.8%) [71]. While studies comparing TNS and SNM are lacking, lower risk profile, minimally invasive nature, and lower (initial) costs might favor TNS, although SNM was more intensively investigated. Patient preference and compliance are other aspects to consider when choosing the neuromodulation procedure. OnabotulinumtoxinA (onabotA) injection in the detrusor muscle represents a well-established therapeutic alternative for refractory detrusor overactivity and urgency incontinence both in the idiopathic and neurogenic forms. The procedure is minimally invasive (by cystoscopy under local anesthesia) and can be performed in the outpatients setting. In a retrospective study, onabotA obtained in 48 patients with diabetes and refractory detrusor overactivity a similar success rate as in patients without diabetes (56% vs. 61%), but those with diabetes had a higher 6 month rate of large post-void residual and of general weakness [72]. Thus, patients should receive preliminary information on the drug safety profile and adequate training in clean intermittent catheterization if motivated to start treatment. Augmentation cystoplasty is another option to treat refractory detrusor overactivity. No data are available on comparison of this alternative with SNM or onabotA injection in the general or diabetic population. Urinary diversion is the last surgical choice to treat symptoms that are refractory to any other therapeutic approach.

Diabetic Neuropathy: Clinical Management—Genitourinary Dysfunction in Diabetes

2.6.4 Treatment of Detrusor Underactivity Despite preclinical studies with cholinergic drugs and intravesical cannabinoids, no pharmacological treatment has been validated for detrusor underactivity. Clean intermittent self- or aided-­ catheterization still represents the preferred option for patients with underactive detrusor and high post-void residual or no detrusor contractility. Treatment reduces bacteriuria and infections compared to indwelling catheterization [73]. Frequency of daily catheterizations should be tailored to symptoms and degree of underactivity and to maintain voiding volumes less than 400– 500 mL. Patient education on technique is essential and a third-party catheterization for patients with poor manual dexterity or cognitive dysfunction is a preferable option to indwelling catheterization. In a systematic review, TNS showed limited efficacy in patients with idiopathic non-­ obstructive urinary retention with an objective success rate (reduction in number of catheterizations or catheterized volume) up to 41% and a subjective success rate (patient’s request for continued chronic treatment) up to 59% [55]. No studies are available in patients with diabetes. SNM represents a therapeutic option in patients with diabetes and detrusor underactivity with a success rate of 66.7% [70] but with a possible increased risk of infection. SNM might enable simultaneous pancreas and kidney transplantation in candidate patients with detrusor acontractility requiring clean intermittent catheterization and at high risk of recurrent urinary infections by restoring voiding and preventing urinary infections [74]. 2.6.5 Treatment of Stress Urinary Incontinence The selective serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine increases the stimulation of the spinal cord receptors of the pudendal motor neurons and improves the resting tone and contraction strength of the striated urinary sphincter. Duloxetine was found to improve female stress urinary incontinence and related QoL. Side effects are nausea and vomiting, xero-

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stomia, constipation, dizziness, insomnia, somnolence, and fatigue and can lead to premature discontinuation [75]. Surgical treatment includes, depending on the underlying cause of incontinence, adjustable continence therapy balloons, urethral slings, artificial urinary sphincter, and other open or laparoscopic assisted incontinence surgeries with progressively increasing invasiveness. The surgical procedure should be tailored to the patient and performed by expert functional urologist in referral centers. As for other prosthetic implants, diabetes and obesity were associated with mesh erosion for trans-vaginal and trans-obturator sling surgery [76]. Stress urinary incontinence rarely occurs in males unless as a consequence of prostatic surgery. Surgical options are similar in the general and diabetic populations and include balloons, slings, and artificial sphincter implantation. Figure 2 presents a therapeutic algorithm for bladder dysfunction in diabetes.

2.7 Barriers to Effective Management of Diabetic Bladder Dysfunction Despite significant advancement in the last two decades, the natural history and pathophysiology of diabetic bladder dysfunction are still poorly known. It remains underrepresented in research, epidemiological studies do not adopt standardized diagnostic criteria and are most cross-­ sectional, therapeutic trials are very few, thus limiting the possibility to build treatment evidence, with data on tolerability and treatment adherence very limited. Cost-effectiveness studies on diagnostic and treatment pathways are lacking and awareness of bladder dysfunction is not widespread in clinical practice. Diagnosis often occurs at an advanced stage, and management is almost exclusively in the hands of urologists [56]. Nonetheless, the evidence of a beneficial role of the lifestyle intervention, of glycemic control and even of the choice of antihyperglycemic drugs [77] as well as the prognostic cardiovascular meaning of the LUTS in males

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[6], points to the need for a holistic and multidisciplinary approach to the prevention and management of diabetic bladder dysfunction (including the general practitioner, urologist, endocrinologist, neurologist, gynecologist, and cardiologist).

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3.1 Epidemiology of Diabetic Erectile Dysfunction

those without [80]. Moreover, although related to age and diabetes duration, ED starts early in diabetes, might be present in 32% of patients with recently diagnosed type 2 diabetes, as documented by SUBITO-DE study [83], and may be associated with undiagnosed diabetes, as in the NHANES study, with an odds ratio of 2.2 that reached a value of 8.7  in the 40–59 age group [84]. The MMAS provided an incidence rate of ED of 26 cases/1000 man-years [85]. In Italian men with diabetes the incidence of ED was 68 cases/1000 person-years, more than twice that seen in the MMAS [86]. In summary, both the prevalence and incidence of ED are more than tripled and doubled, respectively, in males with diabetes compared to healthy people. ED develops 10–15 years earlier in men with diabetes. ED starts early in diabetes and can be present at diabetes diagnosis or even precede it.

3.1.1 Prevalence of Diabetic Erectile Dysfunction According to the Fourth International Consultation on Sexual Medicine [78] ED is defined as the consistent or recurrent inability to attain and/or maintain penile erection sufficient for sexual satisfaction. In the population-based Massachusetts Male Aging Study (MMAS), the prevalence of moderate and severe ED was 35% [79]. Many studies documented an association between ED and diabetes. A meta-analysis of 145 studies showed a prevalence of ED of 59.1% in diabetes, of 37.5% in type 1 diabetes and of 66.3% in type 2 diabetes [80]. This meta-analysis highlighted the heterogeneity of the included studies with regard to the prevalence rate (from 35% to 80%), the countries, the diagnostic approach, and the information on diabetic complications. In the eight studies comparing men with diabetes and healthy controls, the prevalence was 51.6% and 25.5%, respectively, with an odds ratio for ED of 3.62 [80]. In a large Italian cross-sectional study, the mean prevalence of ED in men with diabetes was 35.8% [81], compared to 12.8% in the general population [82]. Available data suggest that ED develops in people with diabetes 10–15 years earlier than in

3.1.2 Clinical Correlates, Comorbidities, and Risk Factors of Diabetic Erectile Dysfunction Population-based studies have shown that in addition to age, clinical correlates or comorbidities of ED were pelvic surgery, diabetes (an age-­ adjusted odds ratio of 3.95), LUTS, hypertension, heart disease, heavy smoking, and depression, with instead a protective role of education, physical activity, and alcohol drinking [87, 88]. Clinical correlates of ED in diabetes were found to be advancing age, diabetes duration, poor glycemic control, hypertension, hyperlipidemia, sedentary lifestyle, smoking, and diabetic complications [89]. However, in the cited meta-­ analysis by Kouidrat et al. [80] only hypertension was a moderator of ED presence in men with diabetes. When considering longitudinal studies, in the MMAS, lower levels of education, diabetes, heart disease, and hypertension were independent predictors of ED [85], while in people with diabetes, age, diabetes duration, renal disease, and hypertension played a predictive role for ED [86]. In the UroEDIC II study, ED was present in 45% of men with type 1 diabetes and in more than half the cases it was associated with other urological complications, with age, poorer glyce-

3 Male Sexual Dysfunction in Diabetes Male sexual dysfunction includes ED, abnormalities of orgasmic, ejaculatory function, sexual desire, enjoyment, and failure of genital response. Although diabetes may well affect different aspects of sexual health, most attention has been focused on ED.

Diabetic Neuropathy: Clinical Management—Genitourinary Dysfunction in Diabetes

mic control, and other diabetic complications including CAN [10]. Moreover, during a 16-year follow-up the rate of incident ED was 43.4 cases per 1000 person-years [90]. Risk of ED increased by 21% with each 10 mmHg of systolic BP elevation but only in those not under antihypertensive medications [90]. Similarly, in type 2 diabetes in the Look AHEAD trial, at a cross-sectional level, every 10 mmHg increase in systolic/diastolic BP was associated with a 30%/10% increased prevalence of ED [91]. In summary, in men with diabetes, clinical correlates of ED are age, diabetes duration, glycemic control, hypertension, hyperlipidemia, sedentary lifestyle, smoking, diabetic complications, and LUTS, with age, duration, glycemic control, hypertension, and renal disease being longitudinal predictors of ED, and with an overall prominent role of hypertension. Depression and QoL In the general population, depression is common among patients with ED with a frequency ranging from 8.7% to 43.1% [92], with an interrelationship between depression and ED [92]. Depression and diabetes share reciprocal susceptibility and comorbidities and the prevalence of symptoms of depression in patients with diabetes is around 30% [93]. In this context, the effect of ED on mental health is of extreme relevance. In the SUBITO-DE study, ED and severe depression were already associated in patients with newly diagnosed type 2 diabetes [83]. In Italian QuED study in type 2 diabetes, ED was associated with higher diabetes-specific health distress, worse psychological adaptation to diabetes, severe depressive symptoms (present in 45.6% of patients with frequent ED), lower scores in the mental components of QoL, and a less satisfactory sex life [94]. The impact of ED on QoL was independent of the presence of depression [94]. After 3 years of follow-up, a worsening of physical functioning scores was observed only in patients with ED at baseline, while the newly developed ED was preceded by a deterioration in all QoL dimensions and a worsening in depressive symptoms and was in turn associated with an increase in depressive symptoms and decrease in

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QoL [95]. In the UroEDIC study, at EDIC year 17, the presence of ED was associated with worse QoL (an odds ratio of 3.01) and higher level of psychiatric symptoms independently of depression or microangiopathic complications [96]. Moreover, men with history of effective treatment of ED had almost identical QoL as those who had never experienced ED [96]. Possible mechanisms linking depression and ED in diabetes are both biological and psychological and might also include hypogonadism, autonomic dysfunction, and the presence of comorbidities. In summary, in the diabetic scenario where depression and diabetes already have a reciprocal relationship, the presence of ED increases the risk of depression and vice versa, the association might be present at diagnosis of type 2 diabetes. ED has an adverse impact on QoL, independent of depression, with a tripled risk of having low QoL in type 1 diabetes. The relationship, also in this case, is bidirectional given that ED predicts low QoL and low QoL (together with depression) predicts the development of ED. Cardiovascular Disease There is enough evidence that ED shares the same risk factors as cardiovascular diseases and in addition, ED in itself is actually considered an early sign of forthcoming cardiovascular disease with a time window of 2–5 years before its development [97]. At least five meta-analyses have confirmed the association between metabolic syndrome and its components with up to 2.6-fold increase in ED, in particular fasting blood glucose [98] and hypertension [99, 100]. Past and current smoking and cannabis use were associated with higher risk, while physical activity and moderate alcohol exerted a protective role in other meta-analyses focused on these lifestyle factors [97, 101]. Conversely, two large meta-­ analyses showed that ED was associated with increased risk of cardiovascular disease, coronary heart disease, stroke, and all-cause mortality with the highest pooled relative risk of coronary heart disease (up to 1.62) [102, 103]. Moreover, the risk associated with ED was higher at younger ages, and a grading effect of ED severity in predicting cardiovascular events was suggested

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[103]. In the ED population not only conventional cardiovascular risk factors but also other factors may increase the cardiovascular risk including organic factors such as low testosterone and PRL levels, psychological and relational aspects like depression and reduced sexual intercourse [97]. In summary, cardiovascular disease increases the risk of ED in diabetes, and in the general population there is evidence that (1) traditional cardiovascular risk factors increase the risk of ED, (2) lifestyle changes are able to improve ED, (3) ED is associated with a relative risk of developing cardiovascular disease ranging from 1.34 to 1.62 (a magnitude similar to that of main cardiovascular risk factors), and (4) ED can be considered a low-cost biomarker for the need for more intensive cardiovascular risk factor modification.

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gonadism associated with both ED and cardiovascular morbidity [97].

Diabetic Neuropathy Considering, among the many available studies, those with larger sample sizes and standard assessment of CAN and ED, the overall findings suggest that CAN is associated with ED [9, 81, 109]. In a cross-sectional Italian study, peripheral vascular disease, cardiac disease, nephropathy, autonomic neuropathy, polyneuropathy, diabetic foot, and retinopathy were all independent correlates of ED in diabetes, with the greatest odds for autonomic neuropathy (4.3 vs. 3.6, 3.0 and 2.5 of diabetic foot, polyneuropathy, and arteriopathy) [81]. However, in a subsequent 2.8-year follow-up study, the relative risk of ED associated with autonomic neuropathy was 1.16 compared to 3.79 of diabetic foot, 2.02 of coronary artery disease, 1.97 of renal disease, 1.86 of polyMechanisms Linking Erectile Dysfunction neuropathy, and 1.75 of peripheral vascular disand Cardiovascular Risk ease [86]. In the UroEDIC study, ED development The common risk factors, their mutual associa- at EDIC year 17 was associated with lower cartion, and the role of ED as a harbinger of cardio- diovascular reflex tests (CARTs) at DCCT closevascular events suggest a shared out and EDIC year 16/17 [9]. CAN diagnosis at pathophysiological basis. The first link is vascu- EDIC year 16/17 was associated with 2.65 greater lar disease: the artery size hypothesis suggests adjusted odds of ED or LUTS (not of ED only) that an equally sized atherosclerotic plaque [9]. In the same cohort at EDIC year 17, CAN would be tolerated less and compromise flow had unadjusted odds for ED of 2.82 [10]. more in the smaller penile arteries than in coroRegarding diabetic polyneuropathy, the nary arteries, which is the reason why ED will UroEDIC study showed an association between precede by 2–5  years coronary artery disease confirmed diabetic polyneuropathy and ED [104]. Another possibility regards an impairment [110]. Moreover, at EDIC year 17, the presence of endothelium-dependent and endothelium-­ of neuropathic symptoms was associated with independent vasodilation before the development unadjusted odds for ED of 2.15, while retinopaof atherosclerotic plaque and more likely to cause thy and microalbuminuria had odds of 2.11 and ED than angina. The observed benefit of type 5 2.83, respectively [10]. In two small studies in phosphodiesterase inhibitors (PDE5Is) on the patients with type 1 and type 2 diabetes, ED was incidence of cardiovascular disease in men with associated with impairment in measures of both ED [105] and of major adverse cardiac events in large (neuropathic symptoms, vibration percepmen with diabetes and silent coronary artery dis- tion threshold, sural and peroneal nerve ampliease [106] might involve endothelial dysfunc- tude, and conduction velocity) and small fiber tion. In fact, PDE5Is in patients with diabetes or function (thermal thresholds, deep breathing test, high cardiovascular risk were able to improve intraepidermal nerve fiber density, and corneal penile and systemic endothelial function, reduce confocal microscopy parameters) [111, 112]. ET-1 and endothelial inflammatory mediators, These and other studies have advocated a greater and increase circulating endothelial progenitor association of ED with abnormalities in small cells [107, 108]. Another linking factor is hypo- than in large nerve fiber function [111–113].

Diabetic Neuropathy: Clinical Management—Genitourinary Dysfunction in Diabetes

In summary, CAN diagnosis in cross-sectional studies is associated with ED with increased odds up to 4, while in longitudinal studies its predictive power is lower and equivalent or less than that of other diabetic complications. Similarly, the presence of diabetic polyneuropathy is associated with at least double the risk of ED in both cross-sectional and longitudinal studies, with a possible (but not definitively shown) preferential link with small fiber function abnormalities.  echanisms Linking Erectile Dysfunction M and Diabetic Neuropathy The association of diabetic neuropathy with ED has biological soundness. Impaired sensation of the penis takes away local information to the brain and the afferent arm of reflex erection, abnormal motor function impacts on skeletal muscles participating in erection; autonomic neuropathy affects arterial dilation through impaired NO release and NO-synthase function of nonadrenergic noncholinergic (NANC) neurons, and trabecular smooth muscle relaxation of the corpus cavernosum [114]. In vitro examination of the corpus cavernosum tissue of men with diabetes showed impairment of autonomically mediated relaxation of smooth muscle as well as reduction in endothelium-dependent relaxation [115]. Dysfunction and degeneration of the NANC nerves of the corpus cavernosum contribute to the NO defect, the main culprit of ED, which follows also the loss of NO endothelial production/activity induced by many factors like the increase in AGEs formation, protein kinase C (PKC) activation, oxidative stress, arginase II, and RhoA/Rho-kinase activity (involved in penile flaccidity), and the presence of androgen deficiency [116].

3.2 Physiology and Pathophysiology of Erectile Function The erectile mechanism is based on the mutual interaction of vascular, neural, hormonal, and psychological processes [117]. The penis remains in its flaccid state as long as the vascular smooth

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muscle cells are contracted. Sexual stimulation causes NO release from nervous terminations (NANC neurons). The NO activates soluble guanylate cyclase raising intracellular cyclic guanosine monophosphate (cGMP) and then intracellular Ca2+, resulting in a relaxation of the smooth muscle in the arteries and arterioles supplying the erectile tissue (Fig. 3). The process is also enhanced by concomitant acetylcholine (Ach)-derived adenylate cyclase activation. Increased blood influx fills the lacunar spaces of corpora cavernosa, causing a compression of the subtunical compressive venules, resulting in almost complete occlusion of venous outflow (venous-occlusion phenomenon). cGMP is hydrolyzed by cellular phosphodiesterase-5 (PDE5), restoring smooth muscle contraction and allowing the penis to return to its flaccid state. Detumescence is also mediated by adrenergic receptor reactivation, which leads to rhythmic contractions of the cavernosal smooth muscle, a decrease in arterial diameter and thereby inducing venous outflow [118]. Testosterone plays a role in nearly every level of the erectile function, from central genesis of sexual desire to pelvic ganglions neurotransmission and smooth muscle and endothelial cells function in the corpora cavernosa [119]. At the central level testosterone promotes the release of stimulatory neurotransmitters such as dopamine, oxytocin, and NO, with an influence during sexual development and later in puberty and adulthood mating behaviors. At the peripheral level, testosterone modulates structure, function, and innervation of trabecular smooth muscle cells, the endothelial function of penile vessels, and fibro-elastic properties of the corpus cavernosum [119, 120]. ED can result from three main abnormalities: (1) an inability to induce the erectile mechanism, (2) a deficiency in the arterial blood supply of the penis, and (3) insufficient maintenance of a proper lacunar blood concentration (venous-­ occlusive dysfunction). These conditions are not mutually exclusive, and different degrees of each can occur in the natural history of ED. While in the past, in the general population under 40, ED was considered in most cases a purely psycho-

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PDE5i 5’ -GMP GTP

PDE5

GC

Ca2+ Sequestration Phospholamban

cGMP

PKG

MYPT

IP3 Receptor Cytoplasmatic Ca2+ reduction

MLKC

Fig. 3  The cyclic guanosine monophosphate (cGMP)signaling pathway in smooth muscle cell in penile vasculature. Nitric oxide activates guanylate cyclase (GC) causing increased synthesis of cGMP. cGMP binds to and activates cGMP-dependent protein kinase (PKG), thereby promoting a cascade of phosphorylation events resulting in the activation of myosin light chain phosphatase (MLCP) that dephosphorylates the light chain of myosin

(MLKC), thereby inducing smooth muscle relaxation. PKG promotes the lowering of intracellular calcium through the inhibition of inositol trisphosphate (IP3) receptor and phosphorylation of phospholamban in sarcoplasmic reticulum. cGMP is broken down at the catalytic site of PDE5, PDE5Is have a high affinity for the PDE5 catalytic site, thereby blocking cGMP access to the site and fostering cGMP accumulation

genic disorder, up to 70% of these cases can actually have organic etiologies [121]. Primary psychogenic ED is dependent on the erectolytic (or anti-erectile) effect of noradrenaline neurotransmission. Stressful or depressive events, generalized anxiety disorders, or other psychological-impacting factors are generally associated with this type of ED.  Organic ED often involves or determines a psychological component, affecting general mood, interpersonal relationships, and overall individual QoL [122]. Vasculogenic is largely the most common nonendocrine organic cause of ED, can involve arterial inflow disorders and/or venous outflow changes (venous-occlusion dysfunction) generally in the setting of generalized atherosclerosis [97, 118]. Neurogenic causes derive from central or autonomic neural damage, which converge in

reducing NO release from terminal nerves [118]. Radical pelvic surgery (nerve-sparing or non-­ nerve sparing) is still a common form of iatrogenic ED [118]. Calcium channel blockers directly act on cavernosal ion channel flux, while β-blockers and thiazide diuretics exercise an indirect reduction in arterial blood flow to the internal pudendal artery. Finally, hypogonadism represents a relevant cause of poor response to first-line therapy of ED [97].

3.3 Multifactorial Pathogenesis of Diabetic Erectile Dysfunction In diabetes many pathogenetic factors of ED may coexist and potentiate each other. Diabetes-­related

Diabetic Neuropathy: Clinical Management—Genitourinary Dysfunction in Diabetes

mechanisms and comorbidities—i.e., the components of metabolic syndrome—can affect endothelial function, micro- and macrovascular function, peripheral nerve function, smooth muscle contractility, psychological function, CNS function, and androgen secretion (Fig.  4). The efficacy on ED of lifestyle interventions (based on Mediterranean diet, weight loss, and exercise) or statin treatment [123, 124] and, at least in type 1 diabetes, intensive glycemic control [110] confirms the pathogenetic role of mechanisms triggered by metabolic and glycemic changes. Inflammation is gaining increasing pathogenetic relevance also in female sexual dysfunction [124].

Inflammation

Neuropathy Psychological distress

↓ Penile sensaon

↓ Cavernosal vasodilaon

orim

Endothelial dysfunction

otor

Macro angiopathy

Sens

Hypogonadism

Micro angiopathy

mic

Dyslipidemia Physical inactivity

Hyperglycaemia Oxidative stress

ono

Hypertension

Depression

Aut

Obesity

3.3.1 Hypogonadotropic Hypogonadism Hypogonadotropic hypogonadism, characterized by low serum testosterone, reduced spermatogenesis, and inappropriately low or normal gonadotropins levels, is associated with obesity, metabolic syndrome, and diabetes [125]. The prevalence of hypogonadism at the onset of diabetes is 17.2% [83] but can reach 50% in the later stages [125]. This relationship is bidirectional and probably based on a vicious circle which involves either central or peripheral mechanisms. Most probably, obesity represents the major player. The increased aromatase activ-

Diabetes

Cofactors/comorbidities

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↑ Cavernosal vasoconstricon ↓ Smooth muscle relaxaon

Erectile dysfunction Fig. 4  Multifactorial pathogenesis of diabetic erectile dysfunction. Cardiovascular risk factors and other metabolic syndrome components exacerbate the effects of hyperglycemia-driven pathways such as AGEs formation and PKC activation, thus promoting oxidative stress and low-grade inflammation. These changes impair the NO bioavailability and synthesis and favor an imbalance between vasodilating and vasoconstrictive mechanisms,

leading to endothelial dysfunction and an impaired erection. Moreover, diabetic complications such as atherosclerotic disease, microangiopathy and neuropathy, diabetes-related hypogonadism, antihypertensive drugs (β-blockers apart from nebivolol, thiazide diuretics, and aldosterone antagonists), and psychological factors are further pathogenetic factors

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ity in adipose tissue enhances testosterone conversion into estradiol, leading to a suppression of central GnRH production [125]. Insulin resistance reduces the central secretion of GnRH and elevates inflammatory mediators [126] and these later may inhibit LHRH stimulated LH release. Moreover, obesity related high leptin concentrations play a role. Leptin has inhibitory effects on Leydig cells, as suggested by human models [127] as well as leptin resistance in the hypothalamic-­ pituitary axis reducing LH release, as suggested in animal models [128]. Further, SHBG levels are reduced in men with obesity and/or type 2 diabetes and are negatively associated with the risk of metabolic disorders [129]. Conversely, hypogonadism increases lipoprotein lipase activity, free fatty acids uptake, and triglyceride content within adipocytes and stimulates adipocyte proliferation and visceral adipose tissue deposition, contributing to visceral obesity [125]. Low testosterone levels are associated with an adverse metabolic profile, promote insulin resistance in men by impairing mitochondrial function [125], and may impair endothelial integrity and promote inflammation [97].

obtained as well as information on other, potentially reversible, causes (smoking, drug, or alcohol abuse). An objective score of erectile ­ function can be achieved through self-­ administered validated questionnaires, which provide a measure of ED severity also useful for cardiovascular risk stratification. The short fivequestion form of the International Index of Erectile Function (IIEF-5) and the Sexual Health Inventory for Men (SHIM) are useful tools for both diagnosis and assessment of treatment response [133]. Nevertheless, structured interviews are generally considered a more reliable instrument than questionnaires as they tend to build a stronger patient–physician relationship and reduce the risk of missing relevant information. So far, the only validated interview on ED that has proven useful in several clinical studies is the Structured Interview on Erectile Dysfunction (SIEDY), composed of 13 items exploring male sexual function [134]. A psychological assessment is recommended in patients with psychiatric disorders or young men with short diabetes duration. It should be taken into account that psychogenic aspects are present in different degrees in all patients independently of the disease stage.

3.4 Diagnosis of Diabetic Erectile Dysfunction

3.4.2 Physical Examination An accurate physical examination in addition to heart rate, BP, waist circumference, and BMI should be focused on the general body habitus, including the chest (body hair distribution and presence of gynecomastia) and genitalia (testicular size, structure, consistency and secondary sexual habits), seeking for signs of hypogonadism or other comorbidities [135]. The cremasteric reflex can also be evaluated. A normal reflex can be elicited if the thoracolumbar erection center is intact. Evaluation of the penis needs to exclude Peyronie’s disease, phimosis or frenulum breve, balanitis, and other diabetes-related

The diagnostic pathway of ED does not differ between diabetes and the general population [130, 131].

3.4.1 History and Questionnaires A detailed family, medical and sexual history, is the primary approach, including the timing of onset, severity, duration of ED, presence of nocturnal erections, and impact on the patient’s sexual and general QoL [132]. A complete medication list, including supplements, should be

Diabetic Neuropathy: Clinical Management—Genitourinary Dysfunction in Diabetes

conditions affecting erectile response. In selected high-­risk patients or patients with LUTS, a digital rectal examination and prostate-specific antigen test are recommended [136]. Neurological evaluation in patients with diabetes is appropriate for frequent and early coexistence of diabetic neuropathy: clinical diagnosis includes assessment of neuropathic and autonomic symptoms and signs using easy-to-use questionnaires and hand-­held devices, while CARTs allow a confirmed diagnosis of CAN [60, 137, 138]. Vice versa annual screening for erectile dysfunction in men with other forms of diabetic neuropathy is recommended by guidelines [60] and is also advisable in any patient with type 2 diabetes or long-­standing type 1 diabetes.

3.4.3 Laboratory Investigations They are driven by the patient’s history and physical examination findings and include glycemic control, lipids profile, renal and hepatic function for cardiovascular and metabolic risk stratification [131]. Morning fasting total testosterone assay and SHBG to calculate free testosterone are always indicated in men with diabetes and ED as well as in men with ED and signs of hypogonadism, hypoactive sexual desire, or incomplete response to PDE5Is [139]. If total testosterone results