Stroke Revisited: Diabetes in Stroke 9811651221, 9789811651229

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Seung-Hoon Lee Dong-Wan Kang   Editors

Stroke Revisited: Diabetes in Stroke

Stroke Revisited

This authoritative book series presents state of the art knowledge on the pathophysiology, prevention, diagnosis, and treatment of stroke, highlighting the many very important advances that have been achieved in recent years. Current issues in management are addressed in detail, equipping readers with an understanding of the rationale for particular approaches in different settings and with a sound knowledge of the role of modern imaging methods, surgical techniques, and medical treatments. The inclusion of numerous high-quality illustrations facilitates understanding of practical aspects and rapid retrieval of fundamental information. The series will be of value for stroke physicians, surgeons, other practitioners who care for patients with stroke, and students. More information about this series at http://www.springer.com/series/15338

Seung-Hoon Lee  •  Dong-Wan Kang Editors

Stroke Revisited: Diabetes in Stroke

Editors Seung-Hoon Lee Department of Neurology Seoul National University Hospital Seoul Republic of Korea

Dong-Wan Kang Department of Neurology Seoul National University Hospital Seoul Republic of Korea

Korean Cerebrovascular Research Institute Seoul Republic of Korea

Korean Cerebrovascular Research Institute Seoul Republic of Korea

ISSN 2522-5588     ISSN 2522-5596 (electronic) Stroke Revisited ISBN 978-981-16-5122-9    ISBN 978-981-16-5123-6 (eBook) https://doi.org/10.1007/978-981-16-5123-6 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021 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 Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

Preface

Professor Seung-Hoon Lee, my mentor and teacher, served as a principal editor for the Stroke Revisited series. I thankfully had the opportunity to write two chapters as a coauthor with Professor Lee, including “Diabetes management after stroke” in Vol. 1—Diagnosis and Treatment of Ischemic Stroke.” Vol. 1 was written to quickly understand a specific topic by simply looking up the textbook in practice. The chapter “Diabetes management after stroke” was also written from that point of view. However, as soon as Vol. 1 was published in 2017, the diabetes guidelines have been significantly updated based on the numerous clinical trials of the emerging antidiabetic medications. In particular, the effects of sodium-­ glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP1-RA) in atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease have been published, resulting in tectonic shift of the guidelines. Vol. 6—Diabetes in Stroke is made into a comprehensive textbook covering (1) basic science of glucose metabolism and diabetes, (2) general treatment principles for diabetes, and (3) effects of diabetes on cerebro-cardiovascular disease and practice in stroke patients. As Professor Lee made the overall composition of this book, he has given me an insight of concepts of diabetes in relation to stroke. The physicians who manage patients with stroke should keep pace with the rapidly changing diabetes guidelines, and have knowledge that encompasses the basic science of diabetes and practice. I wish to express my deep and sincere gratitude for all the authors who have participated. As a physician and a researcher, our ultimate goal is to help the patients live better lives. I hope this book will guide the physicians to better understand diabetes in relation to stroke and give prompt management to the patients. Seoul, Republic of Korea March 2021

Dong-Wan Kang

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Preface

The Stroke Revisited series now presents its final publications. As a principal editor, since Vol. 1:—Diagnosis and Treatment of Ischemic Stroke published in 2017, I sequentially presented Vol. 2:—Hemorrhagic Stroke, Vol. 3—Vascular Cognitive Impairment, and Vol. 4—Pathophysiology of Stroke: From Bench to Bedside. Finally, the contract with Springer Nature to publish six volumes of the Stroke Revisited series is now completed together with the current books: Vol. 5—Dyslipidemia in Stroke and Vol. 6—Diabetes in Stroke. Writing and editing these series in approximately five years, I have done my best to create a complete series, not to leave any scratch on the honor of the publisher and me. Looking back over the years, there are some regrets that it would have been a better book series if I had invested a little more energy. However, working concurrently as a clinical professor at Seoul National University Hospital, chair of the Korean Cerebrovascular Research Institute (KCRI), and CEO of a bio-venture company, Cenyx Biotech Inc., I am comforting myself with this level of achievement. Of course, while continuing to monitor the contents of the books, I commit to maintain the latest level of knowledge by revising, reinforcing, or replacing chapters that have become knowledge of the past. Vols. 1, 2, and 4 are books I put much effort into as the sole principal editor, whereas for Vols. 3, 5, and 6, I am very grateful for the efforts of the coeditors. In the initial contract, Vols. 5 and 6 were planned to have titles of “Small vessel disease” and “Large artery atherosclerosis,” respectively. Writing Vol. 4, Pathophysiology of Stroke, I realized that I put a considerable amount of content prepared for Vols. 5 and 6 into Vol. 4. Therefore, I was exceedingly worried about the necessity of proceeding with the original series. Meanwhile, a new era began with the introduction of various new drugs and biologics for the treatment of dyslipidemia and diabetes. Considering the changed circumstances, I thought it would be better to make books that reflect the development of new drugs in these fields. Since the publisher generously agreed with my idea, Vols. 5 and 6 were presented to you with new themes: dyslipidemia and diabetes in stroke. Vol. 6—Stroke Revisited: Diabetes in Stroke is another comprehensive book that deals with the effects of diabetes mellitus in relation to stroke, basic knowledge, and clinical aspects. Physicians involved in the management of stroke have not been interested in diabetes because it has been studied in the field of endocrine medicine, and antidiabetic drugs have critical side effects such as hypoglycemia. As the number of patients with diabetes worldwide is rapidly increasing, and new diabetes drugs that are effective while s­ ignificantly vii

Preface

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lowering the side effects are emerging, physicians managing stroke also feel a need to accept the current knowledge on diabetes. Notably, new antidiabetic drugs such as sodium-glucose co-transporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists have a superior ability to suppress the occurrence of vascular diseases, including stroke, compared to other classes of drugs. They are now being recommended as first-line therapy in patients with stroke and diabetes. In this book, I invited experts to comprehensively explain the latest findings from the basics of diabetes to clinical practice in relation to stroke. With few clinical studies on the preventive effect of diabetes on stroke, I am confident that this book will be a good guide for clinicians dealing with stroke or diabetes. The six-volume Stroke Revisited series is now completed. I would like to express my deep gratitude to Springer Nature for providing me with this great opportunity. While producing six books up to this point, the KCRI has provided great support for writing these books, and my colleagues have provided valuable help in various ways. I profoundly appreciate it all. In the future, whenever new information is released regarding the contents of the series, partial or full revisions will be made to offer cutting-edge knowledge as much as possible. When I was studying stroke in my youth, I had hard times because of difficulties finding optimal books in the clinical aspects of stroke. The fact that I have produced some books that will help clinicians worldwide is quite rewarding for the rest of my life. Seoul, Republic of Korea March 2021

Seung-Hoon Lee

Contents

Part I Basic Science: Diabetes and Stroke 1 Glucose Metabolism������������������������������������������������������������������������   3 Obin Kwon 2 Pathophysiology and Risk Factors of Diabetes ����������������������������  15 Hae Kyung Kim and Byung-Wan Lee 3 Macro- and Microvascular Complications of Diabetes����������������  25 Wookjin Yang 4 Hyperglycemia in Acute Stroke������������������������������������������������������  33 Sung Hyuk Heo Part II Clinical Significance of Diabetes in Cerebro-cardiovascular Disease 5 Clinical Impact of Diabetes Mellitus in Cardiovascular Diseases��������������������������������������������������������������  43 Chan Joo Lee and Jong-Won Ha 6 Epidemiology of Stroke Patients with Diabetes����������������������������  51 Jae-Kwan Cha 7 Differential Influence of Diabetes on Stroke Subtype������������������  69 Beom Joon Kim Part III Treatment of Diabetes 8 Principles of Diabetes Care and Lifestyle Modification ��������������  83 Min Kyong Moon 9 Metformin and Sulfonylurea���������������������������������������������������������� 109 Sang Soo Kim and In Joo Kim 10 Insulin Therapy�������������������������������������������������������������������������������� 117 Ji-Yeon Park and Kun-Ho Yoon 11 Thiazolidinediones (TZDs)�������������������������������������������������������������� 131 Jong Chul Won

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12 Dipeptidyl Peptidase-4 Inhibitors�������������������������������������������������� 143 Yoo Hyung Kim and Young Min Cho 13 SGLT2 Inhibitors ���������������������������������������������������������������������������� 155 Jee Hee Yoo and Jae Hyeon Kim 14 Glucagon-like Peptide-1 Receptor Agonists���������������������������������� 167 Ja Young Jeon and Hae Jin Kim 15 Standard Pharmacological Treatment of Diabetes Based on the Guidelines������������������������������������������������������������������ 179 Jun Sung Moon and Kyu Chang Won 16 Future Therapies for Diabetes�������������������������������������������������������� 189 Masayuki Shimoda Part IV Actual Clinical Practice in Patients with Diabetes 17 Diabetes in Pregnancy �������������������������������������������������������������������� 201 Han Na Jang and Hye Seung Jung 18 Glucose-Lowering Strategy in Acute Stroke �������������������������������� 211 Jeong-Min Kim 19 Management of Acute Complications of Diabetes Mellitus�������������������������������������������������������������������������� 217 Jae Hyun Bae and Sin Gon Kim 20 Long-Term Glycemic Control for Stroke Survivors �������������������� 229 Dong-Wan Kang

Contents

Contributors

Jae  Hyun  Bae  Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea Jae-Kwan  Cha  Department of Neurology, College of Medicine, Dong-A University, Busan, Republic of Korea Young Min Cho  Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Hospital, Seoul, Republic of Korea Jong-Won  Ha Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea Sung Hyuk Heo  Department of Neurology, Kyung Hee University Hospital, Seoul, South Korea Han Na Jang  Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea Ja  Young  Jeon Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea Hye Seung Jung  Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea Dong-Wan  Kang Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea Korean Cerebrovascular Research Institute, Seoul, Republic of Korea Beom Joon Kim  Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Republic of Korea Hae  Jin  Kim Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea Hae Kyung Kim  Division of Endocrinology and Metabolism, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

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Hee-Young  Kim Korean Cerebrovascular Research Institute, Seoul, Republic of Korea In  Joo  Kim Division of Endocrinology and Metabolism, Department of Internal Medicine, Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea Jae Hyeon Kim  Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Jeong-Min  Kim Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea Sang Soo Kim  Division of Endocrinology and Metabolism, Department of Internal Medicine, Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea Sin  Gon  Kim Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea Yoo Hyung Kim  Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Hospital, Seoul, Republic of Korea Ji-Yeon Kwon  Korean Cerebrovascular Research Institute, Seoul, Republic of Korea Obin Kwon  Seoul National University College of Medicine, Seoul, Republic of Korea Byung-Wan Lee  Division of Endocrinology and Metabolism, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea Chan  Joo  Lee  Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea Seung-Hoon  Lee Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea Korean Cerebrovascular Research Institute, Seoul, Republic of Korea Jun Sung Moon  Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea Min Kyong Moon  Seoul National University College of Medicine, Seoul, Republic of Korea Eun-Sun  Park Seoul National University Hospital, Seoul, Republic of Korea Korean Cerebrovascular Research Institute, Seoul, Republic of Korea

Contributors

Contributors

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Ji-Yeon  Park  Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea Masayuki  Shimoda Department of Pancreatic Islet Cell Transplantation, National Center for Global Health and Medicine, Tokyo, Japan Jong  Chul  Won Department of Internal Medicine, Cardiovascular and Metabolic Disease Center, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Republic of Korea Kyu Chang Won  Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea Wookjin  Yang Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea Jee  Hee  Yoo Division of Endocrinology and Metabolism, Department of Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Kun Ho Yoon  Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Part I Basic Science: Diabetes and Stroke

1

Glucose Metabolism Obin Kwon

Abstract

• Insulin, the glucose-lowering hormone, is the key hormone in glucose regulation. In response to each meal intake, insulin is secreted from pancreatic β-cells, where its proper function is essential for glucose homeostasis. Long-term body energy imbalance (such as obesity) can change insulin level and sensitivity. Counterregulatory hormones include glucagon, epinephrine, and cortisol which prevent hypoglycemia. • Blood glucose concentration is normally maintained within a narrow range. Glucose, the main outcome of carbohydrate digestion, is a major source of cellular energy. Blood glucose can be transported into cells by cell type-specific glucose transporters and utilized to produce ATP. Intracellular glucose can also be converted into other metabolites linked with lipid and protein metabolism. To provide glucose in the fasted state, the liver can synthesize glucose. • The brain is a “consumer” and also a “modulator” in glucose metabolism at the same time. Glucose is the primary fuel for the brain in normal states. During prolonged fasting, increased ketone body can replace the main O. Kwon (*) Seoul National University College of Medicine, Seoul, Republic of Korea e-mail: [email protected]

fuel for the brain. The brain can detect glucose levels, interpret related signals through hormones, and continuously tune the body mechanisms to maintain blood glucose within a predetermined range.

1.1

Pancreatic β-Cell Function

1.1.1 Pancreas The pancreas is a digestive and endocrine organ located in the abdomen. As a digestive organ, the pancreas synthesizes and secretes pancreatic juice, which contains a variety of digestive enzymes, including trypsinogen, lipase, and amylase. These enzymes are produced in exocrine glands consisting of acinar cells, which make up more than 85% of the whole pancreas volume. On the other hand, pancreatic hormones are produced in scattered endocrine glands: these regions containing endocrine cells are called islets of Langerhans. [Note: The word “insulin” is from the Latin word insula, meaning “island.”] Several subsets of hormone-producing cells are distributed in the islet, and each type of cell secretes a distinct hormone. Table 1.1 shows the characteristics of each cell type and the hormones they produce. In glucose metabolism, insulin released from pancreatic β-cells lowers blood glucose levels, and glucagon from pancreatic

© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021 S.-H. Lee, D.-W. Kang (eds.), Stroke Revisited: Diabetes in Stroke, Stroke Revisited, https://doi.org/10.1007/978-981-16-5123-6_1

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O. Kwon

4 Table 1.1  Types and characteristics of endocrine cells in pancreatic islets Cell type Hormone and its action on glucose metabolism Alpha (α) cell Glucagon: increase blood glucose level as a counterregulatory hormone of insulin Insulin: decrease blood glucose level by Beta (β) cell stimulation of cellular uptake Delta (δ) cell Somatostatin: inhibit glucagon and insulin release

Proportion(%) in human 20~35a

Histological distribution in the islet Periphery in rodents

50~70b

Central in rodents

5~10a

Periphery in rodents; central in human

Relatively alower and bhigher proportion in rodents compared to humans

α-cells raises them. These islets make up only about 1~2% of the total pancreas cells but receive 10~15% of their blood flow. This anatomical structure makes it suitable for the islet to release relevant hormones in response to changes in blood content. The composition and structure of the islet vary among species. Compared with rodents, islets of humans and other primates are more heterogeneous in cellular composition and more prominently vascularized [1]. Rodents have relatively higher proportions of β-cells while humans have higher proportions of α- and δ-cells [2]. Rodent islets are organized into a mantle of α- and δ-cells surrounding centrally clustered β-cells [3]. These differences may be the reason behind poor translation across species in the pancreatic regulation of glucose metabolism [4].

1.1.2 Insulin Insulin is the most important hormone regulating the use of energy sources (fuels) by tissues. It is an anabolic hormone in metabolism: it stimulates the synthesis of glycogen, triacylglycerol, and protein. In human disease, insulin is the key treatment for patients with type 1 diabetes or type 2 diabetes with β-cell failure.

1.1.2.1 Synthesis Insulin is a 51-amino acid polypeptide hormone composed of two amino acid chains linked together by two disulfide bonds. The human insulin gene is located on the short arm of chromosome 11 at position 15.5 (11p15.5) [5]. The

synthesis, processing, and intracellular transport of insulin are shown in the upper part of Fig. 1.1. After transcription of the insulin gene inside the nucleus, the mRNA is translated by cytosolic ribosomes. Initial translation results in the formation of an N-terminal signal sequence, which aids the transport of the mRNA-ribosome complex to the rough endoplasmic reticulum (RER). The translated peptide penetrates the RER membrane and is further elongated in its lumen to form preproinsulin (an inactive precursor). Proinsulin is formed from preproinsulin by cleavage of the signal sequence and the formation of two disulfide bonds between the chains. Proinsulin is transported to the Golgi, where it is cleaved into insulin and C-peptide (connecting peptide). Insulin is precipitated with Zn2+ and packaged with the C-peptide into secretory granules stored in the β-cell. The C-peptide level is a good indicator of endogenous insulin production and secretion, because it has a longer half-life compared to insulin and does not exist as a constituent of currently available exogenous insulin analogs [6].

1.1.2.2 Secretion Insulin is stored in vesicles (cytosolic granules) until released by exocytosis in response to proper stimuli. The lower part of Fig.  1.1 briefly describes the pathway to insulin release upon stimulation by glucose. Glucose enters the β-cell via specific glucose transporter proteins, glucose transporter 2 (GLUT2, see Sect. 1.2.2.1. and Table 1.2 below). Intracellular glucose is utilized to increase adenosine triphosphate (ATP) levels within the β-cell, resulting in the inhibition

1  Glucose Metabolism

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Fig. 1.1 Synthesis, processing, intracellular transport, and release of insulin in pancreatic β-cell. ATP adenosine triphosphate, ER endoplasmic reticulum (made in ⓒBioRender— biorender.com)

Table 1.2 Properties of the major isoforms of the glucose transport proteins

Isoform GLUT1

GLUT2

GLUT3

Tissue distribution Cell types with barrier functions (including blood-brain barrier) Human erythrocyte Expressed to some degree in most tissue Liver Kidney Pancreatic β-cell Intestinal luminal surface Brain (neurons)

GLUT4

Adipose tissue Heart muscle Skeletal muscle

GLUT5

Intestinal luminal surface Spermatozoa

GLUT glucose transporter

Characteristics   – Provides a low, constant level of glucose transport necessary for basal cellular processes   – Postnatal switch from GLUT1 to GLUT4 in mice   – High affinity to glucose   – Glucose sensor in pancreatic β-cells and intestinal epithelial cells absorbing glucose   – High capacity, low affinity to glucose   – Major transporter in the central nervous system   – Transports glucose into neurons (with GLUT1)   – High affinity to glucose   – Insulin-dependent expression: sequestered in intracellular vesicles under basal conditions and mobilized to cell surface in the presence of insulin   – High affinity to glucose   – Transports fructose

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(closing) of ATP-dependent K+ channels (K+ATP) on the plasma membrane. This leads to membrane depolarization, which activates voltagegated Ca2+ channels allowing Ca2+ to enter the β-cell. Elevated intracellular Ca2+ stimulates the fusion of insulin-containing vesicles, and insulin is released. First-phase secretion, in which the “readily releasable” pool below the plasma membrane is depleted, usually occurs within 10  min of glucose stimulation. Second-phase secretion is less robust but more gradual and long lasting [7, 8].

1.1.2.3 Regulation of β-Cell Function As β-cell function is critical for glucose homeostasis, insulin secretion is finely regulated by multiple mechanisms. In humans, food intake usually occurs regularly at multiple (usually three or two) times throughout the day. Insulin is secreted in response to each meal: this is a typical example of how insulin secretion is regulated in the short term. Different nutrients have distinct effects on the release of metabolic hormones. Glucose stimulates insulin release and inhibits glucagon release, whereas amino acids stimulate the secretion of both insulin and glucagon. Therefore, the relative amounts of insulin and glucagon in the blood (and thus their final composite effect) after a mixed meal depend on its composition. Other short-term regulation mechanisms related to body energy status will be further described in Sect. 1.2. Normal glucose metabolism. The function of the β-cell is also controlled in a long-term manner. After prolonged starvation, insulin stores decrease markedly [9]. On the other hand, obesity due to chronic overnutrition is associated with insulin resistance and higher demand for insulin. Initially, the body can adapt by increasing β-cell mass, since a small number of β-cells can still proliferate. If continued, however, β-cells gradually become dysfunctional and ultimately fail to compensate sufficiently. This process is found in the natural history of type 2 diabetes, which will be described in detail in the next chapter (“Pathophysiology of diabetes”).

O. Kwon

1.1.3 Glucagon and Other Counterregulatory Hormones In the regulation of blood glucose, insulin is the dominant hormone lowering blood sugar, whereas several counterregulatory hormones increase it. Such a system is advantageous for survival because prolonged and marked hypoglycemia due to energy depletion can be a threat to life. These counterregulatory hormones include glucagon, epinephrine, and cortisol. Glucagon is a polypeptide hormone consisting of 29 amino acids arranged in a single polypeptide chain. It counters many of the actions of insulin. Most importantly, glucagon mobilizes fuel to maintain blood glucose levels. This is achieved by promoting glycogenolysis and gluconeogenesis in the liver and fatty acid release from adipose tissue. Similar to insulin biosynthesis, preproglucagon, a large precursor molecule, is first synthesized and converted to glucagon by proteolytic cleavages. Interestingly, preproglucagon can be processed into different products according to tissue type: in intestinal L cells, glucagon-like peptide-1 (GLP-1) is produced from preproglucagon and works as an insulin secretagogue [10, 11]. Epinephrine is released during periods of stress (such as hypoglycemia) to signal an immediate need for increased fuel availability. When the adrenal medulla is activated by the sympathetic nervous system, epinephrine levels rise rapidly, triggering the fight-or-flight response. It stimulates glucose production by glycogenolysis in muscle and liver and fatty acid release from adipose tissue. Its role during hypoglycemia can be critical if the action of glucagon is impaired [12]. Cortisol is a glucocorticoid released by the adrenal cortex in response to fasting. [Note: in rodents, corticosterone is the primary adrenal corticosteroid.] It stimulates amino acid mobilization from muscle protein to meet changing requirements during periods of stress. Cortisol also promotes hepatic gluconeogenesis and fatty acid release from adipose tissue. Cortisol and

1  Glucose Metabolism

growth hormone (from the anterior pituitary gland) are involved in the prevention or correction of hypoglycemia, but their role is not critical compared with glucagon or epinephrine.

1.2

Normal Glucose Metabolism

1.2.1 H  omeostasis (at the Level of an Organism) Homeostasis is the steady state of conditions for the optimal function of an organism, including humans. Many variables in the body need to be maintained within a narrow range: these include body temperature, acid-base balance, blood oxygen, blood pressure, concentrations of various ions, osmolality, etc. In fact, homeostasis is not a passive state but rather a dynamic equilibrium actively regulated by complex systems with multiple feedback mechanisms. In humans, plasma glucose concentration is also normally maintained within a narrow range, about 72–144 mg/dL (4–8 mmol/L). This range is achieved by a fine balance between glucose influx and efflux. Glucose influx can be either exogenous glucose intake or endogenous glucose production by gluconeogenesis or glycogenolysis. Glucose efflux mainly occurs as glucose utilization in the peripheral tissues and brain. [Note: glucose efflux can also occur as glycosuria (excretion of glucose into the urine) in diabetic patients or by the sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor, a “glycosuric” antidiabetic drug [13].]

1.2.1.1 Glucose in Fed (Absorptive) State Figure 1.2 shows glucose homeostasis in fed and fasting states. Carbohydrates provide a significant proportion of dietary calories for most organisms. Human meals are usually a mix of various polysaccharides, oligosaccharides, and disaccharides. Digestion of dietary carbohydrates occurs mainly in the mouth and intestinal lumen. Amylase (salivary and pancreatic) and various

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glycosidases in the brush border of the intestine sequentially hydrolyze glycosidic bonds in carbohydrates. Mastication (chewing) and peristalsis of the gut mechanically help digestion. Monosaccharides (glucose, galactose, and fructose), the final products of digested carbohydrates, are absorbed by enterocytes (intestinal epithelial cells) of the small intestine. Enterocytes express hexose transporters on their luminal surface: sodium-dependent glucose cotransporter 1 (SGLT1) for glucose and galactose and/or GLUT5 for fructose uptake, respectively [14, 15]. These monosaccharides are released into the portal circulation by GLUT2: so, the liver is the first tissue that absorbed glucose passes through. Elevated blood glucose levels after meal intake induce insulin release from pancreas β-cells. Within the pancreatic islet, insulin from β-cells can affect nearby α-cells directly and/or indirectly [16, 17]. Therefore, secreted insulin can locally inhibit glucagon release first, efficiently lowering blood glucose, especially after meal intake. [Note: current insulin treatment (exogenous insulin injection/infusion) for diabetic patients does not recapitulate this paracrine effect of endogenous insulin.] In healthy individuals, oral glucose induces similar levels of glycemia but greater insulin secretion compared to intravenous glucose; this is called the incretin effect [18, 19]. A portion of the glucose that enters the liver is extracted from circulation. Some are oxidized to generate ATP, and the remainder is converted to glycogen and triacylglycerol or used in other biosynthetic pathways. These anabolic mechanisms are promoted by insulin secreted in the fed state. Glucose from portal circulation that is not metabolized by the liver moves to peripheral tissues. All tissues can utilize glucose as metabolic fuel. Many tissues have small stores of glycogen, while muscle has relatively larger ones. Insulin stimulates glucose uptake by muscle and adipose tissue, two types of tissue that occupy the largest mass in the body. As a result, 2-h postprandial blood glucose is normally controlled under 140 mg/dL (7.8 mmol/L).

O. Kwon

8 Fig. 1.2 Glucose homeostasis in fed vs. fasting state. (a) Interorgan relationships in the fed state; (b) interorgan relationships in the fasting state. Blue and red arrows indicate pathways stimulated by increased insulin and glucagon, respectively, in each state. ATP adenosine triphosphate, FA fatty acid, KB ketone body, TG triacylglycerol (made in ⓒBioRender— biorender.com)

a

b

1.2.1.2 Glucose in Fasting (Postabsorptive) State What happens when we continue to fast for a 12-h period, as in the case of overnight fasting (no food since the previous dinner)? No glucose has been provided from the intestine, and plasma levels of energy sources (including glucose, amino acids and triacylglycerol) fall. Peripheral

tissues need to provide glucose to maintain blood glucose homeostasis, so serum insulin levels are low, and glucagon is rising at this point. Initially, stored fuels are used to produce energy, especially by the liver. It maintains blood glucose levels first by glycogenolysis then by gluconeogenesis using other carbon sources (such as lactate, glycerol, and amino acids). [Note:

1  Glucose Metabolism

Proteolysis in the muscle provides amino acids.] Lipolysis in adipose tissue releases fatty acids, which serve as the major fuel for most organs during fasting. The liver converts most of its fatty acids into ketone bodies through partial oxidation. These are released into circulation; thus, blood levels of fatty acids and ketone bodies increase at the beginning of fasting. Muscle utilizes fatty acids, ketone bodies and (when exercising and available) glucose from glycogenolysis of muscle glycogen. Most other tissues use fatty acids or ketone bodies. However, red blood cells, the brain, and other neural tissues are mainly dependent on glucose. During prolonged fasting, when we continue to fast for longer than a 24-h period, we are in a starved state. Muscle continues to oxidize fatty acids but decreases the use of ketone bodies. The resulting rise in blood ketone body concentration allows the brain to oxidize them for energy. The brain’s demand for glucose decreases, so the rate of gluconeogenesis in the liver declines. This spares the protein in muscle and other tissues from being degraded to supply amino acids for gluconeogenesis. As a result, vital functions can be preserved for as long as possible. These changes in the fuel use patterns of various tissues enable humans to survive extended periods of fasting.

1.2.2 G  lucose Uptake in Cellular Level The inside of the cell is physically and chemically separated from the outside environment by the cell membrane. This barrier is primarily composed of a phospholipid bilayer with the hydrophobic tails facing the interior. As glucose is hydrophilic, specific transporters are needed to facilitate the uptake of glucose across the plasma membrane.

1.2.2.1 Glucose Transporter (GLUT) Glucose transporters are facilitative transport proteins located in the cell membrane that binds to glucose and carry it across the lipid bilayer. The human genome encodes 14 GLUTs [20].

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Table  1.2 describes the major GLUTs found in mammals; each isoform is expressed in a tissue-­ specific manner. In the brain, GLUT1 and GLUT3 transport glucose across the blood-brain barrier and into neurons, respectively. GLUT2 acts as a glucose sensor in pancreatic β-cells. In liver and kidney cells, it is involved both in glucose uptake when blood glucose levels are high and glucose release into circulation when blood glucose levels are low (for example, during fasting). GLUT4 is the major isoform regulated by insulin: upon hormonal stimulation, GLUT4  in intracellular membrane compartments are mobilized to the cell surface, where they function to transport glucose into the cell. This is important for the uptake of increased blood glucose by adipose tissue and skeletal muscle in the fed state.

1.2.2.2 Glycolysis Glycolysis is the intracellular metabolic pathway that converts glucose into pyruvate. In all tissues, glucose is oxidized through the glycolytic pathway to produce energy (as ATP) and other metabolic intermediates. Glucose transported into the cytosol can be phosphorylated by hexokinase, which inhibits sugar molecules from readily penetrating the cell membrane. Thus, glucose-6-phosphate is effectively trapped in the cytosol and becomes committed to further metabolism in the cell. The next step is the conversion to fructose 6-phosphate catalyzed by phosphoglucose isomerase, which can be competitively inhibited by 2-deoxy-D-­ glucose (2DG) [21]. [Note: this chemical has thus been largely used to mimic a glucose-­ deprived state or to block glycolysis in experimental settings.] The next reaction is the rate-limiting step of glycolysis: phosphorylation into fructose 1,6-bisphosphate catalyzed by phosphofructokinase-1. Through several further steps, glucose is finally converted into two pyruvate molecules, yielding a net gain of two ATP molecules (from ADP) and two reduced NADH (from NAD+). If cells are deprived of oxygen (i.e., in a hypoxic state) or lack mitochondria (ex. erythrocytes), NAD+ is regenerated by oxidation of NADH as pyruvate is reduced to lactate. This

O. Kwon

10

process is called anaerobic glycolysis. Otherwise, with an adequate supply of oxygen, pyruvate can be oxidized in mitochondria to acetyl-CoA, a major fuel of the next step, the tricarboxylic acid (TCA) cycle.

1.2.2.3 TCA Cycle and Oxidative Phosphorylation Most of the ATP generated from glucose oxidation is produced in these steps. Breakdown of glucose and other fuels (including fatty acids, amino acids, and ketone bodies) can provide acetyl coenzyme A (acetyl-CoA), the substrate for the TCA cycle. One acetyl-CoA molecule can be oxidized into two molecules of CO2, and energy is transferred to three molecules of reduced nicotinamide adenine dinucleotide (NADH+H+), one flavin adenine dinucleotide (FADH2), and one guanosine triphosphate (GTP). NADH+H+ and FADH2 subsequently donate electrons to O2 via the electron-transport chain, which is coupled to ATP production by oxidative phosphorylation. Thus, the TCA cycle has a central part in generating energy via cellular respiration. Remnant energy can be transformed into heat, which helps maintain body temperature. 1.2.2.4 Gluconeogenesis and Other Related Pathways Synthesis of glucose from compounds other than carbohydrates, called gluconeogenesis, occurs primarily in the liver. [Note: The Greek word “neos” means “new.”] The liver produces glucose to maintain blood glucose levels, especially during fasting. In humans, the major substrates of gluconeogenesis are lactate, glycerol, and amino acids, particularly alanine. Except for three key reactions, gluconeogenesis is mostly a reversal of the glycolytic pathway. The sequences that do not use glycolytic enzymes correspond to the irreversible, regulated steps of glycolysis. These three sequences are the conversion of (1) pyruvate to phosphoenolpyruvate (PEP), (2) fructose 1,6-bisphosphate to fructose 6-phosphate and (3) glucose 6-phosphate to glucose. Intracellular metabolic pathways involving glucose are also closely linked to lipid and pro-

tein metabolism. Several metabolites of glycolysis are connected with the pentose phosphate pathway, which generates sugars, ribose 5-phosphate (a precursor for nucleotide synthesis), and nicotinamide adenine dinucleotide phosphate (NADPH). Synthesis and degradation pathways of triacylglycerol are connected with acetyl-CoA and some other metabolites. Components of the TCA cycle are connected with the urea cycle, which plays an important role in eliminating toxic ammonia derived from the catabolism of amino acids. Thus, the metabolism of all nutrients is tightly intertwined and regulated within an organism.

1.3

Glucose Metabolism in Brain

1.3.1 Brain Glucose Use The brain is both a “consumer” and a “modulator” in glucose metabolism. This section will describe the respective mechanisms by which the brain uses and controls blood glucose. The brain and other neural tissues (and also red blood cells) are very dependent on glucose for their energy needs as they cannot synthesize glucose on their own. Although it represents only 2% of the total body mass, the brain accounts for some 60% (120~150 g/day) of the glucose used by the body in the resting state. This is equivalent to approximately 5.6 mg glucose consumed per 100  g human brain tissue per minute [22]. The brain is given exclusive priority for fuel because of its vital role in orchestrating the functions of all the body organs. Substrates must cross the blood-brain barrier (BBB), including the endothelial cells that form the inner lining of blood vessels, to be metabolized in the brain [23]. One structural component of the BBB is the foot process of astrocytes, where glucose is taken up and catabolized to pyruvate by the glycolytic pathway. Pyruvate is preferentially reduced to lactate in astrocytes, then transported into neurons and converted back to pyruvate [24]. [Note: normal levels of glucose in the cerebrospinal fluid (CSF) are 50~80  mg/dL, lower than blood glucose.]

1  Glucose Metabolism

Neurons in the brain contain no significant storage of glycogen or triacylglycerol, which necessitates complete dependency on the availability of blood glucose. Circulating fatty acids also contribute little to brain energy production during the fed state. Meanwhile, glycogen is stored mainly in astrocytes, but their involvement in brain energetics needs further investigation. In terms of cellular respiration, the brain accounts for about 20% of the body’s basal O2 consumption [25]. The cerebral metabolic rate of oxygen can increase by two- or threefold under certain circumstances in the healthy brain [26]. In aerobic conditions, most of the glucose is oxidized and used to produce ATP through oxidative phosphorylation. However, in the human brain, glucose is also catabolized by aerobic glycolysis, the nonoxidative metabolism of glucose even with adequate oxygen supply [27, 28]. This mechanism is especially upregulated during brain activation to help provide precursors for the biosynthesis of glucose-derived neurotransmitters (such as glutamate and acetylcholine) [29] (also check Sect. 1.2.2.4 above). It also has an important role in providing ATP, albeit occurring heterogeneously in different brain areas and contexts. During the initial stages of fasting, the brain continues to use glucose as the main fuel. As described above, blood glucose in the fasted state is maintained mainly by hepatic gluconeogenesis. In prolonged fasting (for more than 2 weeks), however, plasma ketone body levels significantly increase and surpass glucose as the brain’s primary fuel. Even after several days of starvation, more than 30% of the body’s energy requirements (based on oxygen consumption) can be provided by ketone body oxidation. As the brain and other nervous tissues begin to use ketone bodies, their glucose consumption decreases, using roughly one-third of the glucose (~40  g/ day) required under normal dietary conditions. [Note: As fasting continues from days to weeks, blood glucose levels initially drop to 65–75 mg/ dl, where they are maintained at a steady low level.] These metabolic changes during fasting, which are included in Fig. 1.2, help provide adequate energy supply to all the organs in the body.

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1.3.2 C  entral Regulation of Blood Glucose Levels The brain serves as the regulating center for body homeostasis. It detects glucose levels, interprets related signals through hormones, and continuously tunes body mechanisms to maintain blood glucose within a predetermined range. Some neurons can respond to extracellular glucose levels, i.e., glucose-sensing neurons. Two such groups of neurons exist glucose-excited (GE) neurons vs. glucose-inhibited (GI) neurons. These functionally opposing neurons are found intermingled in many hypothalamic regions, including the arcuate nucleus, ventromedial nucleus, paraventricular nucleus, and lateral hypothalamus [30]. Glucose sensing in the brain is modulated by hormonal status, which reflects body energy homeostasis. The “satiety” hormones leptin (from adipose tissue) and insulin, as well as the incretin GLP-1 (from the small intestine), are released after meal intake. In contrast, the “hunger” hormone ghrelin is secreted from the stomach in the fasting state. These hormones can activate or inhibit relevant glucose-sensing neurons by binding onto their specific receptors. Mounting evidence suggests that hypothalamic glial cells also play an important role in glucose sensing. These cells include astrocytes and tanycytes, specialized ependymal cells lining the lower part of the third ventricle [31, 32]. Notably, the median eminence of the third ventricle has BBB-free areas, which is favorable for glucose transport from the peripheral blood to the nearby arcuate nucleus [33]. The nucleus of the solitary tract in the hindbrain is another brain region containing glucose-sensing cells [34]. This area is a viscerosensory center that collects metabolic signals from the body, especially from the gastrointestinal tract, via vagal afferents. When the body is deprived of glucose, GE neurons are inhibited, and GI neurons are activated, which increases hepatic glucose production while lowering glucose disposal and energy expenditure. Altered neuronal activities also result in higher wakefulness and locomotor activity, which help trigger food-seeking behaviors for glucose replenishment. By coordinating these

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various mechanisms, the brain can simultaneously monitor and control glucose levels. Acknowledgment  This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIT) (No. 2018R1C1B5086453 and 2020R1C1C1008033) and Creative-Pioneering Researchers Program through Seoul National University. We are also very grateful to So Yun Lee and Yena Joo (Seoul National University College of Medicine), who helped prepare the script for publication.

References 1. Cabrera O, Berman DM, Kenyon NS, Ricordi C, Berggren PO, Caicedo A.  The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc Natl Acad Sci U S A. 2006;103(7):2334–9. https://doi.org/10.1073/ pnas.0510790103. 2. Hart NJ, Powers AC.  Use of human islets to understand islet biology and diabetes: progress, challenges and suggestions. Diabetologia. 2019;62(2):212–22. https://doi.org/10.1007/s00125-­018-­4772-­2. 3. Orci L, Unger RH.  Functional subdivision of islets of Langerhans and possible role of D cells. Lancet. 1975;2(7947):1243–4. https://doi.org/10.1016/ s0140-­6736(75)92078-­4. 4. Levetan CS, Pierce SM. Distinctions between the islets of mice and men: implications for new therapies for type 1 and 2 diabetes. Endocr Pract. 2013;19(2):301– 12. https://doi.org/10.4158/EP12138.RA. 5. Owerbach D, Bell GI, Rutter WJ, Brown JA, Shows TB. The insulin gene is located on the short arm of chromosome 11 in humans. Diabetes. 1981;30(3):267–70. https://doi.org/10.2337/diab.30.3.267. 6. Faber OK, Hagen C, Binder C, Markussen J, Naithani VK, Blix PM, et  al. Kinetics of human connecting peptide in normal and diabetic subjects. J Clin Invest. 1978;62(1):197–203. https://doi.org/10.1172/ JCI109106. 7. Henquin JC, Dufrane D, Nenquin M.  Nutrient control of insulin secretion in isolated normal human islets. Diabetes. 2006;55(12):3470–7. https://doi. org/10.2337/db06-­0868. 8. Henquin JC, Nenquin M, Stiernet P, Ahren B. In vivo and in  vitro glucose-induced biphasic insulin secretion in the mouse: pattern and role of cytoplasmic Ca2+ and amplification signals in beta-cells. Diabetes. 2006;55(2):441–51. https://doi.org/10.2337/diabetes.55.02.06.db05-­1051. 9. Nerenberg ST.  Regranulation of beta cells of islets of Langerhans following insulin and starvation. Am J Clin Pathol. 1953;23(4):340–2. https://doi. org/10.1093/ajcp/23.4.340.

O. Kwon 10. Unger RH, Ohneda A, Valverde I, Eisentraut AM, Exton J.  Characterization of the responses of circulating glucagon-like immunoreactivity to intraduodenal and intravenous administration of glucose. J Clin Invest. 1968;47(1):48–65. https://doi.org/10.1172/ JCI105714. 11. Bell GI, Santerre RF, Mullenbach GT. Hamster preproglucagon contains the sequence of glucagon and two related peptides. Nature. 1983;302(5910):716–8. https://doi.org/10.1038/302716a0. 12. Cryer PE, Tse TF, Clutter WE, Shah SD.  Roles of glucagon and epinephrine in hypoglycemic and nonhypoglycemic glucose counterregulation in humans. Am J Phys. 1984;247(2 Pt 1):E198–205. https://doi. org/10.1152/ajpendo.1984.247.2.E198. 13. Mather A, Pollock C.  Glucose handling by the kidney. Kidney Int Suppl. 2011;120:S1–6. https://doi. org/10.1038/ki.2010.509. 14. Lee WS, Kanai Y, Wells RG, Hediger MA. The high affinity Na+/glucose cotransporter. Re-evaluation of function and distribution of expression. J Biol Chem. 1994;269(16):12032–9. 15. Burant CF, Takeda J, Brot-Laroche E, Bell GI, Davidson NO.  Fructose transporter in human spermatozoa and small intestine is GLUT5. J Biol Chem. 1992;267(21):14523–6. 16. Vergari E, Knudsen JG, Ramracheya R, Salehi A, Zhang Q, Adam J, et  al. Insulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion. Nat Commun. 2019;10(1):139. https:// doi.org/10.1038/s41467-­018-­08193-­8. 17. Kawamori D, Kurpad AJ, Hu J, Liew CW, Shih JL, Ford EL, et  al. Insulin signaling in alpha cells modulates glucagon secretion in  vivo. Cell Metab. 2009;9(4):350–61. https://doi.org/10.1016/j. cmet.2009.02.007. 18. Elrick H, Stimmler L, Hlad CJ Jr, Arai Y. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab. 1964;24:1076–82. https://doi.org/10.1210/jcem-­24-­10-­1076. 19. Creutzfeldt W.  The incretin concept today. Diabetologia. 1979;16(2):75–85. https://doi. org/10.1007/BF01225454. 20. Bell GI, Kayano T, Buse JB, Burant CF, Takeda J, Lin D, et  al. Molecular biology of mammalian glucose transporters. Diabetes Care. 1990;13(3):198–208. https://doi.org/10.2337/diacare.13.3.198. 21. Wick AN, Drury DR, Nakada HI, Wolfe JB.  Localization of the primary metabolic block produced by 2-deoxyglucose. J Biol Chem. 1957;224(2):963–9. 22. Erbsloh F, Bernsmeier A, Hillesheim H.  The glu cose consumption of the brain & its dependence on the liver. Arch Psychiatr Nervenkr Z Gesamte Neurol Psychiatr. 1958;196(6):611–26. https://doi. org/10.1007/BF00344388. 23. Daneman R, Prat A.  The blood-brain barrier. Cold Spring Harb Perspect Biol. 2015;7(1):a020412. https://doi.org/10.1101/cshperspect.a020412.

1  Glucose Metabolism 24. Lam CK, Chari M, Lam TK. CNS regulation of glucose homeostasis. Physiology (Bethesda). 2009;24:159– 70. https://doi.org/10.1152/physiol.00003.2009. 25. Clarke DD.  Circulation and energy metabolism of the brain. In: Basic neurochemistry: molecular, cellular, and medical aspects. American Society for Neurochemistry; 1999. 26. Siesjö BK.  Brain energy metabolism. New  York: Wiley; 1978. 27. Fox PT, Raichle ME, Mintun MA, Dence C.  Nonoxidative glucose consumption during focal physiologic neural activity. Science. 1988;241(4864):462–4. https://doi.org/10.1126/ science.3260686. 28. Vaishnavi SN, Vlassenko AG, Rundle MM, Snyder AZ, Mintun MA, Raichle ME. Regional aerobic glycolysis in the human brain. Proc Natl Acad Sci U S A. 2010;107(41):17757–62. https://doi.org/10.1073/ pnas.1010459107. 29. Dienel GA.  Brain glucose metabolism: integra tion of energetics with function. Physiol Rev. 2019;99(1):949–1045. https://doi.org/10.1152/ physrev.00062.2017. 30. Routh VH, Hao L, Santiago AM, Sheng Z, Zhou C. Hypothalamic glucose sensing: making ends

13 meet. Front Syst Neurosci. 2014;8:236. https://doi. org/10.3389/fnsys.2014.00236. 31. Garcia M, Millan C, Balmaceda-Aguilera C, Castro T, Pastor P, Montecinos H, et  al. Hypothalamic ependymal-glial cells express the glucose transporter GLUT2, a protein involved in glucose sensing. J Neurochem. 2003;86(3):709–24. https://doi. org/10.1046/j.1471-­4159.2003.01892.x. 32. Marty N, Dallaporta M, Foretz M, Emery M, Tarussio D, Bady I, et  al. Regulation of glucagon secretion by glucose transporter type 2 (glut2) and astrocyte-dependent glucose sensors. J Clin Invest. 2005;115(12):3545–53. https://doi.org/10.1172/ JCI26309. 33. Knigge KM, Weindl A, Scott DE.  Brain-endocrine interaction. Median eminence: structure and function. In: International symposium on brain-endocrine interaction (1971: Munich). New  York: S.  Karger; 1972. 34. Ritter S, Dinh TT, Zhang Y. Localization of hindbrain glucoreceptive sites controlling food intake and blood glucose. Brain Res. 2000;856(1–2):37–47. https://doi. org/10.1016/s0006-­8993(99)02327-­6.

2

Pathophysiology and Risk Factors of Diabetes Hae Kyung Kim and Byung-Wan Lee

Abstract

Diabetes mellitus (DM) is a group of metabolic disorders that share factors contributing to hyperglycemia including reduced insulin secretion, decreased glucose utilization, and increased glucose production. Many pathways driven by various genetic and environmental factors result in progressive loss of beta cell mass and function, leading to hyperglycemia. Patients with hyperglycemia are predisposed to risk for complications, including cardiovascular diseases, end-stage renal disease (ESRD), non-traumatic lower extremity amputation, and adult blindness. In 2015, a research symposium titled “The Differentiation of Diabetes by Pathophysiology, Natural History and Prognosis” was held by the American Diabetes Association (ADA), Juvenile Diabetes Research Foundation (JDRF), European Association for the Study of Diabetes, and American Association of Clinical Endocrinologists. International experts in various fields, including genetics, immunology, metabolism, endocrinology, and H. K. Kim · B.-W. Lee (*) Division of Endocrinology and Metabolism, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea e-mail: [email protected]; [email protected]

systems biology, overviewed type 1 and type 2 DM, particularly genetic and environmental determinants, risk, progression, and complications. Understanding the pathophysiology of DM and identifying individuals at high risk will help develop appropriate therapeutic approaches.

2.1

Pathophysiology of Diabetes

2.1.1 Type 1 Diabetes Mellitus Type 1 Diabetes Mellitus (T1DM) is generally considered to result from the destruction of insulin-­ producing pancreatic beta cells [1, 2]. Most individuals with T1DM have evidence of islet-directed autoimmunity, although some lack the immunologic and genetic markers. Such individuals, who develop insulin deficiency by unknown and nonimmune mechanisms, are ketosis prone and tend to be of African or Asian heritage. The decline of beta cell function preceding development of T1DM is shown schematically in Fig. 2.1 [3]. In genetically susceptible individuals, the autoimmune process is thought to be triggered by an infectious or environmental stimulus, which can occur as early as in utero and into the first months to years of life, affecting the onset and continuance of beta cell autoimmunity [2].

© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021 S.-H. Lee, D.-W. Kang (eds.), Stroke Revisited: Diabetes in Stroke, Stroke Revisited, https://doi.org/10.1007/978-981-16-5123-6_2

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H. K. Kim and B.-W. Lee

Fig. 2.1  The natural history of type 1 diabetes. Adapted with permission from The Lancet, Copyright Elsevier [3]

Changes in insulin secretion and glucose tolerance occur months to decades after multiple islet autoantibodies are detected [4]. Metabolic changes in T1DM are apparent by a reduction in c-peptide level at least 2  years before onset [5] and fluctuations in blood glucose [6]. Before threshold loss of insulin secretion and beta cell mass, residual functional beta cells exist but are insufficient in number and quality to maintain glucose tolerance. The transition from glucose intolerance to overt diabetes is triggered by various events, such as infection or puberty. After initial clinical presentation of T1DM, the transient phase of endogenous insulin production from residual beta cells has passed, and the individual becomes insulin deficient. Symptoms of the disease are considered to appear when 85–90% of pancreatic beta cells have been destroyed; by the final stage, the autoimmune process has resulted in total elimination of beta cells. A small amount of insulin (as reflected by c-peptide production) is produced in individuals with longstanding T1DM, and individuals with a

50-year history of T1DM demonstrate evidence of insulin-positive cells in the pancreas at autopsy.

2.1.1.1 Stages in the Natural History of T1DM T1DM is a unique pathologic state with autoimmunity and progression to metabolic and clinical derangements. The ADA, JDRF, and Endocrine Society released a joint position statement calling for staging of pre-T1DM (Fig. 2.2) [7]. Stage 1 is defined by the identification of two or more anti-­ islet autoantibodies with normal glucose tolerance on 2-h oral glucose tolerance test (OGTT). Stage 2 refers to an impaired glucose tolerance state in the setting of two or more anti-islet autoantibodies. Finally, stage 3 represents overt diabetes as defined by the ADA criteria. However, there are no evidence-based recommendations for anti-islet autoantibody-­ positive patients, although a previous study demonstrated that close monitoring of high risk patients significantly reduced the rates of diabetic ketoacidosis (DKA) at diagnosis [8].

2  Pathophysiology and Risk Factors of Diabetes

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Fig. 2.2  Staging of pre-type 1 diabetes mellitus. Adapted with permission from Nature Reviews Disease Primers, Copyright Springer Nature (Katsarou et al., Nat Rev. Dis Primers, 2017, 30;3:17016)

2.1.1.2 Genetic Considerations T1DM is a polygenic disorder, with nearly 40 loci that affect disease susceptibility [9]. Genetic concordance in identical twins with T1DM ranges between 40 and 60%, implying that other additional factors are required for development of diabetes. The HLA region on chromosome 6p21 is the major susceptibility gene for T1DM [10]. HLA class II demonstrates the strongest association with T1DM, particularly the DR, DQ, and DP molecules. Table 2.1 summarizes the risk of diabetes by DR and DQ haplotypes [11]. The HLA DR3 and/or DR4 haplotypes are most common in patients with T1DM, and the haplotypes DQA1*0301, DQB1*0302, and DQB1*0201 are found in 40% of children with T1DM compared to 2% of the normal US population. HLA class I also influence risk for T1DM, independent of class II molecules [10]. In addition to MHC class II associations, genome association studies have identified at least 20 additional genetic loci that contribute to susceptibility to T1DM (polymorphisms in the promoter region of the insulin gene, the CTLA-4 gene, interleukin 2 receptor, PTPN22, etc) [12]. Most of the loci associated with risk for T1DM are involved in immune responses that show genetic influences to collec-

Table 2.1 Diabetes risk stratification according to HLA-DR and DQ halotypes DRB1 High risk 0401 or 0403 or 0405 0301 Moderate risk 0801 0404 0101 0901 Moderate protection 0403 0701 1101 Strong protection 1501 1401 0701

DQA1

DQB1

0301 0501

0302 (DQ8) 0201 (DQ2)

0401 0301 0101 0301

0402 0302 0501 0303

0301 0201 0501

0302 0201 0301

0102 0101 0201

0602 (DQ6) 0503 0303

Adapted with permission from Elsevier. This article was published in Williams Textbook of endocrinology 14th edition, Melmed, Shlomo, Koenig, Ronald, Rosen, Clifford, Auchus, Richard, Goldfine, Allison, Chapter 36 Type 1 Diabetes Mellitus, Copyright Elsevier (2020)

tively contribute to aberrant immune effects. This mechanism explains the differing rates of progression of T1DM in adults and children, who showed only minor variations in genetic susceptibility [13].

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2.1.1.3 Pathophysiology Unlike the beta cells in patients with T1DM, other islet cells, such as glucagon-producing alpha cells, somatostatin-producing delta cells, and pancreatic polypeptide-producing (PP) cells, are preserved from autoimmune destruction. However, dysfunctions in hormone secretion from these islet cells in patients with T1DM contribute to metabolic instability. Dysfunction of alpha cells induces fasting and postprandial hyperglucagonemia and impaired glucagon response to hypoglycemia. Studies of the autoimmune process in humans and in animal models of T1DM have identified humoral and cellular abnormalities, including islet cell autoantibodies, activated lymphocytes in the islets, peripancreatic lymph nodes, and T lymphocytes in the systemic circulation that proliferate when stimulated with islet proteins and release cytokines within the insulitis. The precise mechanisms involved in beta cell death are controversial but mainly involve the formation of direct CD8+ T cell cytotoxicity and apoptosis. The mechanisms of beta cell destruction in T1DM involve necrotic cell death by cytotoxic T cells in response to self-­ antigens [14]. Reactive oxygen species also mediate necrotic cell death in T1DM, inducing mitochondrial injury and loss of cell membrane integrity by DNA damage, lipid peroxidation, and protein damage [15]. Lastly, necrotic beta cells release factors including posttranslationally modified antigenic peptides [16] that stimulate the immune response to perpetuate beta cell necrosis. Apoptosis in beta cells in T1DM is associated with the Janus kinases (JAK1, JAK2) and non-receptor tyrosine-protein kinase (TYK2) pathways [17]. Cytokines such as tumor necrosis factor (TNF) trigger apoptosis, which activates Fas/FasL, TNFR1, TNFR2, and the B-cell lymphoma 2 (BCL2) pathway, leading to caspase activation and apoptotic cell morphology, nuclear fragmentation, and chromatin condensation, which have been observed in pancreas from a human patient with T1DM [18].

H. K. Kim and B.-W. Lee

2.1.1.4 Serologic Markers The presence of autoantibodies against beta cell autoantigens is the most distinguishing feature of T1DM compared with type 2 DM (T2DM). Pancreatic islet cell autoantibodies (ICA) are present in the majority (>85%) of patients with new-onset T1DM compared with a significant minority of individuals with newly diagnosed T2DM (5–10%). More than 90% of patients with newly diagnosed T1DM have one or more autoantibodies at onset of disease [19]. Autoantibodies reactive to insulin (IAA), glutamic acid decarboxylase (GADA), insulinoma-associated autoantigen 2 (IA2A), and zinc transporter 8 (ZnT8A) [20] are direct pancreatic islet cell autoantibodies (ICA) and can appear as early as 6 months of age, with a peak incidence before age 2  years, in genetically susceptible individuals [21]. In children with multiple autoantibodies, 70% developed T1DM after 10  years of follow-up, with 80% developing diabetes after 15  years of follow-­up, showing that the number of ICA is proportional to risk of T1DM.  Some studies have demonstrated that IAA concentration correlates with the rate of progression to overt T1DM in children [22, 23]. In addition to its diagnostic value in T1DM, testing for ICA in first-degree relatives or in the general population is useful for identifying nondiabetic individuals at risk for developing the disease. 2.1.1.5 Environmental Factors Numerous environmental factors that influence the pathogenesis of T1DM have been proposed. Differences in disease rates based on geography, seasonality, incidence, and variance among twins support this conclusion. Identification of environmental triggers has been difficult because the exposure event may precede the onset of DM by several years. The potential environmental candidates, either alone or in combination, include infection (particularly viruses), vaccination, and diet. Congenital rubella infection greatly increases the risk for T1DM [24], with mechanistic hypoth-

2  Pathophysiology and Risk Factors of Diabetes

eses ranging from molecular resemblance to long-term T cell dysfunction. In addition, infections with enteroviruses such as coxsackie virus and rotavirus have been reported to be associated with T1DM. Many studies that address the influence of childhood vaccinations in development of T1DM have been performed, but none have provided significant evidence of association [25]. Extensive investigations on dietary factors as environmental triggers of T1DM were performed involving bovine milk, cereals, low vitamin D, and ω-3 fatty acids but dietary interventions with these factors to present have not been therapeutic in many cases.

2.1.2 Type 2 Diabetes Mellitus The pathogenesis of T2DM involves the interaction of genetic and environmental factors. Environmental factors, particularly excessive caloric intake and sedentary lifestyle, play a critical role in the development of T2DM. Epigenetics, medications, circadian rhythm and disruptions, and the microbiome are environmental factors affecting the risk of T2DM. Three pathophysiologic key points in T2DM that lead to hyperglycemia in the fasting state are insulin resistance in peripheral tissues (muscle, liver, adipose tissue), abnormal insulin secretion in response to glucose stimulus, and increased glucose production by the liver. Despite the debate over the primary defect, most studies support the hypothesis that insulin resistance precedes defects in insulin secretion [26]. Factors such as additional insulin resistance factors of puberty, pregnancy, sedentary lifestyle, and excessive dietary intake worsen the secretory burden on pancreatic beta cells.

2.1.2.1 Genetic Considerations The common forms of T2DM are polygenic and are caused by interactions between genes and environmental and epigenetic factors. Risk of diabetes is increased in individuals with a single parent with T2DM and approaches 40% if both parents are diabetic. Genome-wide association

19

studies have identified more than 130 genetic variations associated with T2DM, glucose level, or insulin level, but these variants explain only 15% of disease heritability [27–29]. Recently, dramatic advances in the application of genome-­ wide associations (GWAS) have accelerated the understanding of the role of genes in T2DM; unbiased interrogation of the entire genome to determine disease-specific single nucleotide polymorphisms (SNPs) may provide clues for associated genes in the region. The genes that have been implicated in the pathogenesis of T2DM are shown in Fig. 2.3 [30]. Most prominent is a variant of the microsatellite DG10S478  in intron 3 of the transcription factor 7-like 2 gene (TCF7L2, formerly TCF4), which has been associated with T2DM in several populations and with IGT [31]. Genetic polymorphisms associated with T2DM have been found in genes encoding the peroxisome proliferator– activated receptor γ, inward rectifying potassium channel, zinc transporter, insulin receptor substrate 1, and calpain 10 [32, 33]. The mechanisms involved in the pathophysiology of these genetic loci that increase the susceptibility to T2DM are assumed to be alterations in development or function of islet cells or insulin secretion. Many studies have investigated genetic susceptibility to T2DM, but no definite strategy using a combination of known genetic loci to predict T2DM has been developed.

2.1.2.2 Pathophysiology T2DM is characterized by impaired insulin secretion, insulin resistance, excessive hepatic glucose production, abnormal fat metabolism, and systemic low-grade inflammation. As shown in Fig. 2.4, in the early stages of the disease, normal glucose tolerance is maintained despite insulin resistance due to compensating pancreatic beta cells that increase insulin output. Persistent insulin resistance and compensatory hyperinsulinemia eventually destroy the pancreatic islets to result in impaired glucose tolerance (IGT), which is characterized by postprandial hyperglycemia. Further decline in insulin secretion and hepatic

20

H. K. Kim and B.-W. Lee

Fig. 2.3  Venn diagram of the interaction between loci associated with genome-wide associations for six metabolic traits. BMI, body mass index; WHR, waist-to-hip

ratio. Adapted with permission from Diabetologia, Copyright Springer Nature [30]

glucose overproduction (by glucagon counteracting inadequate insulin suppression) ultimately cause overt diabetes with fasting hyperglycemia [34–36].

fat (especially intra-abdominal obesity), physical activity, diet, gut microbiota, and medications. Many studies have demonstrated that insulin resistance is a major factor in the development of IGT and diabetes [37, 38]. The molecular mechanisms of insulin resistance are triggered by various pathophysiologic processes of the insulin receptor and its adaptor proteins. Although the precise mechanism of insulin resistance has not been discovered, a common mechanism is activation of serine/threonine kinases that phosphorylate the insulin receptor and insulin receptor substrate (IRS) proteins, leading to inhibitory feedback of the insulin cascade. The activities of several serine/threonine protein kinases catalyzing inhibitory phosphorylation of the insulin receptor or IRS proteins are elevated in animal models of insulin resistance

2.1.2.3 Insulin Resistance Insulin resistance indicates an impaired biologic response to either exogenous or endogenous insulin on target tissues, especially muscle, liver, and adipose tissue. Given the pleiotropic actions of insulin, insulin resistance causes decreased insulin-stimulated glucose transport and metabolism in skeletal muscle, impaired ability of insulin to suppress hepatic glucose production, and impaired insulin suppression of adipocyte lipolysis, leading to disorders of multiple metabolic pathways. Insulin sensitivity is influence by several factors including age, weight, ethnicity, body

2  Pathophysiology and Risk Factors of Diabetes

Fig. 2.4 Graph depicting the hyperbolic relationship between insulin secretion and insulin sensitivity. Insulin secretion rises as insulin sensitivity falls when an individual goes from a state of exercise training/being physically active (point A) to detraining/sedentary (point B) and vice versa, that is, bidirectionality of the two arrows from B to A when undergoing exercise training/increasing physical activity levels. A failure of insulin secretion to compensate for a fall in insulin sensitivity is noted when both insulin secretion and insulin sensitivity decline from points B to C, leading to elevated fasting glucose and prediabetes (impaired glucose tolerance). A progressive decline in both insulin secretion and insulin sensitivity to point D indicates type 2 diabetes. Adapted with permission from Comprehensive Physiology, Copyright John Wiley and Sons (Roberts et al., 2013, 3:1–58)

and in insulin-resistant humans [39, 40]. Another mechanism of insulin resistance is protein–protein interactions, which decrease insulin receptor phosphorylation or inhibit its interactions with IRS proteins. Also, mutation in the insulin receptor and autoantibodies to the insulin receptor (type B insulin resistance and acanthosis nigricans) [41, 42] are associated with insulin resistance. The primary site of glucose disposal after a meal is skeletal muscle, which stores glucose in the form of glycogen [43]. In obesity, insulin resistance in skeletal muscle manifests prior to abnormal insulin signaling in adipose tissue and the liver, reflecting the relatively limited nutrient storage capacity of skeletal muscle. Previous studies have demonstrated a deficiency in non-­ oxidative disposal of glucose related to a defect in glycogen synthesis by muscle [44]. Insulin resistance in the liver reflects the failure of hyperinsulinemia to suppress gluconeogenesis, result-

21

ing in fasting hyperglycemia and decreased glycogen storage by the liver in the postprandial state. Early in the course of diabetes, probably after onset of insulin secretory dysfunction and insulin resistance in skeletal muscle, increased hepatic glucose production occurs [45]. Increased lipolysis and free fatty acid flux from adipocytes due to insulin resistance in adipose tissue are eliminated by liver leading to increased synthesis of very-low-density lipoprotein (VLDL) and triglyceride in hepatocytes and secretion from liver. Elevated lipid synthesis in the liver due to insulin resistance is responsible for dyslipidemia in patients with T2DM [46]. Also, enhanced fatty acid delivery from adipose tissue to the liver in insulin-resistant states and lipid accumulation cause steatosis in the liver, which may lead to nonalcoholic fatty liver disease and abnormal liver function [47]. Most excess nutrients are ultimately stored as triglycerides in adipose tissue, and if the storage capacity of adipose tissue is exceeded, lipids and nutrients enter non-storage tissues. This ectopic lipid accumulation occurs in myocytes, hepatocytes, vascular cells, and pancreatic beta cells, producing toxic lipid metabolites that trigger protein kinase C activation to lead to insulin resistance [46]. Uncompensated fat mass expansion in response to overeating is suggested to be an important factor in the development of insulin resistance [48].

2.1.2.4 Special Conditions Inducing Insulin Resistance Diabetes in pregnancy is subdivided into two categories according to trimester of diagnosis: preexisting T2DM is diagnosed during the first trimester, while gestational diabetes (GDM) is diagnosed during the second or third trimester. Insulin resistance is a normal consequence of pregnancy, and maternal insulin secretion can increase 250% to compensate. However, when this compensation is inadequate, GDM develops, which can further develop to overt T2DM [49, 50]. Weight gain and placenta-derived factors such as growth hormones and placental lactogens and beta cell expansion in pregnancy induce insulin resistance in pregnancy [51, 52].

H. K. Kim and B.-W. Lee

22

Many disease states and medications can induce insulin resistance and decreased insulin secretion, leading to glucose intolerance, as shown in Table 2.2.

2.2

Risk Factors of Diabetes

Genetic and environmental risk factors influence inflammation, autoimmunity, and metabolic stress, and the resulting beta cell mass decrement and dysfunction eventually lead to insufficient response to insulin demands. Figure  2.5 schematically shows how risk factors that lead to hyperglycemia, diabetes, and associated microvascular and macrovascular complications increase morbidity and mortality [53]. Therefore, screening tests such as fasting plasma glucose

(FPG) and HbA1c are recommended for individuals with predisposing risk factors for early detection of T2DM for the following reasons: (a) to identify asymptomatic prediabetic and diabetic patients who are unaware of the disorder and (b) to prevent and provide early interventions in diabetes-­ specific complications. The ADA recommendations for patients with predisposing risk factors for DM are listed in Table 2.3. All individuals aged >45 years should be tested every 3  years, while individuals who are overweight (BMI >25  kg/m2 or ethnically relevant definition of overweight) and have one additional risk factor for diabetes should be screened at an earlier age. Routine screening for immunologic markers of T1DM should be considered depending on the clinical benefit for individuals at high risk [54].

Table 2.2  Risk factors for type 2 diabetes mellitus Risk factors for type 2 diabetes mellitus • Overweight or obese • Age 45 or older • A family history of diabetes • African American, Alaska Native, American Indian, Asian American, Hispanic/Latino, Native Hawaiian, or Pacific Islander • High blood pressure • A low level of HDL cholesterol, or a high level of triglycerides • A history of gestational diabetes or gave birth to a baby weighing 9 pounds or more • Not physically active • A history of heart disease or stroke • Depression • Polycystic ovary syndrome (PCOS) • Acanthosis nigricans Adapted from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (https://www. niddk.nih.gov/health-­i nformation/diabetes/overview/ risk-­factors-­type-­2-­diabetes)

Inflammation and autoimmunity • •

Table 2.3  Stressors and medications associated with insulin resistance Stressors Pregnancy Glucotoxicity Surgery Inflammation (From obesity or infection) Overnutrition Drugs Glucocorticoids Human immunodeficiency virus medications Calcineurin inhibitors Mammalian target of rapamycin (mTOR) inhibitors Phosphoinositide 3-kinase inhibitors Statins Adapted with permission from Elsevier. This article was published in Williams Textbook of endocrinology 14th edition, Melmed, Shlomo, Koenig, Ronald, Rosen, Clifford, Auchus, Richard, Goldfine, Allison, Chapter 34 Type 2 Diabetes Mellitus, Copyright Elsevier (2020)

β-cell destruction

Genetic predisposition Environmental factors (viruses, microbiome, physical activity, dietary factors)

Hyperglycemia

Inflammation and metabolic stress

Diabetes (Type 1, 2)

β -cell dysfunction

Fig. 2.5  Schematic diagram demonstrating genetic and environmental risk factors influencing inflammation, autoimmunity, and metabolic stress to induce diabetes

2  Pathophysiology and Risk Factors of Diabetes

References 1. Todd JA.  Etiology of type 1 diabetes. Immunity. 2010;32(4):457–67. 2. Bluestone JA, Herold K, Eisenbarth G.  Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature. 2010;464(7293):1293–300. 3. Atkinson MA, Eisenbarth GS, Michels AW.  Type 1 diabetes. Lancet. 2014;383(9911):69–82. 4. Bonifacio E, Ziegler AG. Advances in the prediction and natural history of type 1 diabetes. Endocrinol Metab Clin N Am. 2010;39(3):513–25. 5. Sosenko JM, Palmer JP, Rafkin LE, Krischer JP, Cuthbertson D, Greenbaum CJ, et al. Trends of earlier and later responses of C-peptide to oral glucose challenges with progression to type 1 diabetes in diabetes prevention trial-type 1 participants. Diabetes Care. 2010;33(3):620–5. 6. Sosenko JM, Skyler JS, Krischer JP, Greenbaum CJ, Mahon J, Rafkin LE, et  al. Glucose excursions between states of glycemia with progression to type 1 diabetes in the diabetes prevention trial-type 1 (DPT-­ 1). Diabetes. 2010;59(10):2386–9. 7. Insel RA, Dunne JL, Atkinson MA, Chiang JL, Dabelea D, Gottlieb PA, et al. Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care. 2015;38(10):1964–74. 8. Elding Larsson H, Vehik K, Bell R, Dabelea D, Dolan L, Pihoker C, et  al. Reduced prevalence of diabetic ketoacidosis at diagnosis of type 1 diabetes in young children participating in longitudinal follow-up. Diabetes Care. 2011;34(11):2347–52. 9. Concannon P, Rich SS, Nepom GT. Genetics of type 1A diabetes. N Engl J Med. 2009;360(16):1646–54. 10. Noble JA, Valdes AM, Varney MD, Carlson JA, Moonsamy P, Fear AL, et  al. HLA class I and genetic susceptibility to type 1 diabetes: results from the type 1 diabetes genetics consortium. Diabetes. 2010;59(11):2972–9. 11. Erlich H, Valdes AM, Noble J, Carlson JA, Varney M, Concannon P, et al. HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes. 2008;57(4):1084–92. 12. Polychronakos C, Li Q. Understanding type 1 diabetes through genetics: advances and prospects. Nat Rev Genet. 2011;12(11):781–92. 13. Howson JM, Rosinger S, Smyth DJ, Boehm BO, Todd JA. Genetic analysis of adult-onset autoimmune diabetes. Diabetes. 2011;60(10):2645–53. 14. Campbell-Thompson M, Fu A, Kaddis JS, Wasserfall C, Schatz DA, Pugliese A, et  al. Insulitis and β-cell mass in the natural history of type 1 diabetes. Diabetes. 2016;65(3):719–31. 15. Wilcox NS, Rui J, Hebrok M, Herold KC.  Life and death of β cells in type 1 diabetes: a comprehensive review. J Autoimmun. 2016;71:51–8.

23 16. Kracht MJ, van Lummel M, Nikolic T, Joosten AM, Laban S, van der Slik AR, et al. Autoimmunity against a defective ribosomal insulin gene product in type 1 diabetes. Nat Med. 2017;23(4):501–7. 17. Marroqui L, Dos Santos RS, Fløyel T, Grieco FA, Santin I, Op de Beeck A, et  al. TYK2, a candidate gene for type 1 diabetes, modulates apoptosis and the innate immune response in human pancreatic β-cells. Diabetes. 2015;64(11):3808–17. 18. Brozzi F, Eizirik DL.  ER stress and the decline and fall of pancreatic beta cells in type 1 diabetes. Ups J Med Sci. 2016;121(2):133–9. 19. Bingley PJ. Clinical applications of diabetes antibody testing. J Clin Endocrinol Metab. 2010;95(1):25–33. 20. Ziegler AG, Nepom GT. Prediction and pathogenesis in type 1 diabetes. Immunity. 2010;32(4):468–78. 21. Ziegler AG, Bonifacio E.  Age-related islet autoantibody incidence in offspring of patients with type 1 diabetes. Diabetologia. 2012;55(7):1937–43. 22. Steck AK, Johnson K, Barriga KJ, Miao D, Yu L, Hutton JC, et al. Age of islet autoantibody appearance and mean levels of insulin, but not GAD or IA-2 autoantibodies, predict age of diagnosis of type 1 diabetes: diabetes autoimmunity study in the young. Diabetes Care. 2011;34(6):1397–9. 23. Parikka V, Näntö-Salonen K, Saarinen M, Simell T, Ilonen J, Hyöty H, et  al. Early seroconversion and rapidly increasing autoantibody concentrations predict prepubertal manifestation of type 1 diabetes in children at genetic risk. Diabetologia. 2012;55(7):1926–36. 24. Shaver KA, Boughman JA, Nance WE.  Congenital rubella syndrome and diabetes: a review of epidemiologic, genetic, and immunologic factors. Am Ann Deaf. 1985;130(6):526–32. 25. Graves PM, Barriga KJ, Norris JM, Hoffman MR, Yu L, Eisenbarth GS, et al. Lack of association between early childhood immunizations and beta-cell autoimmunity. Diabetes Care. 1999;22(10):1694–7. 26. Eriksson J, Franssila-Kallunki A, Ekstrand A, Saloranta C, Widén E, Schalin C, et  al. Early metabolic defects in persons at increased risk for non-­ insulin-­dependent diabetes mellitus. N Engl J Med. 1989;321(6):337–43. 27. Morris AP, Voight BF, Teslovich TM, Ferreira T, Segrè AV, Steinthorsdottir V, et  al. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet. 2012;44(9):981–90. 28. Scott RA, Lagou V, Welch RP, Wheeler E, Montasser ME, Luan J, et  al. Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. Nat Genet. 2012;44(9):991–1005. 29. Gaulton KJ, Ferreira T, Lee Y, Raimondo A, Mägi R, Reschen ME, et  al. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci. Nat Genet. 2015;47(12):1415–25.

24 30. Grarup N, Sandholt CH, Hansen T, Pedersen O. Genetic susceptibility to type 2 diabetes and obesity: from genome-wide association studies to rare variants and beyond. Diabetologia. 2014;57(8):1528–41. 31. Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet. 2006;38(3):320–3. 32. Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet. 2000;26(1):76–80. 33. Mahajan A, Wessel J, Willems SM, Zhao W, Robertson NR, Chu AY, et al. Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. Nat Genet. 2018;50(4):559–71. 34. Kahn SE.  Clinical review 135: the importance of beta-cell failure in the development and progression of type 2 diabetes. J Clin Endocrinol Metab. 2001;86(9):4047–58. 35. Bergman RN, Ader M. Free fatty acids and pathogenesis of type 2 diabetes mellitus. Trends Endocrinol Metab. 2000;11(9):351–6. 36. Yoo S, Yang EJ, Koh G. Factors related to blood intact incretin levels in patients with type 2 diabetes mellitus. Diabetes Metab J. 2019;43(4):495–503. 37. Warram JH, Martin BC, Krolewski AS, Soeldner JS, Kahn CR. Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. Ann Intern Med. 1990;113(12):909–15. 38. Lillioja S, Mott DM, Howard BV, Bennett PH, Yki-­ Järvinen H, Freymond D, et al. Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians. N Engl J Med. 1988;318(19):1217–25. 39. Formisano P, Beguinot F. The role of protein kinase C isoforms in insulin action. J Endocrinol Investig. 2001;24(6):460–7. 40. Itani SI, Zhou Q, Pories WJ, MacDonald KG, Dohm GL. Involvement of protein kinase C in human skeletal muscle insulin resistance and obesity. Diabetes. 2000;49(8):1353–8. 41. Kahn CR, Flier JS, Bar RS, Archer JA, Gorden P, Martin MM, et  al. The syndromes of insulin resis-

H. K. Kim and B.-W. Lee tance and acanthosis nigricans. Insulin-receptor disorders in man. N Engl J Med. 1976;294(14):739–45. 42. Hussain I, Garg A.  Lipodystrophy syndromes. Endocrinol Metab Clin N Am. 2016;45(4):783–97. 43. Marette A, Liu Y, Sweeney G.  Skeletal muscle glucose metabolism and inflammation in the development of the metabolic syndrome. Rev Endocr Metab Disord. 2014;15(4):299–305. 44. Freymond D, Bogardus C, Okubo M, Stone K, Mott D. Impaired insulin-stimulated muscle glycogen synthase activation in vivo in man is related to low fasting glycogen synthase phosphatase activity. J Clin Invest. 1988;82(5):1503–9. 45. Petersen MC, Shulman GI.  Mechanisms of insu lin action and insulin resistance. Physiol Rev. 2018;98(4):2133–223. 46. Samuel VT, Shulman GI. The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J Clin Invest. 2016;126(1):12–22. 47. Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol. 2013;10(11):686–90. 48. Vidal-Puig A.  Adipose tissue expandability, lipotoxicity and the metabolic syndrome. Endocrinol Nutr. 2013;60(Suppl 1):39–43. 49. Barbour LA, McCurdy CE, Hernandez TL, Kirwan JP, Catalano PM, Friedman JE. Cellular mechanisms for insulin resistance in normal pregnancy and gestational diabetes. Diabetes Care. 2007;30(Suppl 2):S112–9. 50. Bellamy L, Casas JP, Hingorani AD, Williams D.  Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis. Lancet. 2009;373(9677):1773–9. 51. Billestrup N, Nielsen JH.  The stimulatory effect of growth hormone, prolactin, and placental lactogen on beta-cell proliferation is not mediated by insulin-like growth factor-I. Endocrinology. 1991;129(2):883–8. 52. Genevay M, Pontes H, Meda P. Beta cell adaptation in pregnancy: a major difference between humans and rodents? Diabetologia. 2010;53(10):2089–92. 53. Skyler JS, Bakris GL, Bonifacio E, Darsow T, Eckel RH, Groop L, et  al. Differentiation of diabetes by pathophysiology, natural history, and prognosis. Diabetes. 2017;66(2):241–55. 54. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S14–s31.

3

Macro- and Microvascular Complications of Diabetes Wookjin Yang

Abstract

This chapter describes the vascular complications of diabetes. Persistent hyperglycemia damages endothelial cells throughout the vascular system. Hyperglycemic injury of large vessels and small vessels advance to macro- and microvascular complications, respectively. Ischemic stroke is a macrovascular complication; in other words, patients with stroke who have diabetes are likely to have other diabetic vascular complications as well. In addition, apart from its effects on mortality and morbidity, macro- and microvascular complications influence the management of patients with stroke. Therefore, stroke physicians should be able to deal with vascular complications when they treat patients with diabetes rather than referring all patients to endocrinologists. Macrovascular complications involve a medium- or large-­sized vessels and manifest as atherosclerosis. Atherosclerotic progression is accelerated under hyperglycemic conditions and leads to cardiovascular diseases, which is a top cause of death in patients with diabetes. Microvascular complications arise from injuries of small vessels including capillaries and small arterioles. Classic diabetic microvascuW. Yang (*) Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea

lar complications include diabetic retinopathy, nephropathy, and neuropathy. Intensive glycemic control may help reduce vascular damage and is an important strategy in preventing and delaying microvascular complications. However, the advantage of intensive glycemic control for avoiding macrovascular complications is controversial: patients with longer diabetes duration and higher cardiovascular risks conferred no benefit. Moreover, the risk of hypoglycemia should be considered in intensive glycemic control. Accordingly, the glycemic target should be individualized weighing the risk of hypoglycemia. Early use of antidiabetics with cardioprotective benefits (GLP-1 RAs or SGLT2 inhibitors) may be considered for patients with cardiovascular risk factors, including ischemic stroke.

Prolonged hyperglycemia causes significant damage to the human vasculature. Under high extracellular glucose concentrations, some types of cells downregulate their glucose transport activity; thus, the glucose uptake of these cells decreases. However, endothelial cells exhibited no significant differences in glucose uptake according to changes in extracellular glucose level, suggesting the lack of an autoregulatory system and a vulnerability to hyperglycemia [1]. Consequently, hyperglycemia is particularly

© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021 S.-H. Lee, D.-W. Kang (eds.), Stroke Revisited: Diabetes in Stroke, Stroke Revisited, https://doi.org/10.1007/978-981-16-5123-6_3

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W. Yang

26

harmful to endothelial cells, and various vascular complications develop as a result of endothelial damage. In this chapter, the vascular complications of diabetes will be discussed.

3.1

Definitions of Macroand Microvascular Complications of Diabetes

There are two categories of vascular complications of diabetes depending on the size of the affected vessel: macro- and microvascular complications (Fig. 3.1). Patients with type 1 diabetes (T1D) and type 2 diabetes (T2D) may develop macro- and microvascular complications before or after the diagnosis of diabetes. Macrovascular complications are triggered by atherosclerosis in large or medium-sized vessels. The progression of atherosclerosis leads to coronary artery disease, ischemic stroke, and peripheral artery disease, which are leading causes of Arteries

Macrovascular Complications

Cardiovascular diseases Cerebrovascular diseases Peripheral artery diseases

Fig. 3.1  Vascular complications of diabetes. Based on the size of the involved vessels, diabetic vascular complications can be classified into macro- and microvascular complications. Macrovascular complications arise from damage to large vessels such as arteries and they include cardiovascular diseases,

death and disability in patients with diabetes. Hyperglycemic injury of small-sized vessels (arterioles, venules, and capillaries) leads to microvascular complications [2]. Typical diabetic microvascular complications include retinopathy, neuropathy, and nephropathy—the so-called “triopathy.” As mentioned in the previous volume, physicians usually confuse diabetic microvascular complications with small vessel occlusion (SVO) stroke, and they may even consider SVO stroke to be a diabetic microvascular complication [3]. However, diabetic microvascular complications and SVO stroke completely differ from each other in anatomy and pathophysiology. To summarize, diabetic microvascular complications originate from capillary endothelial injury and basement membrane thickening caused by hyperglycemia. In contrast, lipohyalinosis involving small-sized arteries or large-sized arterioles caused by hypertensive physical damage is the key mechanism of SVO stroke. In addition, diabetes was found to be associated with an Arterioles

Capillaries

Microvascular Complications

Retinopathy Nephropathy Neuropathy

cerebrovascular diseases, and peripheral artery diseases. Endothelial injuries of small vessels lead to microvascular complications. Typical microvascular complications comprise retinopathy, nephropathy, and neuropathy, well known as “diabetic triopathy” (made in ⓒBioRender— biorender.com)

3  Macro- and Microvascular Complications of Diabetes

27

Fig. 3.2 Pathogenesis of accelerated atherosclerosis under prolonged hyperglycemia. AGEs, advanced glycation end-products; LDL, low-density lipoprotein;

NFκB, nuclear factor κB; PKC, protein kinase C; and RAS, renin–angiotensin system

increased risk of large artery atherosclerotic stroke, but not with that of SVO stroke [4, 5]. Therefore, physicians should be aware that SVO stroke is not a diabetic microvascular complication.

crucial role in the development of endothelial dysfunction and diabetes-induced atherosclerosis (Fig. 3.2) [6]. Histopathologic and radiologic studies on coronary artery specimens have reported that patients with diabetes had larger lipid-rich atheromatous tissues, more macrophage infiltration, more calcification, more thrombi, and larger necrotic core sizes [7–9]. Thus, hyperglycemia results in higher atherosclerotic burden as well as its rapid progression.

3.2

Macrovascular Complications: Atherosclerosis and Cardiovascular Disease

3.2.1 Atherosclerosis in Diabetes Patients with diabetes usually present other features of the metabolic syndrome, such as hypertension, dyslipidemia, and obesity. It may also contribute to atherosclerosis; however, hyperglycemia itself reportedly facilitates atherosclerosis progression. A hyperglycemic environment is believed to produce several changes in vascular cells, viz., auto-oxidation of glucose, increased oxidized low-density lipoprotein cholesterol, increased glucose flux into polyol and hexosamine pathways, and formation of advanced glycation end-products, following which the production of reactive oxygen species is increased and protein kinase C and nuclear factor κB pathways are activated, which leads to endothelial dysfunction that eventually accelerates atherosclerosis. Renin–angiotensin system (RAS) activation in hyperglycemic conditions also plays a

3.2.2 Cardiovascular Diseases in Diabetes One of the most detrimental consequences of the promotion of atherosclerosis in diabetes is cardiovascular diseases such as coronary artery disease. Patients with diabetes have a 70% increase in cardiovascular mortality, which accounts for approximately 44% of deaths in these patients [10, 11]. Furthermore, the outcome of percutaneous coronary intervention is worse in patients with diabetes [12]. Given these risks, the prevention of cardiovascular diseases should be one of the top priorities of diabetes management. Although glycemic control in patients with diabetes cannot be overemphasized, physicians should not be obsessed solely with intensive glycemic control in the management of diabetic macrovascular complications. Intensive glycemic

W. Yang

28

control is generally known to reduce long-term cardiovascular diseases in both types of diabetes [13, 14]. However, several randomized controlled trials including patients with longer diabetes duration and more cardiovascular risk factors demonstrated no significant benefits of intensive glycemic control on cardiovascular outcomes [15]. Moreover, intensive glycemic control may lead to hypoglycemia, which worsens cardiovascular outcomes [16]. Thus, stroke physicians should carefully assess the benefits of intensive glycemic control and the risk of hypoglycemia, considering that patients with stroke are more likely to have multiple cardiovascular risk factors. The American Diabetes Association (ADA) recommends a target HbA1C level of 6.1 mmol/L [14]. A differential effect was noted between diabetic patients with poststroke hyperglycemia (relative risk 1.30, 95% confidence interval [CI] 0.49–3.43) and nondiabetic patients (relative risk 3.07, 95% CI, 2.50– 3.79). Thus, compared with diabetic patients, hyperglycemia resulting from stroke seems to be associated with a higher risk of in-hospital mortality in nondiabetic patients with acute ischemic stroke. Another study showed that higher glucose levels in the emergency room were significantly associated with an increased risk of all-cause mortality (hazard ratio [HR] 2.18, 95% CI, 1.37–

S. H. Heo

38

Cerebral infarction Penumbral tissue Ibfarct core Blood clot

Normoglycemic condition

Hyperglycemic condition

Time

Impaired recannalization ↑Thrombin–antithrombin complexes ↑Tissue factor pathway →↑ coagulation ↑Plasminogen activator inhibitor ↓Recombinant tissue plasminogen activator activity →↑ fibrinolysis

Decreased reperfusion ↓Nitric oxide →↑ vasodilatation ↑Prostaglandins → vasconstruiction

Increased reperfusion injury ↑Oxidative stress → tissue damage, edema, and impaired blood-brain barrier ↑Inflammatory response ↑Cytokines → tissue damage Direct tissue injury Mitochondrial dysfuction Anaerobic glycolysis lactic acidosis Hemorrhagic → conversion

Fig. 4.3  Schematic representation of infarct evolution over time. Hyperglycemia can have deleterious effects on various physiological processes associated with infarct

evolution in patients with acute ischemic stroke. Adapted with permission from Nature Reviews Neurology, Copyright Springer Nature [15]

3.48) and cardiovascular death (HR, 1.91; 95% CI, 1.10–3.61) [16]. It should be noted that hyperglycemia is a poor predictor of the clinical outcome of acute

ischemic stroke patients who undergo thrombolytic treatment with recombinant tissue plasminogen activator (rtPA). In the NINDS trial, hyperglycemia on admission was associated with

4  Hyperglycemia in Acute Stroke

poor neurological recovery. To date, European rtPA label contraindications include any history of prior stroke and concomitant diabetes. Hyperglycemia is associated with reduced rates of recanalization and an increased rate of hemorrhagic transformation when thrombolytic treatment is administered. If reperfusion is successful, the glucose load to the ischemic brain may worsen acidosis and ultimately convert the penumbra to infarcted tissue through the various mechanisms previously discussed. In addition to hyperglycemia, glycemic variability, fluctuation of blood glucose level, could potentially be associated with poor outcomes in stroke patients. A previous study reported that the glucose level range quartile was associated with poor outcomes, even after adjusting for the number of glucose measurements and hypoglycemia [17]. The deleterious effect of glycemic variability can be explained by oxidative stress increasing endothelial cell apoptosis, accumulated epigenetic modifications, and increased risk of severe hypoglycemia. Poor oral intake caused by dysphagia, mental changes and depressive mood, antidiabetic treatment using insulin, and systemic infection such as aspiration pneumonia and urinary tract infection at the acute stroke stage can make glucose control more difficult and worsen the glycemic variability. Studies based on coronary heart disease and intensive care unit data have shown a possible beneficial effect of insulin administration. However, clinical trials for treating hyperglycemia during acute stroke have failed to confirm better functional outcomes. Intensive glycemic control was not associated with favorable functional outcome at 90 days but instead increased hypoglycemic complications. Difficulties in setting the target blood glucose level and controlling blood glucose appropriately could influence these results.

4.4

Conclusion

The immune response to stroke is well known as a major factor in stroke pathophysiology and outcome. Hyperglycemia has shown harmful

39

effects on brain inflammation, especially in patients with stroke. Hyperglycemia affects the salvage of the ischemic penumbra; therefore, glucose control is important while there is still salvageable tissue. However, it is difficult to control hyperglycemia at this stage because of the various medical condition of disabled patients. In acute stroke patients, intensive glucose control has not been shown to be better than the standard treatment. Research to establish appropriate blood glucose targets, balancing hyperglycemic control and reducing hypoglycemic risk, is needed.

References 1. Scott JF, Robinson GM, French JM, O'Connell JE, Alberti KG, Gray CS. Prevalence of admission hyperglycaemia across clinical subtypes of acute stroke. Lancet. 1999;353(9150):376–7. 2. Fu Y, Liu Q, Anrather J, Shi FD.  Immune interventions in stroke. Nat Rev Neurol. 2015;11(9):524–35. 3. Shi K, Tian D-C, Li Z-G, Ducruet AF, Lawton MT, Shi F-D. Global brain inflammation in stroke. Lancet Neurol. 2019;18(11):1058–66. 4. Nakamura A, Otani K, Shichita T. Lipid mediators and sterile inflammation in ischemic stroke. Int Immunol. 2020;32(11):719–25. 5. Iadecola C, Anrather J.  The immunology of stroke: from mechanisms to translation. Nat Med. 2011;17(7):796–808. 6. Anrather J, Iadecola C. Inflammation and stroke: an overview. Neurotherapeutics. 2016;13(4):661–70. 7. McCall AL. Cerebral glucose metabolism in diabetes mellitus. Eur J Pharmacol. 2004;490(1–3):147–58. 8. de Vries MG, Arseneau LM, Lawson ME, Beverly JL.  Extracellular glucose in rat ventromedial hypothalamus during acute and recurrent hypoglycemia. Diabetes. 2003;52(11):2767–73. 9. Powers WJ.  Cerebrospinal fluid to serum glucose ratios in diabetes mellitus and bacterial meningitis. Am J Med. 1981;71(2):217–20. 10. Dasu MR, Devaraj S, Zhao L, Hwang DH, Jialal I.  High glucose induces toll-like receptor expression in human monocytes: mechanism of activation. Diabetes. 2008;57(11):3090–8. 11. Bahniwal M, Little JP, Klegeris A.  High glucose enhances neurotoxicity and inflammatory cytokine secretion by stimulated human astrocytes. Curr Alzheimer Res. 2017;14(7):731–41. 12. Mattson MP, Camandola S. NF-κB in neuronal plasticity and neurodegenerative disorders. J Clin Invest. 2001;107(3):247–54. 13. Muriach M, Flores-Bellver M, Romero FJ, Barcia JM. Diabetes and the brain: oxidative stress, inflam-

40 mation, and autophagy. Oxidative Med Cell Longev. 2014;2014:102158. 14. Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC. Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke. 2001;32(10):2426–32. 15. Kruyt ND, Biessels GJ, Devries JH, Roos YB. Hyperglycemia in acute ischemic stroke: pathophysiology and clinical management. Nat Rev Neurol. 2010;6(3):145–55.

S. H. Heo 16. Hu GC, Hsieh SF, Chen YM, Hsu HH, Hu YN, Chien KL. Relationship of initial glucose level and all-cause death in patients with ischaemic stroke: the roles of diabetes mellitus and glycated hemoglobin level. Eur J Neurol. 2012;19(6):884–91. 17. Kim YS, Kim C, Jung KH, Kwon HM, Heo SH, Kim BJ, et al. Range of glucose as a glycemic variability and 3-month outcome in diabetic patients with acute ischemic stroke. PLoS One. 2017;12(9):e0183894.

Part II Clinical Significance of Diabetes in Cerebro-cardiovascular Disease

5

Clinical Impact of Diabetes Mellitus in Cardiovascular Diseases Chan Joo Lee and Jong-Won Ha

Abstract

Diabetes mellitus plays an important role in the development and progression of atherosclerosis which is a main pathophysiology of cardiovascular diseases. Hypertension is the most common cause of cardiovascular diseases and it is one of the most common comorbidity in diabetic patients. The risk of cardiovascular disease is higher in people with concomitant hypertension and diabetes compared to those with hypertension or diabetes alone. Diabetes and hypertension synergistically contribute to the occurrence of vascular complications with chronic inflammation, oxidative stress, and advanced glycation end products. Coronary artery disease is 2–3 times more common in patients with diabetes mellitus than in those without diabetes, and coronary artery disease is the leading cause of death in diabetic patients. Atherosclerotic changes in multiple coronary arteries are more pronounced in diabetic patients than in nondiabetic patients. Peripheral artery disease is one of the most advanced atherosclerotic vascular complications of diabetes. The presence of peripheral artery disease is closely related C. J. Lee · J.-W. Ha (*) Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea e-mail: [email protected]; [email protected]

to the risk of myocardial infarction, cerebral infarction, and mortality. Poor glycemic control increases the prevalence of peripheral artery disease and has a close relationship with the risk of adverse outcomes after revascularization. Therefore, in diabetic patients, it is crucial to managing multiple cardiovascular risk factors including hypertension to prevent atherosclerotic cardiovascular disease and improve long-term outcomes.

It is predicted that by 2045, more than 7 million people worldwide will develop type 2 diabetes [1]. Cardiovascular disease is the most common comorbidity and cause of death among patients with diabetes [2]. Cardiovascular disease is more prevalent in patients with diabetes mellitus than in those without diabetes mellitus and higher fasting glucose is associated with increased risk of cardiovascular disease [3]. In 2001, the National Cholesterol Education Program Adult Panel III guideline suggested diabetes mellitus as a risk factor with the same risk as coronary artery disease [4]. Following guidelines also regard diabetes as a high risk condition for cardiovascular disease [5, 6]. Although there is controversy about whether diabetes is a risk factor equivalent to coronary artery disease [7], it is clear that diabetes is a factor that significantly affects cardiovascular disease.

© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021 S.-H. Lee, D.-W. Kang (eds.), Stroke Revisited: Diabetes in Stroke, Stroke Revisited, https://doi.org/10.1007/978-981-16-5123-6_5

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C. J. Lee and J.-W. Ha

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5.1

Coronary Artery Disease

Coronary artery disease is the narrowing or blockage of the coronary arteries, which reduces blood flow to the heart muscle. This is mainly caused by the accumulation of atherosclerotic plaques in the subintima of the arterial wall. Coronary artery disease is a major cause of death worldwide, and according to WHO estimates, more than 9 million people died from coronary artery disease in 2016 [8]. The risk factors for atherosclerosis are the same as risk factors for coronary artery disease, including age, family history, dyslipidemia, smoking, obesity, physical activity, and diabetes mellitus (Table  5.1) [9]. Coronary artery disease is 2–3 times more common in patients with diabetes than in those without diabetes mellitus, and coronary artery disease is the leading cause of death in both type 1 and type 2 diabetes mellitus [10, 11]. In the USA, one-third to one-half of people who have had percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) have diabetes mellitus. The efficacy of PCI or CABG is less effective in patients with diabetes mellitus than patients without diabetes mellitus [12]. Mortality rates of diabetic patients after acute myocardial infarction are 1.5 to 2 times higher than those in nondiabetic patients [13]. Diabetes mellitus is associated with poor long-term prognosis of coronary artery disease [14]. Hyperglycemia plays an important role in the development and progression of atherosclerosis. Therefore, the longer period of exposure to hyperglycemia is associated with more severe atherosclerosis [15]. It is not clear how much Table 5.1  Summary of risk factors for coronary artery disease Non-modifiable risk factors • Age • Male sex • Family history of premature myocardial infarction (male ≤55 years or female ≤65 years)

Modifiable risk factors • Hypertension • Diabetes • Dyslipidemia – Smoking – Obesity • Physical inactivity

blood glucose level enhances atherosclerosis. However, patients with mild hyperglycemia on fasting, defined as impaired glucose tolerance, also have more subclinical coronary artery disease than those with normoglycemia [16]. In diabetic patients, atherosclerotic changes in multiple coronary arteries are more pronounced than nondiabetic patients, and a longer duration of diabetes mellitus increases the risk of mortality from coronary artery disease [17, 18]. Since the relationship between coronary artery disease and diabetes is quite strong, several strategies for preventing coronary artery disease are needed in diabetic patients. The main symptom of coronary artery disease is chest pain, but diabetic patients often do not feel the symptoms of myocardial ischemia. Therefore, diabetic patients have a high incidence of silent myocardial ischemia and a high risk of sudden cardiac death [19]. To prevent asymptomatic and severe coronary artery disease, management of multiple risk factors is necessary in diabetic patients. The United Kingdom Prospective Diabetes Study (UKPDS) follow-up study provides clear evidence for a reduction in risk of coronary artery disease through control of diabetes mellitus. This study randomly assigned newly diagnosed type 2 diabetes mellitus patients to an intensive glycemic control group and a standard glycemic control group, for a median 10.7 years. The reduction in myocardial infarction was marginal in the first 10  years, but the last 10  years extended period, the intensive glycemic control group reduced the risk of myocardial infarction and all-cause death by 15% and 13%, respectively [20]. Although there are studies such as the ACCORD trial, which showed that intensive lowering of HbA1c increased the risk of death [21], the results of meta-analysis support that glucose lowering treatment has the benefit of reducing the risk of myocardial infarction [22].

5.2

Peripheral Artery Disease

Peripheral artery disease (PAD) is defined as atherosclerotic occlusive disease of lower extremities, which reduces blood flow to the feet and

5  Clinical Impact of Diabetes Mellitus in Cardiovascular Diseases

legs. The prevalence of advanced atherosclerotic vascular complications such as peripheral artery disease in diabetic patients is relatively high [23]. It is estimated that more than 200 million people worldwide have PAD [24]. Since more than 50% of PAD patients do not have symptoms, the prevalence may have been underestimated [25]. The presence of PAD is closely related to the risk of myocardial infarction, cerebral infarction, and mortality [26]. In addition, the leg amputation caused by PAD increases the burden of socioeconomic costs as it results in disability [27]. Diabetes mellitus is the most important risk factor for the development of PAD.  Diabetic patients are at a 2–4 times higher risk of developing PAD [7]. It is also known that 30% of patients with PAD have diabetes [27]. The second important risk factor is smoking, which increases the risk of PAD by 2 times [28]. Age, hypertension, and dyslipidemia are also known as risk factors for PAD. Duration, severity of diabetes, sex, and peripheral neuropathy are associated with an increased risk of developing PAD. In the UKPDS of 3834 subjects, the longer the prevalence of diabetes was significantly associated with the higher the prevalence of PAD [29]. A 1% increase in HbA1c increases the risk of PAD by 28% and increases the risk of amputation [29, 30]. In the Framingham study, diabetes increased the risk of intermittent claudication, the main symptom of PAD, by 3.5 times in men but 8.6 times in women [31]. In diabetic patients, peripheral neuropathy is often preceded by PAD. Since peripheral neuropathy diminishes pain perception it is more common in diabetic patients to present PAD as more advanced disease than nondiabetic patients [26]. There is controversy about how intensive glycemic control helps lower the risk of cardiovascular disease in diabetic patients with PAD, but poor glycemic control increases the prevalence of PAD and has a close relationship with the risk of adverse outcomes after revascularization [32]. In patients receiving endovascular therapy for PAD, suboptimal glycemic control with preprocedural HbA1c > 7.0% was associated with an increased risk of adverse events compared to optimal gly-

45

cemic control [33]. In the follow-up study of the ACCORD trial, intensive glycemic control lowered the risk of leg amputation [34]. Therefore, managing diabetes appears to be effective in reducing the complication of PAD.

5.3

Hypertension, Atherosclerosis

Hypertension is the most common cause of cardiovascular disease, and the prevalence of hypertension is over 30% in adults. In 2015, the number of hypertensive patients worldwide is estimated at 1.4 billion, and the extent to which hypertension contributes to stroke and coronary artery disease incidence is estimated to be 54% and 47%, respectively [35, 36]. Hypertension and diabetes are common chronic conditions, with 50 percent of diabetic patients having high blood pressure and 20 percent of hypertensive patients having diabetes [37]. The occurrence of hypertension and diabetes seems to affect each other in both direction. Several epidemiological studies have shown that the presence of hypertension predicts future diabetes, and that patients with diabetes are more likely to develop hypertension than people without diabetes [38, 39]. This appears to be due to insulin resistance leading to the progression of diabetes and hypertension [39]. In a cohort study of 49,775 people, hypertension and diabetes independently increased the risk of coronary artery disease, whereas the combination of hypertension and diabetes dramatically increased the risk [40]. Likewise, the risk of fatal and nonfatal stroke was higher in people with concomitant hypertension and diabetes compared to those with hypertension alone or diabetes alone [41]. As mentioned above, diabetes and hypertension synergistically contribute to the occurrence of vascular complications and various mechanisms work (Fig. 5.1). Insulin resistance appears several years before diabetes occurs, causing the adipocytes of subcutaneous or visceral fat to become hypertrophy [42]. Hypertrophic adipocytes are susceptible to cell death and macro-

C. J. Lee and J.-W. Ha

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Fig. 5.1  Putative mechanisms of vascular complication from diabetes and hypertension. RAGE receptor for advanced glycation end products; AGEs advanced glycation end products

phages gather around them [43]. Macrophage causes chronic inflammation in the body by releasing inflammatory cytokines [44]. And the continuous insulin resistance increases lipolysis from the hypertrophic adipocytes, and the blood concentration of the atherogenic lipoprotein such as small dense low density lipoprotein, triglyceride rich lipoprotein increases [45]. Hyperglycemia and lipid oxidation production induces the generation of reactive oxygen species by activating NADPH oxidase, leading to oxidative stress in blood vessels [46, 47]. In diabetes, advanced glycation end products (AGEs), a compound in which sugar is bound to the amino acid group of proteins and nucleic acids, increase in the blood, which binds to the receptor for advanced glycation end products (RAGE) and activates the innate immune system, the AGE-RAGE axis [48]. Activation of this signaling pathway results in increased ROS, increased inflammatory cytokines, and the expression of adhesion molecules in vascular endothelial cells [48]. In diabetic patients, chronic inflammatory signals and increased oxidative stress lead to fibrosis of blood vessels, calcification, and deterioration of endothelial cell function, leading to the overall arteriosclerosis process. The accompanying hypertension in diabetic patients accelerates the progression of arteriosclerosis by further promoting these phenomena [49]. It is crucial to managing hypertension in diabetic patients because hypertension and diabetes are common, and both factors have a significant

effect on the risk of cardiovascular disease. Although each guideline suggests slightly different target blood pressure in diabetic patients, lowering SBP to