World Clinics- Diabetology: Type 2 Diabetes Mellitus [1 ed.] 9789352501038, 9789351520016

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World Clinics Diabetology

Type 2 Diabetes Mellitus

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World Clinics Diabetology

Type 2 Diabetes Mellitus Editor-in-Chief Viswanathan Mohan MD FRCP PhD DSc FNASc FASC FNA FACP FACE FTWAS

Guest Editor

Ranjit Unnikrishnan MD Dip Diab (UK)

January 2014 Volume 1 Number 1

Jaypee Brothers Medical Publishers (P) Ltd. New Delhi • London • Philadelphia • Panama

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Jaypee Brothers Medical Publishers (P) Ltd

Headquarters Jaypee Brothers Medical Publishers (P) Ltd 4838/24, Ansari Road, Daryaganj New Delhi 110 002, India Phone: +91-11-43574357 Fax: +91-11-43574314 Email: [email protected] Overseas Offices J.P. Medical Ltd 83 Victoria Street, London SW1H 0HW (UK) Phone: +44-2031708910 Fax: +02-03-0086180 Email: [email protected]

Jaypee-Highlights Medical Publishers Inc City of Knowledge, Bld. 237, Clayton Panama City, Panama Phone: +1 507-301-0496 Fax: +1 507-301-0499 Email: [email protected]

Jaypee Medical Inc The Bourse 111 South Independence Mall East Suite 835, Philadelphia, PA 19106, USA Phone: +1 267-519-9789 Email: [email protected]

Jaypee Brothers Medical Publishers (P) Ltd 17/1-B Babar Road, Block-B, Shaymali Mohammadpur, Dhaka-1207 Bangladesh Mobile: +08801912003485 Email: [email protected]

Jaypee Brothers Medical Publishers (P) Ltd Bhotahity, Kathmandu, Nepal Phone: +977-9741283608 Email: [email protected] Website: www.jaypeebrothers.com Website: www.jaypeedigital.com © 2014, Jaypee Brothers Medical Publishers All rights reserved. No part of this issue may be reproduced in any form or by any means without the prior permission of the publisher. Inquiries for bulk sales may be solicited at: [email protected] This issue has been published in good faith that the contents provided by contributors contained herein are original, and is intended for educational purposes only. While every effort is made to ensure the accuracy of information, the publisher and the editors specifically disclaim any damage, liability, or loss incurred, directly or indirectly, from the use or application of any of the contents of this work. If not specifically stated, all figures and tables are courtesy of the contributing authors. Where appropriate, the readers should consult with a specialist or contact the manufacturer of the drug or device. Cover images: (Left) Sensor-augmented pump therapy. Courtesy: Jothydev Kesavadev. (Right) Acanthosis nigricans. Courtesy: Kalpana Thai. World Clinics Diabetology: Type 2 Diabetes Mellitus January 2014, Volume 1, Number 1 ISSN: 2347-5110 ISBN: 978-93-5152-001-6 Printed in India

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Contributors Editor-in-Chief Viswanathan Mohan MD FRCP PhD DSc FNASc FASC FNA FACP FACE FTWAS Chairman and Chief Diabetologist Dr. Mohan’s Diabetes Specialities Centre Director and Chief of Diabetes Research Madras Diabetes Research Foundation Chennai 600 086, Tamil Nadu, India

Guest Editor Ranjit Unnikrishnan MD Dip Diab (UK) Vice Chairman and Consultant Diabetologist Dr. Mohan’s Diabetes Specialities Centre and Madras Diabetes Research Foundation Chennai 600 086, Tamil Nadu, India

Contributing Authors RM Anjana MD Dip Diab (UK) PhD Diabetologist and Joint Managing Director Dr. Mohan’s Diabetes Specialities Centre Chennai 600 086, Tamil Nadu, India Gaurav Beswal MRCGP PG Dip Diab DFSRH DRCOG Dr. Mohan’s Diabetes Specialities Centre Chennai 600 086, Tamil Nadu, India Jaikrit Bhutani MBBS Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences Rohtak 124 001, Haryana, India

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Type 2 Diabetes Mellitus

Neeta R Deshpande MD Consultant Diabetologist and Bariatric Physician Belgaum Diabetes Centre, Belgaum 590 001, Karnataka, India Professor and Head of Department Department of Medicine, Maratha Mandal Dental College Belgaum 590 010, Karnataka, India Christiani J Henry MSc PhD FIFST (UK) Director, Functional Food Centre Oxford, United Kingdom Director, Clinical Nutrition Research Centre Singapore Institute for Clinical Sciences Singapore Shashank R Joshi MD DM FACP FACE FRCP Endocrinologist, Lilavati and Bhatia Hospital Mumbai, Maharashtra, India Consultant Endocrinologist Department of Endocrinology Grant Medical College and Sir Jj Group of Hospitals Mumbai 400 008, Maharashtra, India Sanjay Kalra MD DM Consultant Endocrinologist, Department of Endocrinology Bharti Hospital and B.R.I.D.E. Karnal 132 001, Haryana, India Bhupinder Kaur MSc Senior Research Officer Clinical Nutrition Research Centre Singapore Institute for Clinical Sciences Singapore Jothydev Kesavadev MD CEO and Director Jothydev’s Diabetes and Research Centre Trivandrum 695 032, Kerala, India Ajay Kumar MD FRCP Consultant Physician and Diabetologist Diabetes Care and Research Centre Patna 800 020, Bihar, India vi

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Contributors

Sunder Mudaliar MD FRCP (Edin) FACP FACE Staff Physician Section of Diabetes/Metabolism Va San Diego Healthcare System Clinical Professor of Medicine University of California at San Diego San Diego, CA, USA Kameshwari Padmanabhan MBBS Cochin, Kerala, India Rakesh Parikh MBBS MRCPS FCPS Dip Diab Consultant Diabetologist, S K Soni Hospital Principal Investigator, D Clinarch Jaipur 302 013, Rajasthan, India Rakesh K Sahay MD DM FACE FICP Professor of Endocrinology Department of Endocrinology Osmania Medical College and Hospital Hyderabad 500 095, Andhra Pradesh, India Kalpana Thai MBBS Mrcpch (Child Health) PG Dip in Health Sciences (Diab) Consultant Pediatric Diabetologist Dr. Mohan’s Diabetes Specialities Centre Chennai 600 086, Tamil Nadu, India Sudha Vidyasagar MD Head of the Department Department of Medicine, Kasturba Medical College Manipal 576 104, Karnataka, India

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Contents Editorial.......................................................................................................... xi Viswanathan Mohan

Abbreviations.................................................................................................. xiii Diet-based Management and Treatment of Diabetes.................................... 1 Christiani J Henry, Bhupinder Kaur

Physical Activity and Type 2 Diabetes........................................................... 20 RM Anjana

Sulfonylureas.................................................................................................. 34 Sudha Vidyasagar

Metformin: Old Wine in a New Bottle—the Evidence-based First-line Agent in Type 2 Diabetes............................................................... 45 Shashank R Joshi

Alpha-glucosidase Inhibitors......................................................................... 55 Sanjay Kalra, Jaikrit Bhutani

Pioglitazone.................................................................................................... 66 Neeta R Deshpande

Dipeptidyl Peptidase-4 Inhibitors.................................................................. 74 Gaurav Beswal, Ranjit Unnikrishnan, Viswanathan Mohan

Glucagon-like Peptide-1 Analogues.............................................................. 87 Ajay Kumar

Insulin Therapy in Type 2 Diabetes Mellitus................................................. 105 Rakesh Parikh, Kameshwari Padmanabhan

Insulin Pumps in Type 2 Diabetes Mellitus................................................... 120 Jothydev Kesavadev

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Type 2 Diabetes Mellitus

Sodium-glucose Cotransporter Type-2 Inhibitors in the Treatment of Type 2 Diabetes.................................................................. 134 Sunder Mudaliar

Type 2 Diabetes in Children.......................................................................... 158 Kalpana Thai

Role of Insulin Analogues in Type 2 Diabetes............................................... 180 Rakesh K Sahay

Self-monitoring of Blood Glucose in Type 2 Diabetes.................................. 208 Ranjit Unnikrishnan

x

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World Clin Diabetol. 2014;1(1):xi.

Editorial

Viswanathan Mohan MD FRCP PhD DSc FNASc FASC FNA FACP FACE FTWAS

Editor-in-Chief

Diabetes Mellitus has become a global problem worldwide. It is estimated that there are 382 million people with diabetes worldwide. China has now become the new diabetes capital of the world with 98 million people with diabetes and India is in second place with 65 million people with diabetes. Type 2 diabetes constitutes 95% of all types of diabetes seen in most parts of the world, while other types like type 1 diabetes, gestational diabetes and secondary form of diabetes are less common. A lot of advances are taking place in the therapy of type 2 diabetes. In this issue of the “World Clinics of Diabetology”, some of the recent advances in the therapy of type 2 diabetes are presented by authors who are well known experts in the field. We have completed a range of topics ranging from dietary therapy of diabetes, physical activity, oral drugs and insulin in this issue with upto-date reviews written by world class diabetologists. I am confident that this would be a valuable addition to any library and would be useful to not only to practicing physicians and diabetologists but also to postgraduate students. We would welcome your valuable feedback so that we can further improve future issues of the “World Clinics in Diabetology series”. Viswanathan Mohan MD FRCP PhD DSc FNASc FASC FNA FACP FACE FTWAS

Chairman and Chief Diabetologist Dr. Mohan’s Diabetes Specialities Centre Director and Chief of Diabetes Research Madras Diabetes Research Foundation Chennai 600 086, Tamil Nadu, India Email: [email protected] Website: www.drmohansdiabetes.com

© 2014 Jaypee Brothers Medical Publishers. All rights reserved.

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Abbreviations



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4-T The Treating to Target in Type 2 Diabetes study AACE American Association of Clinical Endocrinologists ACE Angiotensin-convertingenzyme ACEI Angiotensin-convertingenzyme inhibitor ADA American Diabetes Association ADOPT A Diabetes Outcome Progression Trial study ADVANCE Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation study AEs Adverse events AGIs Alpha-glucosidase inhibitors AHEAD Action for Health in Diabetes AIRg Acute insulin response to glucose ALT Alanine transaminase AMPK Adenosine monophosphate-activated protein kinase AN Acanthosis nigricans ARB Angiotensin receptor blocker AST Aspartate transaminase ATP Adenosine triphosphate AUC Area under curve BHI Biphasic human insulin BIAsp Biphasic insulin aspart BID Twice daily BIDS Bedtime insulin daytime sulfonylurea BMI Body mass index BMS Bristol-Myers Squibb BNF British National Formulary





BNP Brain natriuretic peptide BP Blood pressure CANVAS CANagliflozin cardioVascular Assessment Study CAT2DM Childhood- and adolescent-onset T2DM CGM Continuous glucose monitoring CHICAGO Carotid IntimaMedia Thickness in Atherosclerosis Using Pioglitazone study CHOs Carbohydrates CI Confidence interval CrCl Creatinine clearance CRP C-reactive protein CSII Continuous subcutaneous infusion of insulin CV Cardiovascular CVD Cardiovascular disease CYP Cytochrome P450 DCCT Diabetes Control and Complications Trial DEXA Dual-energy X-ray absorptiometry DIGAMI Diabetes mellitus, insulin glucose infusion in acute myocardial infarction study DIO Oral disposition index DKA Diabetic ketoacidosis DM Diabetes mellitus DNA Deoxyribonucleic acid DPP Diabetes Prevention Programme DPP-4 Dipeptidyl peptidase-4 DPP-4Is Dipeptidyl peptidase-4 inhibitors DPS Diabetes Prevention Study DURABLE DURAbility of Basal versus Lispro mix 75/25 insulin Efficacy trial

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Type 2 Diabetes Mellitus

EASD European Association for the Study of Diabetes EDIC Epidemiology of Diabetes Interventions and Complications Trial eGFR Estimated glomerular filtration rate ER Endoplasmic reticulum ESRD End-stage renal disease EU European Union FCPD Fibrocalculous pancreatic diabetes FDA Food and Drug Administration FDCs Fixed-drug combinations FFA Free fatty acid FPG Fasting plasma glucose GDM Gestational diabetes mellitus GDR Glucose disposal rate GI Glycemic index GIP Glucose-dependent insulinotropic peptide/ polypeptide GIR Glucose infusion rate GL Glycemic load GLP-1 Glucagon-like peptide-1 GLP-1Ras Glucagon-like peptide-1 receptor agonists GLUT-2/4 Glucose transporter 2/4 GPRS General packet radio service GUIDE GlUcose control In type 2 diabetes: Diamicron MR versus glimEpiride study GV Glycemic variability HbA1c Glycosylated hemoglobin HDL High-density lipoprotein HDL-C High-density lipoprotein cholesterol HGP Human Genome Project HMG-CoA 3-hydroxy-3methylglutaryl-CoA HNF Hepatocyte nuclear factor HNF-1α Hepatocyte nuclear factor-1 alpha HOMA Homeostasis Model of Assessment



HRQoL Health-related quality of life ICMR-INDIAB Indian Council of Medical Research–India Diabetes study IDeg Insulin degludec IDPP Indian Diabetes Prevention Programme IgG Immunoglobulin G IGT Impaired glucose tolerance INCG Indian National Consensus Group IPT Insulin pump therapy IR Insulin resistance IRS Insulin-resistance syndrome ISF Insulin sensitivity factor IV Intravenous KDOQI Kidney Disease Outcome Quality Initiative LAR Long-acting release LDL Low-density lipoprotein LDL-C Low-density lipoprotein cholesterol LEAD-6 Liraglutide Effect and Action in Diabetes-6 LKB1 Liver kinase B1 MACE Major adverse cardiovascular events MDI Multiple daily insulin; Multiple daily injections MEN Multiple endocrine neoplasia MeRIA MEta-analysis of Risk Improvement under Acarbose MI Myocardial infarction MNT Medical nutrition therapy MODY Maturity onset diabetes in the young MPC Model predictive control MRI Magnetic resonance imaging MRP-2 Multidrug resistance protein-2 MTC Medullary thyroid cancer Na/K ATPase Adenosine triphosphatasemediated sodiumpotassium pump

xiv

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Abbreviations

NAFLD Nonalcoholic fatty liver disease study NEFAs Non-esterified fatty acids NF-κB Nuclear factor-kappa B NICE National Institute of Clinical Excellence NIDDM Non-insulin-dependent diabetes mellitus trial NPH Neutral protamine Hagedorn NS Not significant NSAIDs Nonsteroidal antiinflammatory drugs OADs Oral antidiabetic agents OD Once daily OGLDs Oral glucose lowering drugs OHAs Oral hypoglycemic agents PAI-1 Plasminogen activator inhibitor-1 PCOS Polycystic ovarian syndrome PD Pharmacodynamic PDA Personal digital assistant PERISCOPE Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation trial P-GP P-glycoprotein PI Prescribing information PID Proportional-integralderivative PPAR-γ Peroxisome proliferatoractivated receptor-gamma PPG Postprandial glucose PREDICTIVE Predictable Results and Experience in Diabetes through Intensification and Control to Target: An International Variability Evaluation Study PROACTIVE PROspective pioglitAzone Clinical Trial In macrovascular Events PTCA Percutaneous transluminal coronary angioplasty PVD Peripheral vascular disease PYY Peptide YY



QD QoL QW RAIAs

Once daily Quality of life Once weekly Rapid-acting insulin analogues RBS Random blood sugar RCT Randomized controlled trials RHI Regular human insulin RI Renal impairment RR Rate ratio; Risk ratio; Relative risk RT-CGM Real-time continuous glucose monitoring SAPT Sensor-augmented pump therapy SAT Subcutaneous adipose tissue SBP Systolic blood pressure SGA Small for gestational age SGLT-1/2 Sodium-glucose cotransporter type-1/2 SIADH Syndrome of inappropriate antidiuretic hormone secretion SMBG Self-monitoring of blood glucose SNP-G319S Single-nucleotide polymorphism STAR 3 Sensor-augmented pump Therapy for A1c Reduction 3 study STOP Study to Prevent SUR-1 Sulfonylurea receptor 1 SUs Sulfonylureas t1/2 Half-life T1DM Type 1 diabetes mellitus T2DM Type 2 diabetes mellitus TGF-β1 Transforming growth factor beta-1 TNF Tumor necrosis factor TODAY Treatment Options for type 2 Diabetes in Adolescents and Youth trial TZDs Thiazolidinediones UGDP University Group Diabetes Program study UGT Uridine 5′-diphosphoglucuronosyltransferase

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UGT1A9 Uridine 5′-diphospho-(UDP)glucuronosyltransferase 1A9 UKPDS United Kingdom Prospective Diabetes Study ULN Upper limit of normal range UPR Unfolded protein response



US United States USFDA US Food and Drug Administration UTIs Urinary tract infections VAS Visual analogue scales VAT Visceral adipose tissue VLDL Very-low-density lipoprotein VVAE Vulvovaginal adverse events

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World Clin Diabetol. 2014;1(1):1-19.

Diet-based Management and Treatment of Diabetes *,1Christiani J Henry MSc PhD FIFST (UK), 2Bhupinder Kaur MSc

1 Functional Food Centre, Oxford, United Kingdom Clinical Nutrition Research Centre, Singapore Institute for Clinical Sciences, Singapore

1,2

ABSTRACT A diet rich in refined carbohydrates is believed to be a major factor contributing to the rising incidence of type 2 diabetes mellitus in Indians. Understanding the role of refined carbohydrates on blood glucose excursions is necessary for the proper selection and formulation of foods. This review presents simple and practical ways in which Indian dietaries may be modified not only to lower blood glucose response, but also to enable consumers to enjoy the diverse variety of Indian foods. Practical recommendations are provided that will enable diabetics to consume nutritious and highly palatable foods. The time has come for both consumers and food manufacturers to appreciate the importance of consuming low glycemic foods in order to abate the escalating incidence of type 2 diabetes.

INTRODUCTION Asia is emerging as the epicenter of the diabetes epidemic with China and India leading the world with the greatest number of people with diabetes. An estimated 61.3 million individuals are affected by diabetes in India, and this number is expected to increase to a staggering 101.2 million by the year 2030.1 Population studies have shown that diabetes affects both rural and urban populations in India with the numbers increasing at an alarming rate.2,3 This has been attributed to changes in diet and lifestyle patterns with the latter having a profound role in the etiology of diabetes. With the increasing prevalence of diabetes and related chronic diseases, greater research attention is necessary to curb its further escalation. Dietary interventions have, therefore, gained considerable interest in diabetes *Corresponding author Email: [email protected] © 2014 Jaypee Brothers Medical Publishers. All rights reserved.

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management and treatment. Their primary aim is to maintain a modest and stable postprandial blood glucose concentration when consuming a carbohydrate-rich diet.4 Whilst pharmacological intervention has been the bedrock of diabetes management for several decades, there is increased support for the use of diet in the management and treatment of diabetes.

ETIOLOGY OF TYPE 2 DIABETES IN INDIANS Indians are more prone to insulin resistance, developing metabolic syndrome and have an increased risk for developing type 2 diabetes compared to other ethnic groups.5 Higher insulin levels to a given glucose load was observed in Asian Indians compared to Europeans with hyperinsulinemia.6 Euglycemic clamp studies demonstrated that insulin resistance was greater among Asian Indians compared to Europeans who were similar in age, sex, and body mass.7-10 The Indian diet is generally characterized as one that is high in carbohydrate content. In India where the two most common staples are rice and wheat-based chapati, their consumption is associated with a rapid rise in blood glucose. Refined grains such as white rice have been linked with the risk of type 2 diabetes and metabolic syndrome among urban South Asian Indians.11,12 The degree of blood glucose excursion after a carbohydrate diet can be described by the glycemic index (GI). The GI is a very useful methodology in assessing the quality of carbohydrate in the diet. An understanding of the GI concept can be of particular benefit in subjects with diabetes and impaired glucose tolerance. Dietary management of diabetes involves a reduction in postprandial hyperglycemia and adequate glycemic control. This may be achieved through the consumption of low GI foods as part of the Indian diet.

ROLE OF GLYCEMIC INDEX IN TYPE 2 DIABETES Jenkins et al. were the first to develop the GI concept, where it was shown to be an important and innovative discovery in nutritional science.13 The GI is defined as a measure of the blood glucose raising ability of the available carbohydrate in foods. It is expressed as a percentage of the incremental area under the glycemic response curve (AUC) elicited by a portion of food containing 50 g available carbohydrate in comparison with the AUC elicited by 50 g glucose in the same subject. The principle is that the slower the rate of carbohydrate absorption, the lower the rise of blood glucose level and the lower the GI value.14 A GI value of greater than or equal to 70 is considered high, a GI value 56–69 inclusive is medium and a GI value less than or equal to 55 is low, where glucose is equal to 100.15 The glycemic load (GL) is a product of the GI and available carbohydrate content per serving 2

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of the food. Both high GI and GL have shown to increase the risk of type 2 diabetes in both Western and Asian populations16-19 although some studies have reported no association with diabetes risk.20-22 The large amount of refined grain consumption (mostly high GI) in the Indian diet, therefore, leads to a higher dietary GL. An important body of evidence exists to support the preventive and therapeutic potential of low GI diets in diabetes.14,23 Low GI foods may reduce insulin demand and lipid concentrations, improve blood glucose control and reduce body weight, thus preventing diabetes-related cardiovascular events.17,18,24,25 A metaanalysis by Brand-Miller et al. demonstrated that choosing low GI foods in place of conventional or high GI foods exhibited a small but clinically important effect on medium-term glycemic control in patients with diabetes. This diet-based intervention was similar to the effects seen using pharmacological agents.15 There have been numerous studies providing useful information on the GI of various Indian foods and their effect on blood glucose and lipid levels26-31 although a bulk of GI research has been conducted on Western foods. One of the main impediments in the use of GI tables worldwide has been the uncertainty of the applicability and consistency of international tables to different ethnic groups. One study examined the role of ethnicity on GI when subjects were resident of their own countries.32 The glycemic response to common foods (sweet biscuits and breakfast cereals) was higher in Asian Indian subjects compared to United Kingdom (UK) Caucasian subjects, but no significant differences in GI values for the test foods between the two group of subjects was observed.32 This suggests the potential of the applicability of Western GI tables with the Indian population.

GLYCEMIC INDEX OF COMMONLY CONSUMED INDIAN STAPLES A typical Indian diet is high in carbohydrates with cereal-based foods, such as rice and wheat providing the bulk of the energy. Whole grains, such as millet, sorghum, amaranth and barley were commonly used in ancient Indian cooking prior to the “Green Revolution” in 1951, after which refined rice and wheat became popular.33 Per capita consumption of refined grains tripled in India and the country became the world’s foremost exporter of rice and wheat.33 Traditional cereal-based Indian diets were not only rich in dietary fiber, but also in other micro- and phytonutrients.34 With modernization, mechanical milling led to an increased total rice yield but produced a highly refined rice grain with starchy endosperm.11 Polished rice and other highly refined cereals, such as white flour, finger millet and semolina are mostly high GI (Table 1). 3

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Henry and Kaur Table 1: Glycemic Index (GI) of Common Staples (Cereals and Legumes) in the Indian Diet35 Food

Glycemic index (GI)

Cereals White rice (Oryza sativa), boiled (India)

69

Parboiled rice, eaten as part of a traditional Indian meal (India)

99

Sona Masuri (India)

72

Ponni rice (India)

70

Surti Kolam (India)

77

Basmati, white, boiled (Mahatma brand, Sydney, Australia)

58

Brown basmati rice

75

White and brown basmati rice (60% white basmati, 40% brown basmati)

59

Basmati with wild rice (83% easy-to-cook basmati) and 17% North American wild rice

63

Easy-to-cook basmati rice

80

Chapati (unleavened bread made from refined wheat flour and water)

64

Whole wheat flour chapati/roti

45

Naan (leavened bread made from white flour, water and yeast)

80

Finger millet/ragi

84

Pearl millet/bajra

55

Sorghum/jowar (roasted bread made from sorghum flour)

77

Semolina, steamed, and gelatinized (India)

84

Idiyappam or string hoppers (steamed fresh vermicelli made from red or white rice flour)

103 (red)

Legumes Bengal gram/chickpeas

33

Kidney beans

28

Black beans

20

Green lentils

30

Red lentils

26

Moong beans

42

Peas

22

Split peas, yellow, boiled

32

Majority of the Indian diet consists of these cereal-based staples. Understanding the GI of these staples is necessary for proper selection and modifications of foods that may be of particular benefit to Indians who are more insulin-resistant and/ or have diabetes.6,8 Almost half of the daily caloric intake of South Indians is derived from refined grains, particularly white rice and rice products12 whilst 4

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wheat consumption is higher in Northern India.36 From an epidemiological study, a typical South Indian meal was found to have more rice and less of other foods, such as legumes, fruits, vegetables, and dairy products.12 The greater quantity of rice eaten and its associated GL is regarded as a major contributing factor to a higher prevalence of diabetes and associated complications. Therefore, Southern regions of India were found to have a higher prevalence of diabetes than Northern regions.3,11 The GI of foods is influenced by several factors, such as the nature of starches, macronutrients, fiber, the cooking/preparation method, cooking time, particle size as well as processing conditions. An analysis of these factors will be useful in making food choices and modifications necessary to develop diabetic foods for Indians.

Glycemic Response of Rice Rice variety significantly influences GI. This varietal effect on GI appears to be mainly mediated by its amylose content. Basmati rice is a popular rice in the Indian diet. White basmati rice with intermediate amylose content (20–25%) has been shown to have a GI of 5837 and 50.38 Some studies show that parboiling reduces the GI of rice.38,39 A reduced glycemic response was observed in healthy subjects who consumed parboiled Sri Lankan rice compared to the unparboiled version.40 Other factors may also influence the digestibility and GI of rice. Indian rice varieties Sona Masuri (medium grain rice), Ponni (medium grain rice), and Surti Kolam (polished short grain rice) have shown to be high GI (72, 70, and 77, respectively) when they were cooked under similar conditions.41 These three types of rice were fully polished rice, void of fiber and high in starch, resulting in a higher rate of digestion, therefore, leading to poor glycemic control. Other studies have shown that brown rice has a lower GI than white rice42 while some have shown it to be high GI. It seems that the GI of brown rice types is affected by the bran constituents (perhaps micronutrients) and not just the bran alone. It is therefore not possible to assume that brown rice has low GI. White rice as opposed to brown rice is more often consumed by Indians due to its taste, consistency and shorter cooking time. Therefore, white rice has been more desirable in Indian dishes. Basmati rice and parboiled rice may be good options for an Indian ricebased meal.

Glycemic Response of Flatbreads Flatbreads made using wheat flour (chapati) contribute a major portion of energy notably in North Indian diets. Compared to rice, less work has been done on the effects of different flatbreads on blood glucose responses. North Indian meals 5

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traditionally have a form of flatbread, either unleavened or leavened. Most GI studies have examined the glycemic responses of bread consumed in the Western diet but few studied the breads in Asian diets. A study by Radhika et al. showed that whole wheat flour used to make chapati has a low GI.43 Whole wheat flour chapati with the wheat bran and germ present is typically low-to-medium GI but if refined wheat flour (i.e. white flour) is used, the GI is higher due to the removal of bran (Table 1). Furthermore, α-amylase inhibitors present in wheat can withstand cooking temperature and were found to be effective in reducing blood glucose response.44 More recently, a study evaluated the glycemic and insulin responses of different South Asian flatbreads. Flatbread, such as naan and refined chapati were reported to be high GI.45 Other flatbreads, such as chickpea flour chapati was of medium GI and whole wheat chapati was of low GI.45

Glycemic Response of Other Cereals Other popular grains include millet or ragi which can be processed to make porridges, idli (Indian fermented steamed cake), dosa (Indian fermented fried pancake), and roti (unleavened bread). A recent detailed review by Shobana et al. highlighted that finger millet was a cereal grain that possesses components that were likely to lower GI.46 A study comparing the glycemic response of pearl millet (bajra), barley and maize in healthy and type 2 diabetic individuals showed that the glycemic response to pearl millet and barley, but not maize, was signi­ficantly lower than the glycemic response to white bread, particularly in individuals who were healthy.47

Glycemic Response of Legumes Besides cereals, legumes also form a major source of protein and carbohydrates intake in the Indian diet. It is usually consumed as an accompaniment (dal) to a cereal staple or processed to make snacks. Generally most legumes are low GI (Table 1). Their low GI has been attributed to the high-fiber and polyphenol content, and the slow-digesting starch characteristics. In an early study, Jenkins et  al. have showed that dietary fiber in legumes and dals (dehusked and split legumes) are more viscous than the fiber content of cereals and millets.48 A number of researchers investigated the blood glucose responses of leguminous seeds in the Indian diet. Indian snacks are traditionally made using dehusked legumes. The glycemic response of cheela, an Indian snack was studied by Batra et al.49 Whole legumes (green gram and Bengal gram) showed a GI lowering effect. In addition, green gram produced a lower GI than Bengal gram, because of the higher protein and crude fiber content in the former.49 The presence of protein and viscous fiber helps to lower glycemic response. A systematic review and meta-analysis showed 6

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that pulses were able to reduce blood glucose and insulin in both normal and diabetic subjects.50 The use of pulses with low GI diets was reported to reduce the amount of glycosylated hemoglobin and fructosamine that are markers of longterm maintenance of blood glucose.50 Overall, wholegrain foods and legumes showed a lowering of blood glucose response. However, the GI of most Indian wholegrain foods and legumes have not been tested using standardized methodology.32,43

Processing Techniques Affecting Glycemic Index Processing techniques, such as puffing, instantiation and fermentation have shown to affect GI and increase starch digestibility. Instant (easy-to-cook) basmati rice, which is pregelatinized rice, results in a significantly higher GI than raw basmati rice. Puffing of finger millet is commonly used to make Indian snacks. An in vitro study showed puffed finger millet had an increase in rapidly digestible starch content and lower slowly digestible starch content, with a decrease in resistant starch content of finger millet.51 The fermentation process of finger millet in making dosa was found to increase the starch digestibility.52 Idiyappam (string hoppers), which are steamed fresh rice vermicelli, have high GI.53 Certain processes disrupt the structure of rice, promote gelatinization and therefore increase the GI.

Cooking Method and Cooking Time Affecting Glycemic Index Cooking method also affects GI. Carbohydrate foods that had been roasted or baked showed significantly higher blood glucose responses, and therefore a higher GI than the same foods that had been boiled or fried (Bahado-Singh et al. 2006). Cooking time has also shown to influence starch gelatinization and therefore GI. Basmati rice cooked for longer times elicited greater glycemic responses.38 White basmati rice cooked for 10 min had a GI of 50 (low), but basmati and wild rice, brown and white basmati rice cooked for 25 min had high GI.38

MANIPULATING THE GLYCEMIC INDEX OF INDIAN FOODS The consumption of large carbohydrate rich meals is common in the Indian diets. The addition of ingredients to staples and supplementing these staples with accompaniments could lower the GI and overall GL of a traditional Indian meal.

The Potential of Adding Ingredients to Reduce Glycemic Response Barley b-glucan is a natural soluble dietary fiber that has shown to lower glycemic response when incorporated into carbohydrate foods. High molecular weight 7

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barley b-glucan was able to reduce the GI of chapati when tested in healthy subjects.54 The GI values for chapati (Indian flatbreads) with 4 g and 8 g b-glucan were 43–47% less than the control chapatis made of whole wheat flour. The functional properties of b-glucans have always been attributed to their ability to delay carbohydrate digestion and absorption from the gut by increasing the viscosity of the stomach and intestinal contents and forming a protective layer incorporating readily digestible carbohydrates.55 Another study also found that moderate amounts of β-glucan (~3 g) along with a low GI breakfast have lipidlowering effects in type 2 diabetics.56 The GI of rotis (unleavened flatbread) made of whole wheat flour was reduced with a newly developed “atta mix” containing Bengal gram, psyllium husk, and debittered fenugreek flour in healthy nondiabetic subjects.43 The therapeutic effects of Bengal gram (legume), psyllium/ispaghula husk, and debittered fenugreek powder on lowering postprandial glucose levels are likely to be due to high viscous soluble fiber, the galactomannans (polysaccharides) that are not hydrolyzed by the digestive enzymes. Soluble fiber results in high viscous intestinal contents with gelling properties that could delay gastric emptying and also intestinal absorption.43 Mani et al. investigated the glycemic response in type 2 diabetics subjects who were given 50 g portions of five different conventional meals containing semolina cooked by two different methods, or combinations of semolina and pulse (black gram dal, green gram dal or Bengal gram dal)28 (Table 2). There were no significant differences in GI among the meals except for roasted semolina and semolina-black gram dal meals. But meals based on steam-cooked semolina and semolina-Bengal gram dal elicited a significantly lower blood glucose response at 1 hour postprandially and semolina-black gram dal at 2 hours postprandially. The cooking method had an influence on the GI by affecting starch digestion and therefore postprandial blood glucose response.57,58 Table 2: Glycemic Index (GI) of Semolina Meals28 Ingredients

Glycemic index (GI)

Semolina-steamed with gelatinization

55

Semolina + black gram dal

46

Semolina + green gram dal

62

Semolina + Bengal gram dal

54

Semolina-roasted at 105° with resultant gelatinization when water is added

76

All dals were soaked for 4 hours, ground to paste and fermented. Meals were cooked 20 min, 400 mL water added during cooking and 5 g groundnut oil. Meals were approximately isocaloric.

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Finger millet (20%) incorporated into idli, dosa, chapati, rice string hoppers and kozhukattai (steamed rice balls), fed to type 2 diabetics (n = 6) for a month, showed a significant decrease in postprandial blood glucose, but the limitation of the study was the small sample size.59 Finger millet incorporated into noodles also showed a lower GI when compared to refined wheat flour-based noodles.60 A study examined the glycemic response of four formulations (popped rice, expanded rice, wheat and finger millet) combined with legumes in normoglycemic subjects showed that the wheat-based formulation had the lowest GI of = 55.61 The other formulations were high GI. The finger millet-based formulation, which used polished finger millet, had a GI of 93. The rice-based formulation that used popped rice had a GI of 105 and expanded rice had a GI of 109. This showed that processing techniques and low dietary fiber content had a considerable effect on increasing the GI of foods, even if legumes were present.

Spices and Herbs Several spices and herbs, such as curry leaf, turmeric, fenugreek and cinnamon are used by Indians to add characteristic flavor and aroma to dishes. Many of these spices and herbs provide beneficial effects on glycemic control by possessing antidiabetic or blood glucose lowering properties based on successful in vitro and in vivo studies, where mostly has been investigated using animal models.62 The constituents of spices have insulin-stimulating and hypoglycemic effects.63 Fenugreek (methi) is known to play a role in glycemic control, delaying gastric emptying and regulating insulin secretion due to the presence of soluble fiber.64 Incorporating fenugreek in the form of seeds and flour into Indian foods lowered postprandial glucose levels in type 2 diabetics.65-68 Cinnamon is known for its potential role on insulin action and was found to improve blood glucose profiles in diabetics.69 Several other researchers reported the effectiveness of cinnamon in controlling blood sugar in type 2 diabetics.70,71 Turmeric is a widely used spice in Indian cooking where it functions as a coloring and flavoring agent. Curcumin is an active polyphenol present in turmeric. Human clinical trials have shown dietary curcumin to possess anti-hyperglycemic effects in type 2 diabetics72 and significantly reduce type 2 diabetes development in prediabetics.73 Due to curcumin’s poor absorption in the digestive system,74 its beneficial effects on type 2 diabetes still remains to be elucidated. Curry leaf (Murraya koenigii) is a popular aromatic herb known to be used in curry and chutney. A selection of studies have shown hypoglycemic properties of curry leaf powder in controlling the fasting and postprandial blood glucose level among type 2 diabetics.75 Overall, spices and herbs used in Indian foods potentially have strong antidiabetic and glucose lowering effects in diabetics but much remains to be researched using more longterm human intervention trials. 9

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Meal Accompaniments The conventional meal pattern of most Indians is the use of a staple, for example, boiled white rice or refined wheat chapati, accompanied by a constellation of dishes, such as legumes, vegetables and yogurt. Some of these accompaniments play a crucial role in lowering the GI of a carbohydrate staple. Table 3 represents a selection of accompaniments that can be practically adopted to lower the glycemic response of carbohydrate-rich foods. Table 3: Glycemic Index (GI) of Indian Staple Foods with/without Accompani­ ments26,29,35,53,76 Food

Glycemic index (GI)

With accompaniment

Glycemic index (GI)

White rice; lowamylose

Mediumto-high

Rice with lentil and cauliflower curry

60

White rice; highamylose

Low-tomedium

Rice, boiled served with Lagenaria vulgaris (bottle gourd) and (Lycopersicon esculentum) tomato curry

69

Brown rice

50

Parboiled rice with green leaf curry (Amaranthus)

58

Basmati rice

47

Parboiled rice with gravy (soya meat)

56

Parboiled rice with green leaf curry and gravy

55

Red rice with lentil curry, boiled egg + Centella asiatica (gotu kola) salad and coconut gravy (Kiri hodi)

63

Red rice with lentil curry, boiled egg + Centella asiatica (gotu kola) salad and coconut gravy (kiri hodi) and Lasia spinosa (kohila) salad

57

Red rice with lentil curry, boiled egg + Centella asiatica (gotu kola) salad, coconut gravy and Trichosanthes cucumerina (snake gourd) salad

61

Red rice with lentil curry: Red rice (82% starch), Lentils curry (18% starch)

60

Rice-based

Rice roti

Pongal (rice and roasted green gram dal, pressure cooked)

103

90

Red rice with coconut gravy

99

Dosa (parboiled and raw rice, soaked, ground, fermented and fried) with chutney

77

String hopper (wheat flour) with coconut sambol, egg and coconut gravy

104

String hopper (red rice flour) with coconut sambol, egg and coconut gravy

103

Pongal with sambar

54

Continued 10

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Continued

Table 3: Glycemic Index (GI) of Indian Staple Foods with/without Accompani­ ments26,29,35,53,76 Food

Glycemic index (GI)

With accompaniment

Glycemic index (GI)

Idiyappam (steamed rice flour dough with tender coconut) eaten with Bengal gram curry

86

Idli (parboiled and raw rice + black dal, soaked, ground, fermented and steamed) with chutney

77

Puttu (rice flour, steamed with tender coconut) eaten with Bengal gram curry

79

Appam (thin pancake made from fermented rice flour batter with tender coconut) eaten with Bengal gram curry

90

Chapati, wheat, served with bottle gourd and tomato curry

66

Chapati with green gram dal

44

Wheat-based Chapati

64

Chapati (maize flour)

59

Naan

80

Chapati and dal

Semolina-based Semolina, steamed and gelatinized

54

Semolina, roasted then gelatinized with water

55

Uppittu (roasted semolina and onions, cooked in water)

67

Upma kedgeree (millet, legumes, fenugreek seeds; roasted and cooked in water)

18

Millet products Millet/ragi

84

Other Indian foods Dhokla (chickpea-based + wheat semolina)

35

Punjabi meal

68

Uttapam with chutney

63

South Indian meal

63

Curd rice with curry leaves chutney

65

Adai with chutney

70

Bengali meal

70

Rasam rice with papad

78

Gujarati meal

83

Sambar rice

83

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Legumes accompanied with a carbohydrate staple have shown a blood glucose lowering effect in several studies. White bread with a GI of 100 when given with lentils moong (Phaseolus mungo) had a GI of 45 and with mash (Phaseolus aureus) a GI of 56.77 In conventional Indian foods, rice combined with legumes (Bengal gram, peas and green gram) and a combination of ricedal (green gram dal and red gram dal, both dehusked and split) was studied to determine the GI in type 2 diabetic subjects.78 Rice and rice plus peas showed a higher GI while all other rice combinations produced lower glycemic indices. Overall, all the foods with leguminous seeds were able to significantly lower blood glucose response postprandially.78 Bengal gram dal and rajma (kidney beans; Phaseolus vulgaris) in a carbohydrate meal would be most effective in reducing postprandial plasma glucose levels than wheat and rice alone.31 Green gram and Bengal gram promote insulin secretion due to the protein content and form a complex with starch to decrease susceptibility to amylolytic digestion. A comparison of the glycemic responses of three Sri Lankan bread-lentil meals had no significant differences in GI (white sliced bread = 77, wholemeal bread = 77, ordinary white bread = 80 and wholemeal bread + lentil curry = 61).53 However, including legumes to bread helped reduce the GI of bread and lower postprandial glucose concentrations. Yogurt, where it is called dahi in Hindi, has been shown to significantly reduced the GI of the rice when consumed together (prior to or after a carbohydrate meal).79

Indian Snacks Popular traditional Indian snack foods include upma and dhokla. Upma is made from semolina and dhokla from chickpea, both mostly eaten in South India and Gujarat, respectively. The GI of the snacks were low (GIs: upma 18, dhokla 35).29 The higher GI of dhokla compared to upma was attributed to the fermentation process, which resulted in rapid digestion of carbohydrate and absorption of sugar, compared to upma.80 The study demonstrated that these two food products had a hypoglycemic effect in diabetic subjects. A study by Krishnamoorthy et al. investigated the GI of seven traditional Indian snacks modified in composition and preparation to determine their glycemic and insulinemic response in type 2 diabetics.81 The snacks were standardized in terms of weight. Exclusion of starchy ingredients from the original recipe, such as potatoes, refined flour, and inclusion of whole and split lentils (with intact husk) lowered the GI of Indian vegetarian snacks which are commonly medium-to-high GI (Table 4). In addition, vegetables, such as radish, cabbage, carrot, bottle gourd were included for fiber that also contributed to lowering the GI of the snacks by suppressing the postprandial glycemic response.81 This study provided a new insight into how Indian snacks could be modified to be suitable for diabetics without causing hyperglycemic effects. 12

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Diet-based Management and Treatment of Diabetes Table 4: Indian Snacks and Modifications81 Modified Indian vegetarian snacks for reduced glycemic response

Modifications necessary

Poha (rice flakes and ground nuts) and lemon tea

Excluded potato

Sprouted and cooked lentils (moth bean, Bengal gram whole) and buttermilk

Used moth bean, Bengal gram whole

Broken wheat upma (broken wheat, green gram whole) and chutney

Used medium sized broken wheat (in place of semolina) and whole green gram dal

Thalipeeth (wheat flour, Bengal gram dal flour, green gram dal flour) and chutney

Included whole green gram flour, Bengal gram dal flour (in place of chana dal and urad dal)

Brown idli (parboiled rice, black gram dal) and sambhar (red gram dal)

Included intact black gram dal (in place of dehusked black lentils)

Raddish paratha (wheat flour, moth bean flour, Bengal gram dal flour) and curd

Included moth bean flour and Bengal gram flour

Dhokla (parboiled rice, Bengal gram dal, green gram dal) and chutney

Used parboiled rice, Bengal gram dal and green gram dal (in place of chickpea flour)

Krishnamoorthy et al. further investigated their systematic study of modifying Indian foods by looking at mixed meals and their effects on glycemic and lipidemic responses.82,83 The redesigned meals included five to six low GI items, with each meal having a GL ranging from 15.58 to 23.8 g, and energy content ranging from 403 to 502 calories.82 The low GI of each meal was attributed to the whole grains, lentils and pulses (husk intact), with each meal showing good postprandial glycemic control in both normal and type 2 diabetics. The next study by the authors was the first to report improved blood glucose, glycosylated hemoglobin (HbA1c) and lipid profiles in type 2 diabetics after consuming low GI and low-to-medium GL Indian diets (vegetarian mixed meals and snacks) in type 2 diabetics over a period of 4 weeks.83 Several combined dietary factors, such as multigrain carbohydrate sources, high fiber, high amylose rice variety, legumes, inclusion of more vegetables (no starchy tubers) and spices were beneficial in bringing about the hypoglycemic effect of the meals. These systematic studies have provided significant evidence on how simple modifications of the Indian diet could improve blood glucose control in diabetics. Fruits are rich in carbohydrates and produce different glycemic responses. Brand-Miller et al. reported that tropical fruits may produce higher responses of postprandial blood glucose than temperate fruits (Brand-Miller, et al. 1997). However, fruits, such as jackfruit, guava, plum, unripe papaya and pomegranate are reported to be lower GI.84,85 When raw jackfruit was cooked with its flesh and seeds together with coconut and onions, it showed a lowering of postprandial 13

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blood glucose.86 Larger and more defined studies are required to establish the benefits of several tropical fruits in prevention/treatment of obesity and diabetes. More preliminary data are needed when recommending a full range of tropical fruits for diabetics. William et al. (1995) studied the effect of Indian vegetables (bitter gourd, curry leaves and drumstick leaves) in a meal on the blood glucose response in diabetics. The meals with vegetables had produced significantly lower blood glucose response compared to the standard meal without vegetables and a glucose standard. A detailed review by Kaushik et al. also highlighted vegetables commonly used in Indian cooking, such as cabbage, bottle gourd, bitter gourd and green leafy vegetables to have an antidiabetic effect.87

CONCLUDING REMARKS AND RECOMMENDATIONS If there is one scientific point that the reader can take home from this article is that all carbohydrates do not elicit the same blood glucose response.

Figure 1: Suggestions to reduce glycemic response to a carbohydrate-rich Indian diet.

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All carbohydrates do not produce similar physiological response. The recognition that the carbohydrates we consume may be classified into low and high GI foods has dramatically altered our dietary management of type 2 diabetes. Cereal staples like rice and wheat contribute largely to the diets of the Indian population. Consumers would gain great benefit by selecting low GI foods in their battle to reduce the risk of developing type 2 diabetes. In Indian, where type 2 diabetes is a major affliction, the time has come for consumers to demand for low GI products and for manufacturers to develop them (Figure 1).

Editor’s Comment This article provides a comprehensive review of the concept of glycemic index (GI) and how knowledge of this concept can be used to improve glycemic control in patients with diabetes. This assumes importance in light of the fact that more than 65% of the calories of the average Indian diet come from carbohydrates. Therefore, modifying the quantity and quality of ingested carbohydrates can have wideranging effects on glycemic control. The authors also explain, in simple terms, how the GI of common food items can be inexpensively altered to improve their nutritional profile. The information presented in this article will be of use to all clinicians who deal with patients with diabetes, particularly those in the primary care sector, who often do not have access to a qualified dietician. Viswanathan Mohan

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Henry and Kaur 55. Lazaridou A, Biliaderis CG. Molecular aspects of cereal b-glucan functionality: Physical properties, technological applications and physiological effects. J Cereal Sci. 2007;46:101-18. 56. Kabir M, Oppert JM, Vidal H, Bruzzo F, Fiquet C, Wursch P, et al. Four-week low-glycemic index breakfast with a modest amount of soluble fibers in type 2 diabetic men. Metabolism. 2002;51:819-26. 57. Wong S, O'Dea K. Importance of physical form rather than viscosity in determining the rate of starch hydrolysis in legumes. Am J Clin Nutr. 1983;37:66-70. 58. Behall KM, Scholfield DJ, Canary J. Effect of starch structure on glucose and insulin responses in adults. Am J Clin Nutr. 1988;47:428-32. 59. Geetha C, Parvathi EP. Hypoglycemic effect of millet incorporated breakfast items on selected non-insulin dependent diabetic patients. Indian J Nutr Diet. 1990;27:316-20. 60. Shukla K, Srivastava S. Evaluation of finger millet incorporated noodles for nutritive value and glycemic index. J Food Sci Technol. 2011:1-8. 61. Shobana S, Kumari SR, Malleshi NG, Ali SZ. Glycemic response of rice, wheat and finger millet based diabetic food formulations in normoglycemic subjects. Int J Food Sci Nutr. 2007;58:363-72. 62. Modak M, Dixit P, Londhe J, Ghaskadbi S, Paul A Devasagayam T. Indian herbs and herbal drugs used for the treatment of diabetes. J Clin Biochem Nutr. 2007;40:163-73. 63. Tapsell LC, Hemphill I, Cobiac L, Patch CS, Sullivan DR, Fenech M, et al. Health benefits of herbs and spices: the past, the present, the future. Med J Aust. 2006;185:S4-24. 64. Sauvaire Y, Ribes G, Baccou JC, Loubatieères-Mariani MM. Implication of steroid saponins and sapogenins in the hypocholesterolemic effect of fenugreek. Lipids. 1991;26:191-7. 65. Madar Z, Abel R, Samish S, Arad J. Glucose-lowering effect of fenugreek in non-insulin dependent diabetics. Eur J Clin Nutr. 1988;42:51-4. 66. Madar Z, Shomer I. Polysaccharide composition of a gel fraction derived from fenugreek and its effect on starch digestion and bile acid absorption in rats. J Agricultural Food Chem. 1990;38:1535-9. 67. Sharma RD, Raghuram TC. Hypoglycaemic effect of fenugreek seeds in non-insulin dependent diabetic subjects. Nutr Res. 1990;10:731-9. 68. Sharma RD, Sarkar A, Hazra DK, Mishra B, Singh JB, Sharma SK, et al. Use of fenugreek seed powder in the management of non-insulin dependent diabetes mellitus. Nutr Res. 1996;16:1331-9. 69. Khan A, Safdar M. Role of diet, nutrients, spices and natural products in diabetes mellitus. Pakistan J Nutr. 2003;2:1-12. 70. Soni R, Bhatnagar V. Effect of cinnamon (Cinnamomum cassia) intervention on blood glucose of middle aged adult male with non-insulin dependent diabetes mellitus (NIDDM). Studies on Ethno-Medicine. 2009;3:141-4. 71. Anuradha V, Devi A. Hypoglycemic effect of cinnamon and cumin seed powder on type 2 diabetes. Indian J Nutr. 2004;41:370-4. 72. Srinivasan M. Effect of curcumin on blood sugar as seen in a diabetic subject. Indian J Med Sci. 1972;26: 269‑70. 73. Chuengsamarn S, Rattanamongkolgul S, Luechapudiporn R, Phisalaphong C, Jirawatnotai S. Curcumin extract for prevention of type 2 diabetes. Diabetes Care. 2012;35:2121-7. 74. Maradana MR, Thomas R, O'Sullivan BJ. Targeted delivery of curcumin for treating type 2 diabetes. Mol Nutr Food Res. 2013;57:1550-6. 75. Kirupa LS, Kavitha R. Hypoglycemic effect of Murraya koenigii (curry leaf) in type 2 diabetes mellitus. Int J Food Sci Nutr. 2012;2. 76. Urooj A, Puttaraj S. Glycaemic responses to cereal-based Indian food preparations in patients with noninsulin-dependent diabetes mellitus and normal subjects. Br J Nutr. 2000;83:483-8. 77. Akhtar MS, Asim AH, Wolever T. Blood glucose responses to traditional Pakistani dishes taken by normal and diabetic subjects. Nutr Res. 1987;7:696-706. 78. Mani UV, Bhatt S, Mehta NC, Pradhan SN, Shah V, Mani I. Glycemic index of traditional Indian carbohydrate foods. J Am Coll Nutr. 1990;9:573-7. 79. Sugiyama M, Tang AC, Wakaki Y, Koyama W. Glycemic index of single and mixed meal foods among common Japanese foods with white rice as a reference food. Eur J Clin Nutr. 2003;57:743-52.

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Diet-based Management and Treatment of Diabetes 80. Wolever TM. The glycemic index. World Rev Nutr Diet. 1990;62:120-85. 81. Krishnamoorthy G, Pande AS, Moulick ND. Traditional Indian snacks modified to attain low glycaemic index and confirmed suitable to be consumed without hyperglycaemic effect in type 2 diabetics. J Indian Med Assoc. 2011;109:222-9. 82. Pande A, Krishnamoorthy G, Moulick N. Effect of redesigned Indian mixed meals on blood glucose and insulin levels in normal versus type 2 diabetic subjects—a comparative study. Int J Food Sci Nutr. 2011;62:881‑92. 83. Pande A, Krishnamoorthy G, Moulick ND. Hypoglycaemic and hypolipidaemic effects of low GI and medium GL Indian diets in type 2 diabetics for a period of 4 weeks: a prospective study. Int J Food Sci Nutr. 2012;63:649-58. 84. Fatema K, Rahman F, Sumi N, Kobura K, Afroz A, Ali L. Glycemic and insulinemic responses to pumpkin and unripe papaya in type 2 diabetic subjects. Int J Nutr Metab. 2011;3:1-6. 85. Fatema K, Sumi N, Rahman F, Kobura K, Ali L. Glycemic index determination of vegetable and fruits in healthy Bangladeshi subjects. Malays J Nutr. 2011;17:393-9. 86. Hettiaratchi UP, Ekanayake S, Welihinda J. Nutritional assessment of a jackfruit (Artocarpus heterophyllus) meal. Ceylon Med J. 2011;56:54-8. 87. Kaushik G, Satya S, Khandelwal RK, Naik SN. Commonly consumed Indian plant food materials in the management of diabetes mellitus. Diabetes Metab Syn Clin Res Rev. 2010;4:21-40.

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World Clin Diabetol. 2014;1(1):20-33.

Physical Activity and Type 2 Diabetes RM Anjana MD Dip Diab (UK) PhD Dr. Mohan’s Diabetes Specialities Centre Chennai 600 086, Tamil Nadu, India

ABSTRACT Physical activity has myriad benefits in individuals with, or at risk for, diabetes. In those with prediabetes, several randomized clinical trials (RCT) have shown that regular exercise can lead to a decreased incidence of type 2 diabetes mellitus (DM). In those with diabetes, exercise aids metabolic control and may have a small role in preventing complications. The effects of regular aerobic training includes low fasting plasma insulin levels, increased insulin sensitivity in liver and muscle and increase in highdensity lipoprotein (HDL) cholesterol and more favorable lipid profile while regular resistance training can increase muscle strength and muscle mass, and increase glucose utilization even in the resting state. In individuals with type 2 diabetes, regular moderate-intensity aerobic activity could result in a fall in blood glucose levels with minimal risk of hypoglycemia. While the majority of patients with type 2 diabetes can benefit from a structured exercise program, some forms of physical activity may be detrimental, particularly for individuals with long-standing diabetes with complications and there may be need for a proper clinical evaluation before starting an exercise program.

Introduction Type 2 diabetes is the most common form of diabetes and has attained epidemic proportions worldwide. It is estimated that 366 million people have diabetes as of 2011; this number is estimated to increase to 552 million by 2025.1 The largest increases in the prevalence of diabetes are found in low- and middle-income countries. A recent nationwide study in India estimated that there are 62 million people with diabetes in India as of 2011.2 Diabetes is the leading cause of end-

Email: [email protected] © 2014 Jaypee Brothers Medical Publishers. All rights reserved.

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stage renal disease and nontraumatic lower extremity amputations worldwide as well as a major cause of preventable blindness. Diabetes is also a major modifiable risk factor for cardiovascular disease (CVD). Diabetes and its complications impose a heavy burden not only on the affected individual but also on the family and the society at large. In the management of type 2 diabetes, lifestyle factors, such as dietary therapy and physical activity are of paramount importance. Physical activity has myriad benefits in individuals with, or at risk for, diabetes. There is now substantial data to show that in individuals with “prediabetes”, regular physical activity can help retard or prevent progression to diabetes. In patients who already have diabetes, it can help reduce hyperglycemia and may also help prevent many of the complications of diabetes. This review examines the biological effects of physical activity on glucose metabolism and discusses the evidence relating to physical activity in the prevention and control of type 2 diabetes.

DEFINITIONS Caspersen et al.3 have defined physical activity as any bodily movement produced by the contraction of skeletal muscles resulting in energy expenditure. Exercise is a subcategory of physical activity, which is planned, structured and repetitive, done to maintain or improve one or more components of physical fitness. Physical inactivity is defined as a state of no marked increase in energy expenditure above resting level. It corresponds to a usual energy expenditure of less than 1.5 kcal/kg/day.3 Aerobic activities can be defined as those activities that use oxygen to adequately meet energy demands during exercise via aerobic metabolism. Aerobic activity usually involves large muscle groups repetitively and rhythmically and can be performed for extended periods of time. This helps improve cardiorespiratory fitness. Examples include walking, running, and cycling. On the other hand, resistance or strength training involves physical training of a muscle or groups of muscles to improve muscle strength and endurance, e.g., weightlifting.

BIOLOGICAL EFFECTS OF EXERCISE ON GLUCOSE METABOLISM Effects of Aerobic Activity in a Healthy Individual During aerobic activity, the contracting muscle requires a constant source of energy. Various neuroendocrine processes are in place to ensure that this is indeed the case for any contracting muscle. These processes are mediated, on the one hand, by neural feedback mechanisms originating from the muscle, the splanchnic vascular bed and the carotid sinus, and on the other, by hormonal changes, such 21

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Figure 1: Glucose metabolism during exercise in a normal individual.

as suppression of insulin secretion and increase in the levels of counterregulatory hormones, such as glucagon, catecholamines, and cortisol. During the first 5–10 min of moderate intensity aerobic exercise, the muscle derives its fuel from the breakdown of its own stores of glycogen (glycogenolysis) (Figure 1). Once this is depleted, the next source of fuel is from glucose and nonesterified fatty acids (NEFAs), which are taken up from the circulation. Hormonal changes such as suppression of insulin secretion and increase in counterregulatory hormone levels are essential to maintain sufficiently high circulating levels of glucose and NEFAs, so that the muscle is not depleted of fuel. Circulating levels of NEFAs increase during exercise consequent to an increase in lipolysis as well as a decrease in re-esterification of NEFAs to triglycerides. Sustained moderateintensity activity can thus approximately lead to a tenfold increase in fat oxidation. Similarly, the blood glucose levels are maintained during exercise by an increase in hepatic glucose output, which in a normal individual, is sufficient to maintain blood glucose levels in the normal range in spite of the increased utilization by the muscle. In the liver, glycogen is converted to glucose (glycogenolysis) and released into the circulation. The liver can also produce glucose from non-carbohydrate precursors, a process known as gluconeogenesis. The chief substrates for gluconeo­ genesis in the setting of exercise are lactate (from the contracting muscle, a process known as Cori’s cycle) and glucogenic amino acids (particularly alanine, a process called Cahill’s cycle). Although glycogenolysis and gluconeogenesis occur in many other tissues, liver is the only organ that can release free glucose into the 22

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circulation in the non-fed state, since the enzyme glucose-6-phosphatase, which converts glucose-6-phosphate to free glucose, is present only in the liver. In a normal individual, hepatic glucose output can increase up to fourfold to meet the needs of the exercising muscle. On account of the suppression of insulin secretion occurring during moderate exercise, the risk of hypoglycemia is rather negligible in normal individuals. When vigorous intensity exercise is performed, the catecholamines have the upper hand. Epinephrine and norepinephrine levels rise about 15-fold from baseline levels. These hormones not only increase the hepatic glucose output (by promoting glycogenolysis and gluconeogenesis) but also have powerful lipolytic activity. They also paradoxically prevent glucose entry into muscles, resulting in hyperglycemia. Thus, sustained vigorous exercise can lead to a mild-to-moderate increase in blood glucose levels even in normal individuals. The effects of regular aerobic training include:

• Low fasting plasma insulin levels4 • Increased insulin sensitivity in liver and muscle5 • Increase in HDL cholesterol and a more favorable lipid profile.6 Effects of Resistance Training in a Healthy Individual

In contrast to aerobic exercise, resistance training mainly has long-term physiological effects. During the first 6 weeks, increase in muscle strength is mediated through improved muscle recruitment without muscle hypertrophy. There also occur increases in blood flow to the muscle. When the muscle is forced to contract at or near its maximal strength for more prolonged periods of time, more significant qualitative and quantitative changes occur, which are listed below:7

• Increased muscle mass (hypertrophy) • Changes in the quality of muscle: || || ||

Increased muscle capillary density Change of fiber type from IIb to IIa Biochemical changes: –– Increase in the number of glucose transporters (GLUT-4) and their relocation to the muscle surface –– Increased postreceptor insulin signaling –– Increased activity of hexokinase –– Increased activity of glycogen synthase.

All of these favor glucose utilization, and therefore, lower the blood glucose levels. The effects of exercise are known to last for 48–72 hours postexercise, after which the effects will wane. 23

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The effects of regular resistance training include:7

• Up to 30% increase in muscle strength • 10–12% increase in muscle mass • Increased stamina and ability to sustain high-intensity exercise for longer periods of time

• Increased glucose utilization even in the resting state • Increased postural stability in older individuals. Effects of Exercise in an Individual with Type 2 Diabetes Aerobic exercise and resistance training improve glucose disposal in type 2 diabetes through similar mechanisms. Individuals with type 2 diabetes have both hepatic and peripheral insulin resistance, both of which can be expected to favorably respond to regular moderate-intensity aerobic activity. Although hepatic glucose output rises during moderate-intensity aerobic activity, this is more than compensated for by the increase in peripheral glucose uptake, resulting in a fall in blood glucose levels. Simultaneously, there is a fall in plasma insulin levels, ensuring that the risk of hypoglycemia is minimal (unless the patient with type 2 diabetes is on exogenous insulin or sulfonylureas). The decrease in glycogen content with exercise is similar in individuals with or without diabetes; however, the decrease is more in obese individuals with diabetes than those without.8 The increase in muscle mass following regular resistance training provides an additional storage space for plasma glucose, since a larger muscle takes up more glucose even in the resting state. Regular resistance training can also bring about loss of adipose tissue, particularly visceral adipose tissue, which is one of the main contributors to insulin resistance in type 2 diabetes.9 Thus, overall, in an individual with type 2 diabetes, moderate-intensity exercise can cause decrease in blood glucose with minimal risk of hypoglycemia. However, as detailed above, vigorous exercise carries a small risk of producing transient hyperglycemia, particularly if the baseline blood glucose levels are high.

EXERCISE (COMBINED AEROBIC AND RESISTANCE TRAINING) FOR PREVENTION OF DIABETES: THE EVIDENCE Several large prospective cohort studies have linked higher levels of cardio­ respiratory fitness and physical activity to reduced risk of developing type 2 diabetes.10-15 A number of landmark clinical trials have been designed to demonstrate the effect of supervised exercise programs, with or without concomitant dietary modification, in preventing the development of type 2 24

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diabetes. The earliest of these trials was the nonrandomized Malmo trial,16 in which 260 men with impaired glucose tolerance (IGT) were offered a 6–12 months intervention program of supervised exercise programs and diet counseling. After 6 years, 161 of these men were compared with 56 other men with IGT who were originally offered, but declined to follow the same intervention program. The cumulative incidence of diabetes in the intervention group was found to be 11% as compared to 21% in the control group. The first of the randomized trials of lifestyle intervention for prevention of diabetes, the Da Qing study, was conducted in China.17 This was followed by the Diabetes Prevention Study (DPS) in Finland,18 the Diabetes Prevention Program (DPP) in the United States (US),19 and the Indian Diabetes Preven­tion Program (IDPP) in Chennai, India.20 More recently, a study from Japan involving 458 men with IGT showed that intensive lifestyle modification was able to reduce the risk of diabetes by 67%.21 These trials are summarized in table 1. While all the above trials demonstrate that the benefits of lifestyle modification on prevention of diabetes last at least as long as the intervention is continued, there is now emerging data on the long-term benefits of such interventions. The median 7-year follow-up of the DPS showed that not only was the marked reduction in the risk of type 2 diabetes in the intervention group sustained, but the absolute risk difference between the groups in fact increased during the post-intervention period.22 Similarly, the 20-year follow-up of the Da Qing cohort showed that the lifestyle modification group continued to have a lower incidence of type 2 diabetes compared to control participants.23 These data suggest that intensive lifestyle modification, even for a limited time, can have long-term benefits as far as risk of type 2 diabetes is concerned. While the benefits of lifestyle modification in prevention of diabetes are unequivocal, it is not clear to what extent these findings can be translated to the general population, given that the lifestyle interventions advised to the intensive control groups in the trials mentioned above were both cost- and labor-intensive. Also, while the Da Qing Study showed that the effects of diet and exercise were not additive, the other three trials did not allow the assessment of the relative importance of physical activity compared to diet. It has also been found in the DPP and DPS that the extent of protection from diabetes was directly linked to weight loss;24 the benefit accrued to those in the intensive treatment arm who did not lose weight is not clear.

EXERCISE FOR METABOLIC CONTROL IN TYPE 2 DIABETES: THE EVIDENCE While the options for pharmacotherapy of type 2 diabetes have expanded exponentially over the past decade and a half, lifestyle modification (including 25

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2005

Japanese trial in impaired glucose tolerance (IGT)21 458 males with impaired glucose tolerance

• Diet and exercise 4 years • Control

lifestyle

2.5 years

• Placebo • Metformin • Lifestyle • Metformin and

2006

Indian Diabetes Prevention Program (IDPP)20

Control—9.3% Intervention—3.0%

Control—55% Lifestyle—39.3% Metformin—40.5% Metformin and lifestyle—39.5%

Placebo—11% Metformin—7.8% Lifestyle—4.8%

2–8 years (study termi­ nated 1 year earlier than planned)

• Placebo • Metformin • Lifestyle • Diet and exercise

1996–1999 3,234 overweight subjects with impaired glucose tolerance Aged >25 years

Diabetes Prevention Program (DPP)19

531 subjects with impaired glucose tolerance Aged 35–55 years

Controls—22% Intervention—10%

• Diet and exercise 4 years • Control

Controls—68% Diet—44% Exercise—41% Diet and exercise—46%

Results (cumulative incidence of diabetes)

1993–1998 523 overweight subjects with impaired glucose tolerance Aged 40–64 years

6 years

Follow-up

Finnish Diabetes Prevention Study (DPS)18

1986–1992 577 subjects with • Diet only impaired glucose • Exercise only tolerance • Diet and exercise Aged >25 years • Control

Interventions

Da Qing Study17

Study subjects

Year

Study

Table 1: Exercise and Diabetes Prevention-Evidence

Lifestyle—67%

Lifestyle—28.5% Metformin—26.4% Lifestyle and metformin—28.2%

Lifestyle—58% Metformin—31%

58%

Diet—46% Exercise—32% Diet and exercise—41%

Risk reduction

Anjana

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increasing physical activity) retains an important place in the diabetologists’ armamentarium. A meta-analysis by Boule et al.25 attempted to systematically review and quantify the effects of exercise on glycosylated hemoglobin (HbA1c) and body mass in type 2 diabetes. Only trials (both randomized and nonrandomized) involving interventions of 8 weeks or longer and which included verification of exercise intervention through direct supervision or exercise diaries were included. Studies, which involved pharmacological co-interventions were excluded from the analysis. Applying these criteria, only 14 of a potential 2,700 articles were considered for the analysis. Twelve of these dealt with aerobic exercise, while the remainder dealt with resistance training. The meta-analysis found that exercise reduced HbA1c by a mean of 0.66% in the intervention group when compared to the control group. This reduction is of a similar order of magnitude to that brought about by many of the currently available antidiabetic drugs. Interestingly, there were no significant changes in the body mass between the two groups. There is also some evidence to show that more intensive exercise regimens can reduce HbA1c to an even greater degree (Table 2).26 While the greatest interest has been focused on the role of aerobic exercise in type 2 diabetes, it has become increasingly clear that resistance training also has a beneficial effect in these patients. It has been shown that resistance exercise improves insulin sensitivity to the same extent as aerobic training, particularly in older men.36,37 In the same subcategory of patients, there is also evidence to show that resistance training can reduce HbA1c levels,38,39 and that the benefits of aerobic and resistance exercise are additive.40 Smaller meta-analyses by Snowling and Hopkins41 and Thomas et al.42 have also investigated the effect of aerobic and resistance training in individuals with type 2 diabetes and have shown that exercise, in general, improves glycemic control. A recent systematic review43 analyzed nine trials of resistance exercise involving 372 persons with type 2 diabetes. This review found that progressive resistance training improved strength and produced reductions in HbA1c which, though of small magnitude (to the tune of 0.3%), were likely to be clinically significant in these patients. Another meta-analysis by Chudyk and Petrella44 evaluated 34 trials investigating aerobic exercise, alone or in combination with resistance training and found that the reduction in HbA1c brought about by aerobic exercise alone was 0.6%, as compared to 0.67% for combined training. In addition to the glucose lowering effects of exercise, individuals with type 2 diabetes can also be expected to benefit from reductions in cardiovascular risk factors brought about by physical activity, as well as from the improvement in general sense of well-being. 27

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Mean age (years)

52.5

54.2 55.6 56.6 55.5 52.7 45.5 64.7 50.7 69.4

Author name and year of study with location

Ronnemma, et al. 1986, Finland27

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Wing, et al. 1988, US Study28

Wing, et al. 1988, US Study28

Raz, et al. 1994, Israel29

Lehmann, et al. 1995, Switzerland30

Dunstan, et al. 1997, Australia31

Mourier, et al. 1997, France32

Honkola, et al. 1997, Finland33

Dunstan, et al. 1998, Australia34

Tessier, et al. 2000, Canada35

59

63

45

83

74

52

35

30

16

67

Male (%)

Table 2: Exercise for Metabolic Control—the Evidence

RCT

RCT

RCT

RCT

RCT

Controlled clinical trial

RCT

RCT

RCT

Randomized controlled trial (RCT)

Type of trial

Aerobic

Resistance

Resistance

Aerobic

Aerobic

Aerobic

Aerobic

Aerobic

Aerobic

Aerobic

Type of exercise intervention

Baseline Post

Baseline Post

Baseline Post

Baseline Post

Baseline Post

Baseline Post

Baseline Post

Baseline Post

Baseline Post

Baseline Post

7.5 (1.2) 7.6 (1.2)

8.2 (1.7) 8.0 (1.7)

7.5 (1.3) 7.4 (0.9)

8.5 (1.9) 6.2 (0.6)

8.8 (2.7) 8.1 (2.7)

7.5 (1.6) 7.5 (1.6)

12.5 (2.9) 11.7 (2.6)

10.6 (1.8) 8.2 (1.1)

9.7 (1.6) 8.0 (1.3)

9.6 (1.6) 8.6 (1.9)

Exercise Group

7.3 (1.7) 7.8 (1.5)

8.1 (1.9) 8.3 (2.2)

7.7 (1.3) 8.1 (1.3)

7.4 (1.0) 7.7 (1.3)

8.1 (1.4) 7.6 (1.4)

7.8 (1.7) 8.4 (1.7)

12.4 (4.0) 12.9 (4.2)

10.9 (1.9) 9.0 (1.2)

9.4 (1.7) 7.9 (1.7)

10.0 (1.5) 9.9 (1.7)

Control Group

Glycosylated hemoglobin mean (standard deviation)

Anjana

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Physical Activity and Type 2 Diabetes

EXERCISE FOR PREVENTION OF COMPLICATIONS IN TYPE 2 DIABETES: THE EVIDENCE Several large cohort studies have shown that higher levels of aerobic fitness and/ or higher habitual physical activity levels are associated with significantly lower overall and cardiovascular mortality in type 2 diabetes, even after adjusting for potential confounders, such as age, hyperlipidemia, hypertension, smoking status, and body mass index (BMI).45 However, more recently, the Look AHEAD (Action for Health in Diabetes) trial, which aimed to assess the benefits of a lifestyle intervention program resulting in weight loss on the prevention of CVD in patients with type 2 diabetes, was prematurely terminated since the intensive program did not show any significant cardiovascular benefit.46 This was in spite of study subjects losing significant amounts of weight and keeping it off, and achieving significant improvements in systolic and diastolic blood pressure (BP), HDL cholesterol, triglycerides, HbA1c and treadmill fitness levels, at least in the short-term.46 Subjects also reported improvements in sleep apnea and mobility, and a reduction in the need for diabetes medications. The reason for the lack of cardioprotection in this study is as yet unclear. There is currently little data on the benefits of physical activity on preventing or retarding the development of microvascular diabetes complications, over and above its obvious benefit in reducing hyperglycemia. Individuals with advanced complications need to exercise caution while performing certain kinds of exercise, as detailed below.

CONTRAINDICATIONS TO EXERCISE IN DIABETES While the majority of patients with type 2 diabetes can benefit from structured exercise programs, some forms of physical activity may be detrimental to those with certain comorbidities and complications. This is particularly true for individuals with long-standing diabetes, who have one or more of the advanced vascular complications of diabetes, which may be worsened by exercise.47 These are set out in table 3.

Evaluation of the Diabetic Patient Before Starting an Exercise Program A patient should begin an exercise program in consultation with his/her treating physician, especially before starting high endurance exercises.47 The following categories of patients should undergo formal cardiac evaluation before initiating an exercise program:

• Age greater than 35 years

29

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Anjana Table 3: Exercise in Patients with Complication of Diabetes Complication

Acceptable activity

Discouraged activity

Proliferative retinopathy

• Low-impact cardiovascular conditioning • Swimming • Walking

• High-impact activity • Valsalva’s maneuver • Weightlifting • Jogging

Nephropathy

• Low-to-moderate intensity exercise

• High-intensity exercise

Peripheral neuropathy (insensate feet)

• Swimming • Bicycling • Rowing

• Treadmill • Jogging • Prolonged walking

Autonomic neuropathy

• • • • •

• Exercise in extremes of temperature

Type 2 DM greater than 10 years duration Any additional CVD risk factor Significant microvascular disease, e.g., proliferative diabetic retinopathy Peripheral vascular disease (PVD) Autonomic neuropathy.

In contrast to individuals with type 1 diabetes, persons with type 2 diabetes have a low risk of developing hypoglycemia even after strenuous physical activity. The risk is somewhat higher in those patients who are on insulin or insulin secretagogues like sulfonylureas. Nevertheless, it is advisable that all patients with diabetes ensure adequate fluid and carbohydrate intake prior to and during vigorous exercise and carry a source of easily absorbed carbohydrate with them whenever they exercise. Those who exercise outside their homes should carry an identification card, detailing the nature of their illness so that appropriate assistance can be provided to them should hypoglycemia occur.

RECOMMENDATIONS FOR EXERCISE IN DIABETES Based on the results of the studies and meta-analyses quoted above, the American Diabetes Association has published guidelines for physical activity in diabetes.48 These recommendations state that:

• Adults with diabetes should be advised to perform at least 150 min of

moderate-intensity aerobic physical activity per week. Exercise should be spread over at least 3 days in a week with no more than 2 consecutive days without exercise • Resistance training twice a week is advised for all patients with diabetes who have no contraindications to the same. 30

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Physical Activity and Type 2 Diabetes

CONCLUSION It is now widely accepted that physical activity has a beneficial effect in the prevention and treatment of type 2 diabetes. However, more information is needed on whether a rigorously implemented exercise program can bring about a reduction in diabetes complications, which are the major cause of morbidity and mortality associated with this disorder. In the absence of contraindications, every patient with type 2 diabetes should be advised to engage in regular physical activity, which includes a combination of aerobic and resistance training.

Editor’s Comment This article reviews the evidence of benefits of physical activity and exercise on prevention and control of type 2 diabetes. While it is clear from the results of several large trials that lifestyle modification, including but not limited to exercise, can help prevent diabetes, application of this knowledge in a real-world setting remains challenging. It is of interest to note that exercise interventions are at least as effective as some of the currently available antidiabetic drugs in bringing down the glycosylated hemoglobin levels, a fact that should encourage all who care for patients with diabetes to include exercise in the treatment prescription. Some of the precautions and contraindications to exercise in diabetes have also been detailed. Viswanathan Mohan

REFERENCES 1. Unwin N, Whiting D, Guariguata L, Ghyoot G, Gan D (Eds). International Diabetes Federation: Diabetes Atlas, 5th edition. Brussels, Belgium: International Diabetes Federation. 2011; pp. 11-74. 2. Anjana RM, Pradeepa R, Deepa M, Datta M, Sudha V, Unnikrishnan R, et al. Prevalence of diabetes and prediabetes (impaired fasting glucose and/or impaired glucose tolerance) in urban and rural India: phase I results of the Indian Council of Medical Research-INdia DIABetes (ICMR-INDIAB) study. Diabetologia. 2011;54:3022-7. 3. Caspersen CJ, Powell KE, Christenson GM. Physical activity, exercise and physical fitness: definitions and distinctions for health-related research. Public Health Rep. 1985;100:126-31. 4. Koivisto VA, Yki-Järvinen H, DeFronzo RA. Physical training and insulin sensitivity. Diabetes Metab Rev. 1986;1:445-81. 5. DeFronzo RA, Sherwin RS, Kraemer N. Effect of physical training on insulin action in obesity. Diabetes. 1987;36:1379-85. 6. Halbert JA, Silagy CA, Finucane P, Withers RT, Hamdorf PA. Exercise training and blood lipids in hyperlipidemic and normolipidemic adults: a meta-analysis of randomized, controlled trials. Eur J Clin Nutr. 1999;53:514-22. 7. Sigal RJ, Kenny GP, Wasserman DH, Castaneda-Sceppa C. Physical activity/exercise and type 2 diabetes. Diabetes Care. 2004;27:2318-39.

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Anjana 8. Sriwijitkamol A, Coletta DK, Wajcberg E, Balbontin GB, Reyna SM, Barrientes J, et al. Effect of acute exercise on AMPK signaling in skeletal muscle of subjects with type 2 diabetes: a time-course and dose-response study. Diabetes. 2007;56:836-48. 9. American College of Sports Medicine Position Stand. Exercise and physical activity for older adults. Med Sci Sports Exerc. 1998;30:992-1008. 10. Helmrich SP, Ragland DR, Leung RW, Paffenbarger RS. Physical activity and reduced occurrence of noninsulin-dependent diabetes mellitus. N Engl J Med. 1991;325:147-52. 11. Manson JE, Rimm EB, Stampfer MJ, Colditz GA, Willett WC, Krolewski AS, et al. Physical activity and incidence of non-insulin-dependent diabetes mellitus in women. Lancet. 1991;338:774-8. 12. Manson JE, Nathan DM, Krolewski AS, Stampfer MJ, Willett WC, Hennekens CH. A prospective study of exercise and incidence of diabetes among US male physicians. JAMA. 1992;268:63-7. 13. Burchfiel CM, Sharp DS, Curb JD, Rodriguez BL, Hwang LJ, Marcus B, et al. Physical activity and incidence of diabetes: the Honolulu Heart Program. Am J Epidemiol. 1995;141:360-8. 14. Lynch J, Helmrich SP, Lakka TA, Kaplan GA, Cohen RD, Salonen R, et al. Moderately intense physical activities and high levels of cardiorespiratory fitness reduce the risk of non-insulin-dependent diabetes mellitus in middle-aged men. Arch Intern Med. 1996;156:1307-14. 15. Hu FB, Sigal RJ, Rich-Edwards JW, Colditz GA, Solomon CG, Willett WC, et al. Walking compared with vigorous physical activity and risk of type 2 diabetes in women: a prospective study. JAMA. 1999;282:1433-9. 16. Eriksson KF, Lindgärde F. Prevention of type 2 (non-insulin-dependent) diabetes mellitus by diet and physical exercise. The 6-year Malmö feasibility study. Diabetologia. 1991;34:891-8. 17. Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: The Da Qing IGT and Diabetes Study. Diabetes Care. 1997;20:537-44. 18. Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, Ilanne-Parikka P, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343-50. 19. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403. 20. Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V, et al. The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian prevent type 2 diabetes in Asian Indian Subjects with impaired glucose tolerance (IDPP-1). Diabetologia. 2006;49:289-97. 21. Kosaka K, Noda M, Kuzuya T. Prevention of type 2 diabetes by lifestyle intervention: a Japanese trial in IGT males. Diabetes Res Clin Pract. 2005;67:152-62. 22. Eriksson KF, Lindgärde F. No excess 12-year mortality in men with impaired glucose tolerance who participated in the Malmö Preventive Trial with diet and exercise. Diabetologia. 1998;41:1010-6. 23. Li G, Zhang P, Wang J, Gregg EW, Yang W, Gong Q, et al. The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year follow-up study. Lancet. 2008;371:1783-9. 24. Tuomilehto J. Nonpharmacological therapy and exercise in the prevention of type 2 diabetes. Diabetes Care. 2009;32:S189-93. 25. Boulé NG, Haddad E, Kenny GP, Wells GA, Sigal RJ. Effects of exercise on glycemic control and body mass in type 2 diabetes mellitus: a meta-analysis of controlled clinical trials. JAMA. 2001;286:1218-27. 26. Boulé NG, Kenny GP, Haddad E, Wells GA, Sigal RJ. Meta-analysis of the effect of structured exercise training on cardiorespiratory fitness in Type 2 diabetes mellitus. Diabetologia. 2003;46:1071-81. 27. Rönnemma T, Mattila K, Lehtonen A, Kallio V. A controlled randomized study on the effect of long-term physical exercise on the metabolic control in type 2 diabetic patients. Acta Med Scand. 1986;220:219-24. 28. Wing RR, Epstein LH, Patemostro-Bayles M, Kriska A, Nowalk MP, Gooding W. Exercise in a behavioural weight control programme for obese patients with Type 2 (non-insulin-dependent) diabetes. Diabetologia. 1988;31:902-9.

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Physical Activity and Type 2 Diabetes 29. Raz I, Hauser E, Bursztyn M. Moderate exercise improves glucose metabolism in uncontrolled elderly patients with non-insulin-dependent diabetes mellitus. Isr J Med Sci. 1994;30:766-70. 30. Lehmann R, Vokac A, Niedermann K, Agosti K, Spinas GA. Loss of abdominal fat and improvement of the cardiovascular risk profile by regular moderate exercise training in patients with NIDDM. Diabetologia. 1995;38:1313-9. 31. Dunstan DW, Mori TA, Puddey IB, Beilin LJ, Burke V, Morton AR, et al. The independent and combined effects of aerobic exercise and dietary fish intake on serum lipids and glycemic control in NIDDM. A randomized controlled study. Diabetes Care. 1997;20:913-21. 32. Mourier A, Gautier JF, De Kerviler E, Bigard AX, Villette JM, Garnier JP, et al. Mobilization of visceral adipose tissue related to the improvement in insulin sensitivity in response to physical training in NIDDM. Effects of branched-chain amino acid supplements. Diabetes Care. 1997;20:385-91. 33. Honkola A, Forsén T, Eriksson J. Resistance training improves the metabolic profile in individuals with type 2 diabetes. Acta Diabetol. 1997;34:245-8. 34. Dunstan DW, Puddey IB, Beilin LJ, Burke V, Morton AR, Stanton KG. Effects of a short-term circuit weight training program on glycaemic control in NIDDM. Diabetes Res Clin Pract. 1998;40:53-61. 35. Tessier D, Ménard J, Fülöp T, Ardilouze J, Roy M, Dubuc N, et al. Effects of aerobic physical exercise in the elderly with type 2 diabetes mellitus. Arch Gerontol Geriatr. 2000;31:121-32. 36. Cauza E, Hanusch-Enserer U, Strasser B, Ludvik B, Metz-Schimmerl S, Pacini G, et al. The relative benefits of endurance and strength training on the metabolic factors and muscle function of people with type 2 diabetes mellitus. Arch Phys Med Rehabil. 2005;86:1527-33. 37. Dunstan DQ, Daly RM, Owen N, Jolley D, De Courten M, Shaw J, et al. High-intensity resistance training improves glycemic control in older patients with type 2 diabetes. Diabetes Care. 2002;25:1729-36. 38. Castaneda C, Layne JE, Munoz-Orians L, Gordon PL, Walsmith J, Foddvari M, et al. A randomized controlled trial of resistance exercise training to improve glycemic control in older adults with type 2 diabetes. Diabetes. 2002;25:2335-41. 39. Sigal RJ, Kenny GP, Wasserman DH, Castaneda-Sceppa C. Physical activity/exercise and type 2 diabetes. Diabetes Care. 2004;27:2518-39. 40. Church TS, Blair SN, Cocreham S, Johannsen N, Johnson W, Kramer K, et al. Effects of aerobic and resistance training on hemoglobin A1c levels in patients with type 2 diabetes: a randomized controlled trial. JAMA. 2010;304:2253-62. 41. Snowling NJ, Hopkins WG. Effects of different modes of exercise training on glucose control and risk factors for complications in type 2 diabetic patient: a meta-analysis. Diabetes Care. 2006;29:2518-27. 42. Thomas D, Elliott EJ, Naughton GA. Exercise for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2006:CD002968. 43. Irvine C, Taylor NF. Progressive resistance exercise improves glycaemic control in people with type 2 diabetes mellitus: a systematic review. Aust J Physiother. 2009;55:237-46. 44. Chudyk A, Petrella RJ. Effects of exercise on cardiovascular risk factors in type 2 diabetes: a meta-analysis. Diabetes Care. 2011;34:1228-37. 45. National Institutes of Health. (2012). Weight loss does not lower heart disease risk from type 2 diabetes. NIH News 2012. [online] Available from www.nih.gov/news/health/oct2012/niddk-19.htm. [Accessed September, 2013]. 46. Jakicic JM, Egan CM, Fabricatore AN, Gaussoin SA, Glasser SP, Hesson LA, et al. Four-year change in cardiorespiratory fitness and influence on glycemic control in adults with type 2 diabetes in a randomized trial: the Look AHEAD Trial. Diabetes Care. 2013;36:1297-303. 47. American Diabetes Association. Physical activity/exercise and diabetes. Diabetes Care. 2004;27:S58-62. 48. American Diabetes Association. Standards of medical care in diabetes—2013. Diabetes Care. 2013;36:s11-66.

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Sulfonylureas Sudha Vidyasagar MD Department of Medicine, Kasturba Medical College, Manipal 576 104, Karnataka, India

ABSTRACT Sulfonylureas (SUs) are powerful oral hypoglycemic drugs used in the treatment of type 2 diabetes mellitus (T2DM). They act by stimulating pancreatic insulin secretion to control fasting and postprandial sugars. Their efficacy is somewhat offset by their tendency to cause dangerous hypoglycemia and significant weight gain.   Evolving data over several decades and from recent trials have cast a shadow on their role in improving macrovascular outcomes in diabetes. This has led to their being relegated to second choices in the algorithm for treatment of T2DM. However, their low cost and easy availability make them attractive choices for patients in developing countries.   In this article, we look at the place of SU in the treatment options for DM, and review the evidence for their efficacy and safety in the control of blood sugars. We also assess their use in high-risk groups and special situations. Their role in prevention of microvascular and macrovascular outcomes in diabetes is debated; further, their role in the preservation of β-cell function is also discussed.

INTRODUCTION The SUs have been in vogue for the past 6 decades and still figure in the choice of drug therapy for T2DM. This is a testimony to the efficacy of these drugs. However, in recent times, especially with the advent of newer oral hypoglycemic drugs, their current status in the treatment of T2DM is being debated. While their efficacy is unquestioned, doubt has been cast regarding their adverse effects, especially on cardiovascular (CV) morbidity and mortality. Further, their longterm effects on β-cell function resulting in hastened apoptosis has been mooted.

Email: [email protected] © 2014 Jaypee Brothers Medical Publishers. All rights reserved.

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In this review, we will attempt to relook at the evidence for efficacy and safety of this group of oral drugs, and look at the evidence for the current use of these drugs.

CLASSIFICATION In the present era, the first-generation SUs, such as acetohexamide, chlorpropamide, tolazamide, and tolbutamide are not being used commonly. Better drugs with longer duration of action, the second-generation agents, such as glipizide, glyburide, and glimepiride have replaced them.

MECHANISM OF ACTION Sulfonylureas are insulin secretagogues. They bind to the receptors sulfonylurea receptor 1 (SUR 1), present on the β-cells of the pancreas, and inhibit the potassium channel, which leads to calcium influx and release of insulin.1 They may have some effect on insulin receptors or postreceptor changes in insulinbinding in the periphery.2 However, these extrapancreatic effects, which have been described for SUs like glimepiride, may be of minimal clinical importance.

PHARMACOKINETICS The second-generation SUs act longer than the first and can be given once or twicea-day. Further, the biological action of drugs like glibenclamide is prolonged due to the fact that their metabolites are active. This is the reason why hypoglycemia due to this drug may last up to 24 hours.3 Since, they suppress hepatic glucose output and cause increased insulin secretion, SUs decrease both fasting, and postprandial sugars.

EFFICACY Sulfonylureas are highly effective hypoglycemic drugs. They lower blood glucose concentrations by over 20% as monotherapy.4 Thus, their efficacy is similar to that of metformin averaging about 1.5% reduction of HbA1c. In combination with metformin, they are very effective and such combinations are popular in India due to the cost advantage and decreased pill burden.5 There have been concerns about the decrease of efficacy after some time, as seen in A Diabetes Outcome Progression Trial (ADOPT) study. In this study where SU, metformin, and glitazones were started as monotherapy, the requirement of second drug to reach target blood sugar and HbA1c came in 2 years for SU whereas the other drugs like metformin and glitazones fared much better.6 The different generation of SU with their duration of action and appropriate dosage is summarized in table 1. 35

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Vidyasagar Table 1: Sulfonylureas (SUs) with Their Duration of Action and Dosage7 Drug

Duration of action (hours)

Daily dose (mg)

First-generation sulfonylureas (SUs) Chlorpropamide

24–72

100–500 OD

Tolbutamide

6–12

1,000–2,000 OD or BD

Glipizide

12–18

5–20 OD or BD

Gliclazide

24

40–240 OD

Glyburide (glibenclamide)

12–24

2.5–20 OD or BD

Glimepiride

>24

2–8 OD or BD

Second-generation SUs

How to Start and Titrate? Sulfonylureas are generally given half an hour before a meal once- or twice a day. If blood glucose levels are not controlled in 2–4 weeks, the dosage can be increased gradually to the maximum dose. This is important to remember because the maximum effect of these drugs may be felt by the patient weeks later and the temptation to increase the dosage at shorter intervals must be curbed. Such inappropriate increase is the main cause of post-hospital discharge hypoglycemia in several patients. The maximum efficacy of all SU may be felt at 50% of maximum recommended dose (10 mg for glibenclamide or glipizide) and further increases in dosage do not cause proportionate increase in efficacy. Treatment Failure Unfortunately, SU may fail to be effective in about 20% of patients’ right from initiation in some patients and this is categorized as primary SU failure. Some patients may demonstrate secondary failure which is the waning of efficacy after initial response. This can be seen in 5% of patients on therapy every year.8

SIDE EFFECTS Hypoglycemia Sulfonylureas are well tolerated and have few side effects. The main side effect, which is encountered, is hypoglycemia. Because they increase insulin secretion, this side effect is expected, and is therefore, a class effect. 36

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The fear of hypoglycemia makes many clinicians hesitate to use SU. The risk of hypoglycemia is real, but studies vary regarding the degree of this risk. Contrary to common perception, Shorr and coinvestigators showed in a study, including 14,000 elderly T2DM patients on SU that serious hypoglycemia was rare.9 In United Kingdom Prospective Diabetes Study (UKPDS) to the event rate for major hypoglycemia with SU was 1.4% for glibenclamide and 1.8% for insulin.

Differences among SU Regarding Hypoglycemia Moreover, differences exist between different groups of SU, with the longer acting drugs like glibenclamide and chlorpropamide causing more hypoglycemic attacks than tolbutamide or glipizide.10 Hence, in high-risk groups, such as elderly or chronic renal failure patients and those depends on many other drugs, it is preferable to use short-acting drugs. Glipizide and gliclazide have the advantage of having inactive metabolites which make it safe in these high-risk groups. In the GUIDE (GlUcose control In type 2 diabetes: Diamicron MR versus glimEpiride) study, glimepiride and gliclazide were compared for episodes of hypoglycemia, and it was found that gliclazide arm showed statistically significant lesser episodes of hypoglycemia, making it a safer drug in high-risk patients.11 Such considerations are especially important in the elderly in whom hypoglycemia may not cause autonomic warning symptoms and directly cause neuroglycopenia. In renal failure too, SUs which have long duration of action like glibenclamide are contraindicated.12 Recovery from hypoglycemia also may be prolonged due to delayed excretion of metabolites; hence the patient may need prolonged observation and treatment for recurrence of hypoglycemia.13 It has been also seen that patients on nonsteroidal anti-inflammatory drugs (NSAIDs) along with SU may develop more hypoglycemia as NSAIDs may increase insulin secretion by blocking potassium-dependent adenosine triphosphate channels in β-cells.14 Further the protein binding of SUs may be altered by NSAIDs and can cause increased levels of drug and hypoglycemia. Since these are commonly prescribed drugs for pain and inflammation, this interaction must be kept in mind and patients should be monitored while on both drugs for falling sugar levels. Patients’ education regarding the avoidance of alcohol and irregular meals must be emphasized while staring these drugs as this will go a long way in the prevention of hospitalization and unnecessary interventions. Weight Gain and Other Side Effects All SUs being stimulators of insulin cause weight gain, most patients gain about 1–4 kg, and this effect may plateau out at about 6 months.5 Further, in combination with metformin, this side effect could be very well counteracted. 37

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In UKPDS, it was shown that among the drugs for diabetes, which cause weight gain (SU, insulin and glitazones), SUs cause the least weight gain (1.7 kg for glibenclamide). It is also important to note that inspite of this weight gain, there was reduction in microangiopathy in the SU arm in UKPDS probably suggesting that the weight gain did not offset the reduction in diabetic complications.15 Among the SUs glipizide, gliclazide may cause least weight gain. Infrequent side effects include skin photosensitivity and syndrome of inappropriate antidiuretic hormone secretion (SIADH) due to chlorpropamide. Since these drugs share the SU moiety, they are contraindicated in patients with allergy to sulfonamides. Long-term Effects: Cardiovascular Effects One of the biggest concerns about SU has been their long-term side effects in terms of prevention of diabetic complications. In fact, doubts have been raised about their propensity to increase CV events. The proposed theoretical mechanisms by which SUs increase CV mortality has been that SUs act on potassium channels in β-cells SUR 1 and may have crossreactivity with potassium channels on myocardium SUR 2 (Figure 1).16 This may decrease ischemic conditioning and cause more CV morbidity. However, there may be selectivity among SUs in this effect with gliclazide causing less CV arm.16

CLINICAL EVIDENCE FOR CARDIAC SIDE EFFECTS If we examine the clinical evidence for this apprehension, the data is unclear with several contradictory results in different studies. The UGDP (University Group Diabetes Program) study documented increased CV mortality with patients treated with tolbutamide than in those who were on insulin (12.7% vs 6.2%). Following this, SUs were blamed for the increased mortality and a warning was issued regarding their usage. However,

Figure 1: The sulfonylurea receptor 1 and 2 (SUR 1 and SUR 2) and sulfonylureas (SUs) action on β-cell and cardiac myocyte. The binding may interfere with myocardial protection during ischemia.

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further analysis of the data revealed that the study involved groups with higher CV risk in the SUs arm, which was not controlled for during analysis.17 The tolbutamide used in this study is longer the preferred SU and the results may not be applicable to other SU. But as a consequence of this study SUs in the United States have been labeled as higher CV mortality to be avoided in highrisk groups. On the contrary, the UKPDS that is the largest and longest follow-up study on T2DM did not show this effect.15 Chlorpropamide, glibenclamide, and glipizide that were used in this study, were not associated with adverse CV events. The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study with over 11,000 T2DM patients showed no increased CV mortality with gliclazide, though there was no significant benefit in CV outcome [odds ratio 0.94, 95% confidence interval (CI) 0.84–1.06, p = 0.32].

SULFONYLUREA AND ISCHEMIC PRECONDITIONING Further concerns have been raised about the role of SU in the presence of myocardial infarction (MI). It has been observed that these drugs may bind to the potassium channels and cause decreased coronary vasodilatation and hence larger infarctions. They may also interfere with ischemic preconditioning as mentioned above. Several studies have been done to address this issue: the Mayo Clinic series of patients undergoing Percutaneous Transluminal Coronary Angioplasty (PTCA) showed the odds ratio for death of patients on SU at the time of MI was 2.18 A detailed description of the diabetes mellitus, insulin glucose infusion in acute myocardial infarction (DIGAMI) study also concluded that those on SU had the poorest outcome.19 However, evidence to the contrary came from a French study which recorded lower mortality for patients on SU compared to other drugs and insulin.20 Further, it has been found that the mortality and morbidity for CV events may differ between different SU. Glibenclamide was found to be associated with highest mortality (7.5%) as compared with gliclazide and glimepiride (2.7%).11 In the ADVANCE trial too, gliclazide was used and did not document an increase in CV mortality. This may be due to the fact that gliclazide is selective for pancreatic SU receptors and with less affinity for cardiac SU receptors.21 In a meta-analysis of more than 40 trials, SUs have not been found to have increased mortality, probably putting to rest at least for now fears about their long-term safety.22 But more studies are needed to address this issue before any firm conclusion can be reached. Until then, it is best to avoid SU in the context of an acute coronary event or revascularization where insulin may be the preferred agent. 39

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HbA1c, glycosylated hemoglobin; ULN, upper limit of normal range.

Figure 2: United Kingdom Prospective Diabetes Study (UKPDS) demonstrated loss of glycemic control with all interventions studied.

SULFONYLUREA AND b-CELL FUNCTION Sulfonylureas need functioning β-cells to affect their action, as they are secretagogues. Since the natural course of diabetes involves deterioration of β-cell function, it is a well-known fact that escalating doses of SU may be required as the disease progresses and may lead to secondary failure of these drugs. In the ADOPT study, the need to add a second drug for control of sugars was earliest with the SU group as compared to the glitazone and metformin group.23 This has been cited as one of the disadvantages of this group of drugs, as they may hasten β-cell apoptosis. However, in the UKPDS, the fall in β-cell function was observed for patients not only in the SU arm but in the metformin arm also. This may reflect the natural course of the disease rather than related to the mechanism of action of drug as shown in figure 2.15 Further, the data becomes difficult to interpret with the confounding effect of glucotoxicity in the patients with uncontrolled sugars. There may be some difference in this effect on β-cells between different groups of SUs. Gliclazide, which has experimental evidence to support its free radical scavenging activity, has protective effect on β-cell apoptosis in laboratory studies. How this translates into clinical effect is not clearly defined.24

INDICATIONS AND USAGE Sulfonylureas are second-line drugs after lifestyle and metformin in current American Diabetes Association (ADA) and European Association for de Study of Diabetes (EASD) recommendations. Their efficacy is to be balanced by their long-term side effects making them lower choices in the paradigm of diabetic treatment.25 However in resource poor countries like India, they continue to be used extensively because of their low cost. 40

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USE IN SPECIAL GROUPS SU in Kidney Disease All SUs are excreted by the kidney, and hence, their levels can rise to cause serious hypoglycemia. In chronic kidney disease stage 3–5, SUs, which are long acting, such as glibenclamide are best avoided. Glimepiride causes less hypoglycemia, but glipizide in small doses can be used safely, as it has inactive metabolites.26 Further, hypoglycemia due to these drugs in patients with renal failure can be prolonged and may need glucose infusions for several hours.

SU in Liver Disease Sulfonylureas, which have short half-life, such as glipizide, are generally safe in patients with mild-to-moderate liver disease. However, in severe liver disease, their use must be done with caution as severe hypoglycemia can result in. Hence, they are best avoided in patients with severe liver dysfunction.27

SU in Pregnancy Previously thought to be contraindicated in pregnancy, SUs are now being increasingly used in pregnant women after a study by Langer et al. established their safety.28 This has been supported also by several other studies.29 Larger randomized controlled trials (RCTs) are needed for these drugs to be recommended for routine usage in pregnancy.

SU in Elderly Renal function tends to deteriorate with age and this can lead to poor clearance of SU. This is especially dangerous in the elderly with poor autonomic warning signals with increasing age.30 Hence, long-acting SUs, such as glibenclamide are not recommended over the age of 60 years. SUs, such as gliclazide and glipizide, which has inactive metabolites, can be used judiciously in smaller doses with monitoring.26

SU in Maturity Onset Diabetes in the Young Certain types of maturity onset diabetes in the young (MODY), such as hepatocyte nuclear factors (HNF)-1A and -4A respond extraordinarily well to SU.31 HNF‑1A subgroup is the largest one in the MODY series from United Kingdom. Several patients after diagnosis have been successfully switched over from insulin to SU 41

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and found to have good glycemic control, making them the treatment of choice in this group of patients.32 Further, since they are very sensitive to SU, even low doses of these drugs may achieve excellent control and sometimes hypoglycemia.

CONCLUSION AND CURRENT STATUS To conclude, SUs still remain a very important group of drugs, which are effective in the treatment of T2DM. With their high efficacy and low cost, they are widely used in developing countries such as India where affordability is still a major concern and affects compliance. They are second-line drugs in all major recommendations world over. In combination with metformin, they achieve good glycemic control resulting in reduction of microvascular complications. Their role in the prevention of macrovascular complications is not clear, as is the case with several other antidiabetic drugs. The fear is that they may cause harm by increasing macrovascular morbidity and mortality may need more concrete proof. Their tendency to cause serious hypoglycemia and weight gain must be considered while using them in high-risk groups of patients.

Editor’s Comment Sulfonylureas are the oldest class of oral antidiabetic drugs available today. Notwithstanding concerns regarding their safety and long-term efficacy, they are still going strong as one of the first- or second-line agents for type 2 diabetes. In this chapter, the author examines the evidence for and against the use of sulfonylureas in type 2 diabetes and tries to redefine their role in the current era of designer drugs and incretin-based therapies. Viswanathan Mohan

REFERENCES 1. Panten U, Schwanstecher M, Schwanstecher C. Sulfonylurea receptors and mechanism of sulfonylurea action. Exp Clin Endocrinol Diabetes. 1996;104:1-9. 2. Fleig WE, Noether-Fleig G, Fussgaenger R, Ditschuneit H. Modulation by a sulfonylurea of insulin-dependent glycogenesis, but not of insulin binding, in cultured rat hapatocytes. Evidence for a postreceptor mechanism of action. Diabetes. 1984;33:285-90. 3. Rydberg T, Jönsson A, Karlsson MO, Melander A. Concentration-effect relations of glibenclamide and its active metabolites in man: modeling of pharmacokinetics and pharmacodynamics. Br J Clin Pharmacol. 1997;43:373-81. 4. United Kingdom Prospective Diabetes Study 24: a 6-year, randomized, controlled trial comparing sulfonylurea, insulin, and metformin therapy in patients with newly diagnosed type 2 diabetes that could not be controlled with diet therapy. United Kingdom Prospective Diabetes Study Group. Ann Intern Med. 1998;128:165-75.

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Sulfonylureas 5. Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR, Sherwin R, et al. Management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2006;29:1963-72. 6. Kahn SE, Lachin JM, Zinman B, Haffner SM, Aftring RP, Paul G, et al. Effects of rosiglitazone, glyburide, and metformin on β-cell function and insulin sensitivity in ADOPT. Diabetes. 2011;60:1552-60. 7. Brunton LL, Chabner BA, Knollmann BC (Eds). Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12th edition. New York, USA: McGraw Hill Medical. 2011. 8. Gerich JE. Oral hypoglycemic agents. N Engl J Med. 1989;321:1231-45. 9. Shorr RI, Ray WA, Daugherty JR, Griffin MR. Incidence and risk factors for serious hypoglycemia in older persons using insulin or sulfonylureas. Arch Intern Med. 1997;157:1681-6. 10. Shorr RI, Ray WA, Daugherty JR, Griffin MR. Individual sulfonylureas and serious hypoglycemia in older people. J Am Geriatr Soc. 1996;44:751-5. 11. Schernthaner G, Grimaldi A, Di Mario U, Drzewoski J, Kempler P, Kvapil M, et al. GUIDE study: doubleblind comparison of once-daily gliclazide MR and glimepiride in type 2 diabetic patients. Eur J Clin Invest. 2004;34:535-42. 12. Gangji AS, Cukierman T, Gerstein HC, Goldsmith CH, Clase CM. A systemic review and meta-analysis of hypoglycemia and cardiovascular events: a comparison of glyburide with other secretagogues and with insulin. Diabetes Care. 2007;30:389-94. 13. Krepinsky J, Ingram AJ, Clase CM. Prolonged sulfonylurea-induced hypoglycemia patients with end-stage renal disease. Am J Kidney Dis. 2000;35:500-5. 14. Li J, Zhang N, Ye B, Ju W, Orser B, Fox JE, et al. Non-steroidal anti-inflammatory drugs increase insulin release from beta cells by inhibiting ATP-sensitive potassium channels. Br J Pharmacol. 2007;151:483-93. 15. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-53. 16. Christopher JS, Miles F, Gerard AM. Drugs for diabetes: part 2 sulphonylureas. Br J Cardiol. 2010;17:279-82. 17. Seltzer HS. A summary of criticisms of the findings and conclusions of the University Group Diabetes Program (UGDP). Diabetes. 1972;21:976-9. 18. Garratt KN, Brady PA, Hassinger NL, Grill DE, Terzic A, Holmes DR. Sulfonylurea drugs increase early mortality in patients with diabetes mellitus after direct angioplasty for acute myocardial infarction. J Am Coll Cardiol. 1999;33:119-24. 19. Malmberg K. Prospective randomized study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. BMJ. 1997;314:1512-5. 20. Zeller M, Danchin N, Simon D, Vahanian A, Lorgis L, Cottin Y, et al. Impact of type of preadmission sulfonylureas on mortality and cardiovascular outcomes in diabetic patients with acute myocardial infarction. J Clin Endocrinol Metab. 2010;95:4993-5002. 21. Schramm TK, Gislason GH, Vaag A, Rasmussed JN, Folke F, Hansen ML, et al. Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study. Eur Heart J. 2011;32:1900-8. 22. Selvin E, Bolen S, Yeh HC, Wiley C, Wilson LM, Marinopoulos SS, et al. Cardiovascular outcomes in trials of oral diabetes medications: a systematic review. Arch Intern Med. 2008;168:2070-80. 23. Viberti G, Kahn SE, Greene DA, Herman WH, Zinman B, Holman RR, et al. A diabetes outcome progression trial (ADOPT): an international multicenter study of the comparative efficacy of rosiglitazone, glyburide, and metformin in recently diagnosed type 2 diabetes. Diabetes Care. 2002;25:1737-43. 24. Jennings PE, Belch JJ. Free radical scavenging activity of sulfonylureas: a clinical assessment of the effect of gliclazide. Metabolism. 2000;49:23-6.

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Vidyasagar 25. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364-79. 26. National Kidney Foundation. Kidney Disease Outcome Quality Initiative (KDOQI). Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis. 2007;49:S1-180. 27. Tolman KG, Fonseca V, Dalpiaz A, Tan MH. Spectrum of liver disease in type 2 diabetes and management of patients with diabetes and liver disease. Diabetes Care. 2007;30:734-43. 28. Langer O, Conway DL, Berkus MD, Xenakis EM, Gonzales O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med. 2000;343:1134-8. 29. Conway DL, Gonzales O, Skiver D. Use of glyburide for the treatment of gestational diabetes: the San Antonio experience. J Matern Fetal Neonatal Med. 2004;15:51-5. 30. Burge MR, Schmitz-Fiorentino K, Fischette C, Qualls CR, Schade DS. A prospective trial of risk factors for sulfonylurea-induced hypoglycemia in type 2 diabetes mellitus. JAMA. 1998;279:137-43. 31. Pearson ER, Liddell WG, Shepherd M, Corrall RJ, Hattersley AT. Sensitivity to sulphonylureas in patients with hepatocyte nuclear factor-1alpha gene mutations: evidence for pharmacogenetics in diabetes. Diabet Med. 2000;17:543-5. 32. Shepherd M, Shields B, Ellard S, Rubio-Cabezas O, Hattersley AT. A genetic diagnosis of HNF1A diabetes alters treatment and improves glycaemic control in the majority of insulin-treated patients. Diabet Med. 2009;26:437-41.

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Metformin: Old Wine in a New Bottle—the Evidence-based First-line Agent in Type 2 Diabetes Shashank R Joshi MD DM FACP FACE FRCP Lilavati and Bhatia Hospital, Mumbai, Maharashtra, India Department of Endocrinology, Grant Medical College and Sir JJ Group of Hospitals Mumbai 400 008, Maharashtra, India

ABSTRACT Metformin is the most widely used oral antidiabetic agent worldwide. It has managed to hold onto this position in spite of the advent of several classes of newer molecules on account of its unquestioned efficacy, excellent safety record, pleiotropic benefits and cost-effectiveness. This article will discuss the mechanism of actions, benefits, indications and contraindications of metformin as a first-line agent for the treatment of type 2 diabetes mellitus.

HISTORY French lilac (Galega officinalis) has been employed as an antidiabetic agent in traditional medicine for centuries.1 Studies done toward the end of the 19th century revealed the active component in this plant to be guanidine and attempts were made to utilize this agent for the management of diabetes.2,3 However, the use of guanidine had to be abandoned in view of toxicity, and the advent of insulin therapy at around the same time cooled enthusiasm toward oral glucose lowering agents. It was not until the 1950s that the first-therapeutic agent in the class of biguanides, phenformin, was introduced. Even though effective as an antidiabetic agent, its use was limited by the incidence of serious side effects (lactic acidosis), and it was withdrawn in most parts of the globe by the 1970s, although it remained in use in India for much longer.4,5 Metformin is a biguanide derivative that is structurally distinct from phenformin, and has much less propensity to Email: [email protected] © 2014 Jaypee Brothers Medical Publishers. All rights reserved.

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cause lactic acidosis. This agent was introduced in the 1960s and rapidly replaced phenformin in most countries. However, it was not until 1995 that it was allowed into the US market. Notwithstanding its late introduction to this major market, metformin today ranks as the most widely prescribed antidiabetic agent in the world.

MECHANISM OF ACTION In spite of being in wide clinical use for decades, the mechanism of action of metformin has not yet been clearly elucidated. Metformin has no effect on plasma insulin concentration, although it can cause marginal improvement in b-cell function indirectly by reducing glucotoxicity. Even high doses of metformin do not cause hypoglycemia when administered to nondiabetic individuals.6,7 Unlike phenformin, metformin seems to have no significant effect on gastrointestinal (GI) glucose absorption. Recent studies support the concept that metformin exerts its effects by activating adenosine monophosphate kinase, which functions as the fuel sensor of the cell. Adenosine monophosphate-activated protein kinase (AMPK) inhibits hepatic glucose production, stimulates muscle glucose uptake, and inhibits lipolysis.8,9 However, activation of AMPK also occurs with other insulin sensitizers, such as thiazolidinediones, leading some researchers to speculate that AMPK activation is a nonspecific effect of insulin sensitization.10 The effects of metformin on different tissues are described below.

Liver The liver is the major site of action of metformin. Metformin reduces fasting plasma glucose levels by inhibiting gluconeogenesis. Postulated mechanisms of action include phosphorylation of the insulin receptor and insulin receptor substrate-2, inhibition of key enzymes of gluconeogenesis (phosphoenolpyruvate carboxykinase, fructose 1, 6-biphosphatase and glucose-6-phosphatase) and activation of pyruvate kinase.11-14 It can also possibly inhibit uptake of gluconeo­ genic precursors like alanine and lactate by depolarizing the hepatocyte membrane.15-17 Metformin can also inhibit mitochondrial respiration, depriving the hepatocyte of the energy needed to carry out gluconeogenesis.18,19

Skeletal Muscle In the skeletal muscle, metformin improves glucose uptake by increasing insulin receptor tyrosine kinase activity and glucose transporter 4 translocation and activity.20 46

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Other Effects Recent publications on metformin have focused on its pleiotropic effects, many of which have a direct or potential benefit on cardiovascular risk profile. Effects on Weight Metformin has unequivocally been shown to have beneficial effects on weight gain. Most studies have shown that the agent is either weight neutral or that it produces modest weight reduction.21 This is in contrast to many of the other commonly used therapeutic agents for diabetes [sulfonylureas (SUs), thiazolidinediones and insulin], which bring about weight gain. However, the use of metformin as a weight loss agent in the absence of glucose intolerance cannot be recommended at the present time. It has been postulated that the anorectic effect of metformin contributes to weight loss;22 however, it is almost certain that as yet unidentified additional mechanisms also contribute to this effect. Lipids Metformin is known to beneficially impact the lipid profile. It can reduce triglycerides, total cholesterol and low-density lipoprotein (LDL) cholesterol, as well as increase high-density lipoprotein (HDL) cholesterol,21 particularly the antiatherogenic HDL2 subfraction.23 However, these effects are usually of modest magnitude and have not been observed in all studies. Blood Pressure The effects of metformin on blood pressure (BP) are minimal, although some studies have shown reduction in both systolic24 and diastolic25 BP during metformin use. While weight reduction due to metformin might have contributed to BP lowering, this effect was also observed in studies in which no changes in weight were found to occur. Cardiovascular Disease Evidence is now mounting that metformin can retard or even prevent the development of cardiovascular disease (CVD) in persons with diabetes. In the United Kingdom Prospective Diabetes Study (UKPDS), obese subjects with type 2 diabetes prescribed metformin were found to have a lower incidence of stroke, all-cause mortality and all diabetes-related endpoints compared to those on insulin or SU, despite achieving equivalent degree of glycemic control.26 It has been shown that metformin improves endothelium-dependent vasodilatation and reduces fibrinogen levels and platelet aggregation as well as plasminogen activator 47

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inhibitor-1 (PAI-1) activity.22 Reductions in both fasting and postprandial insulin concentrations as well as a reduction in C-reactive protein levels have also been demonstrated.27,28 All these effects have the potential to reverse endothelial dysfunction and thereby reduce the risk of CVD in patients with diabetes. Polycystic Ovarian Syndrome/Nonalcoholic Fatty Liver Disease Metformin is widely prescribed for treatment of polycystic ovarian syndrome (PCOS). Metformin use has been shown to reduce androgen levels and restore ovulation in these patients.29,30 Use of metformin over the first trimester in women with PCOS who become pregnant has been shown to reduce the high rates of gestational diabetes mellitus (GDM) and first-trimester fetal loss.31 The use of metformin in pregnant women with diabetes who do not have PCOS remains controversial, although some studies have shown that the drug is a safe and efficacious option in this population.32 Since insulin resistance plays a major role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), studies have focused on the utility of insulin sensitizers, such as metformin in the treatment of this condition. The bulk of current evidence suggests that metformin improves hepatic function, but not liver histology, in patients with NAFLD.33 Effects on Malignancy The potential antitumorigenic effects of metformin have recently received wide interest. The possible mechanisms of this effect include: (i) activation of liver kinase B1 (LKB1)/AMPK pathway, (ii) induction of cell-cycle arrest and/or apoptosis, (iii) inhibition of protein synthesis, (iv) reduction in circulating insulin levels, (v) inhibition of the unfolded protein response (UPR), (vi) activation of the immune system, and (vii) eradication of cancer stem cells.34 A recent systematic review and meta-analysis of 53 studies involving more than 1 million patients with type 2 diabetes suggested that use of metformin was associated with a lower risk of cancer death as well as development of liver, pancreas, colorectal, stomach and esophageal cancer.35 However, it is not clear whether metformin has anticancer effects in persons without diabetes. Once this question is answered, it is hoped that metformin can be used as a safe, effective anticancer agent.36

ADVERSE EFFECTS The most frequent adverse effects of metformin therapy involve the GI tract. Around 20% of patients experience abdominal discomfort, diarrhea and anorexia on starting the drug.22 These effects can be minimized by starting at a low dose and uptitrating gradually. Discontinuation of the drug is necessary only in less than 5% 48

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of patients. Use of sustained release preparations can minimize the incidence of GI side effects to a great extent. Hypoglycemia is rare with metformin monotherapy but is possible when the drug is combined with other agents that can cause hypoglycemia, such as insulin or SUs. Prolonged use of metformin has been shown to be associated with vitamin B₁₂ deficiency. In a recent multicentric trial, 390 patients with diabetes mellitus receiving insulin therapy were randomized to receive metformin, 850 mg 3 times daily, or placebo, and followed up for a median period of 4 years; seven patients randomized to metformin had an increased risk of vitamin B₁₂ deficiency (number needed to harm = 14 per 4.3 years) and low vitamin B₁₂ levels (number needed to harm = 9 per 4.3 years).37 Clinically evident deficiency is unlikely if dietary intake of vitamin B₁₂ is adequate. Deficiency can be corrected with vitamin B₁₂ supplements, but the amounts available in general multivitamins might not be sufficient to correct the deficiency.38 Oral calcium supplements have also been shown to be useful in correcting the deficiency.39 The most dreaded side effect of phenformin therapy, lactic acidosis, is extremely rare with metformin.40 The risk can be further reduced if metformin use is avoided in patients who are at high risk of lactic acidosis (cardiac failure, respiratory failure, renal failure, hepatic failure, and severe sepsis).

Drug Interactions The alpha-glucosidase inhibitors have been shown to reduce the bioavailability of metformin; however, the effect on antidiabetic efficacy is minimal. Cimetidine can reduce the renal clearance of metformin.

Contraindications The contraindications for metformin use are listed in the table 1. Table 1: Contraindications to Metformin Use

• Renal disease (serum creatinine >1.5 mg/dL in males or >1.4 mg/dL in females or abnormal creatinine clearance)

• Use of intravenous contrast • Any condition predisposing to tissue hypoxia • Hepatic disease • High alcohol intake • Acute or severe cardiac or respiratory dysfunction • Severely ill or hospitalized patients • Intolerance/allergy to metformin • Previous history of lactic acidosis

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PLACE OF METFORMIN IN DIABETES PHARMACOTHERAPY Metformin is the initial drug of choice for controlling hyperglycemia in diabetes. The American Diabetes Association and the European Association for the Study of Diabetes recommend starting metformin therapy at the time of diagnosis of type 2 diabetes, along with lifestyle modification, provided no contraindications exist to its use.41 The American Association of Clinical Endocrinologists and American College of Endocrinology list metformin as one of the first-choice agents to be used in the management of type 2 diabetes, as monotherapy if the initial glycosylated hemoglobin (HbA1c) is less than 7.5%, or as part of dual or triple therapy if HbA1c levels are higher at initial presentation.42 Metformin therapy should be started at a low dose and slowly uptitrated so as to minimize GI side effects. A dose-response study showed that 2,000 mg daily is the most effective dose of metformin (HbA1c lowered 2% compared to placebo), best given as 1,000 mg with breakfast and dinner to facilitate compliance with therapy.43

Use in Combination Therapy Sulfonylureas: Sulfonylureas are among the most common agents used in combination with metformin. This combination is particularly useful when immediate reduction of hyperglycemia is required with oral therapy. When metformin is added to a patient already on SU, dose titration should be gradual, since the tendency of SU to cause hypoglycemia may reemerge when metformin is added.21,44 The tendency of SU to cause weight gain can be neutralized by concomitant use of metformin. Conversely, SU may be added when glycemic control is suboptimal with metformin alone. SU can be continued at maximal doses when metformin is initiated. Pioglitazone: Metformin reduces insulin resistance in the liver, while pioglitazone acts on insulin resistance in the skeletal muscle. Therefore, the combination of metformin with pioglitazone is a rational therapeutic option. Combined metformin and pioglitazone therapy is a safe and efficacious method of improving glycemic control, without hyperinsulinemia or significant hypoglycemia.22 Metformin can, to an extent, also blunt the weight gain associated with pioglitazone use. Glucagon-like peptide-1 analogues and dipeptidyl peptidase-4 inhibitors: Metformin, by itself, has been postulated to enhance the biological effect of incretins by increasing glucagon-like peptide-1 (GLP-1) secretion, suppressing activity of dipeptidyl peptidase-4 (DPP-4) inhibitors and upregulating the expression of GLP-1 receptor in pancreatic β-cells. Also, DPP-4 inhibitors, by themselves, have a favorable effect on insulin sensitivity. The combination of incretin-based therapies and metformin can, therefore, have additive or even synergistic effect 50

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on metabolic control in patients with type 2 diabetes. Recent studies suggest that combining metformin with DPP-4 inhibitors is a safe and effective therapeutic option in type 2 diabetes.45 Similarly, metformin can also be safely and effectively combined with the GLP-1 agonists, exenatide and liraglutide, although it may exacerbate the GI side effects of these agents. Nowadays, fixed-dose combinations of metformin with SU, pioglitazone and DPP-4 inhibitors are widely available in India. While these formulations do help to enhance compliance by reducing the pill burden, they do not offer flexibility in dosing of the individual components. Insulin: Metformin is the ideal oral agent for combining with insulin. In this case, metformin has been found to have an “insulin-sparing” effect, enabling achievement of good glycemic control with much lower doses of insulin than would otherwise be possible.46-48 This property is of particular usefulness in patients on large doses of insulin, whose insulin dosage may otherwise exceed the capacity of a single syringe, necessitating a second injection at a given time. There is experimental evidence to suggest that such a reduction in insulin dosage may attenuate possible atherogenic effects of high circulating insulin concentrations.49

CONCLUSION Metformin is the oral antidiabetic drug par excellence. It is a safe and effective agent when used as monotherapy, bringing about significant reductions in HbA1c with little or no risk of hypoglycemia. It can also be used in combination with SU, pioglitazone, and incretin-based therapies. When used in combination with insulin, it has insulin-sparing properties and also helps to blunt weight gain. When used appropriately and with gradual uptitration of doses, adverse events are rare with metformin. The use of sustained release preparations has helped in significantly reducing the incidence of GI side effects. The antimalignancy effects of metformin represent a new and exciting avenue for further research.

Editor’s Comment Nowhere else is the aphorism “old is gold” more apt than in the case of metformin. One of the oldest oral antidiabetic agent, not only has it held on to its position as the first-line therapy for type 2 diabetes, but recent evidence has uncovered hitherto unexpected benefits of its use such as its anticancer effect. In this review the author provides a detailed description of the clinical effects, indications and contraindications of metformin, as well as a brief commentary on the recently described pleiotropic effects of this agent. Viswanathan Mohan

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Joshi 46. Nagi DK, Yudkin JS. Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects. A study of two ethnic groups. Diabetes Care. 1993;16:621-9. 47. Leblanc H, Marre M, Billault B, Passa P. [Value of combined subcutaneous infusion of insulin and metformin in 10 insulin-dependent obese diabetics]. Diabetes Metab. 1987;13:613-7. 48. Panikar V, Chandalia HB, Joshi SR, Fafadia A, Santvana C. Beneficial effects of triple drug combination of pioglitazone with glibenclamide and metformin in type 2 diabetes mellitus patients on insulin therapy. J Assoc Physicians Ind. 2003;51:1061-4. 49. Stout RW. Insulin as a mitogenic factor: role in the pathogenesis of cardiovascular disease. Am J Med. 1991;90:62S-5S.

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World Clin Diabetol. 2014;1(1):55-65.

Alpha-glucosidase Inhibitors *,1Sanjay Kalra MD DM, 2Jaikrit Bhutani MBBS

Department of Endocrinology, Bharti Hospital, Karnal 132 001, Haryana, India 2 Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences Rohtak 124 001, Haryana, India 1

ABSTRACT Alpha-glucosidase inhibitors (AGIs) are a modern class of oral antidiabetic drugs, which are approved for both prevention and management of type 2 diabetes mellitus (T2DM). This group of drugs includes acarbose, voglibose and miglitol. Their excellent safety and tolerability, coupled with moderate efficacy, make them suitable for use as monotherapy as well as in combination with other drugs. This class of drugs is unique in its gastrointestinal (GI)based insulin and glucose-independent mechanism of action, and its therapeutic target of postprandial hyperglycemia (PPG). Another unique feature is its demonstration of unquestioned cardiovascular benefits.   This article describes the history of development of AGIs, examines their mode of action in detail, and details the clinical evidence supporting use of these drugs. The various positioning levels in which AGIs can be used are reviewed. It covers issues related to posology, adverse effects, and discusses their place in modern antidiabetes therapy. A detailed analysis of comparative pharmacology of the various AGIs adds weight to the discussion in this article.

INTRODUCTION Type 2 DM is already a widespread epidemic noncommunicable disease. Various drugs, both oral and injectable, have been researched and used in its treatment. These drugs can also be classified according to the mechanisms of action: (i) agents stimulating insulin secretion by the pancreas, (ii) agents increasing sensitivity of target organs to insulin, and (iii) agents decreasing rate of glucose absorption from GI tract. The AGIs are drugs belonging to the third category. *Corresponding author Email: [email protected] © 2014 Jaypee Brothers Medical Publishers. All rights reserved.

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WHAT ARE ALPHA-GLUCOSIDASE INHIBITORS? Alpha-glucosidase inhibitors are a class of oral glucose lowering drugs (OGLDs), used in the treatment for T2DM. Broadly, they act by altering the intestinal absorption of carbohydrates (CHOs) by inhibiting their conversion into simple sugars (monosaccharides). Hence, AGIs significantly lower the blood glucose levels contributed by CHOs. The three AGIs used in clinical practice are acarbose, voglibose and miglitol. There is no other AGI currently in active clinical trials.

Discovery of Alpha-glucosidase Inhibitors The concept of inhibition of α-glucosidase to lower blood glucose levels began almost 3 decades ago. A novel agent, acarbose, was isolated by Schmidt from cultures of Actinoplanes in 1977. Later, Puls et al. developed synthetic AGIs and demonstrated their hypoglycemic action, after which Bayer Pharmaceuticals Ltd introduced them into the commercial market in Germany in 1990. The US Food and Drug Administration (USFDA) approved them for treatment of T2DM in September 1995. Voglibose was first developed and marketed by Takeda Pharmaceuticals Ltd in Japan in 1994. It was derived from an antibiotic validamycin A, produced from Streptomyces hygroscopicus var. limoneus. Voglibose is not available in the US, but it is marketed in India since 2005.1 The story of development of miglitol, by Schmidt, began in 1979. Compounds, such as nojirimycin and deoxynojirimycin, with properties of lowering blood glucose were isolated from microbial cultures of Bacillus and Streptomyces. Later miglitol was semisynthetically developed from 1-deoxynojirimycin. Pfizer popularized miglitol after USFDA approval in December 1996.2 Also, AGIs have also been recovered from natural sources like mushrooms— Maitake (Grifola frondosa) and another plant, Salacia oblonga.3

BASIC PHYSIOLOGY OF CARBOHYDRATE DIGESTION AND ABSORPTION Carbohydrates normally represent the majority of the human diet. As mono-, oligo-, and especially polysaccharides, they form the main bulk of meals and source of energy in humans. Prior to absorption the poly- and oligosaccharides undergo enzyme-catalyzed breakdown into simple monosaccharide form. This breakdown occurs in two steps: starch is first cleaved by the enzyme alpha amylase. The second is breakdown of oligo- or polysaccharides by membrane-bound enzymes of the epithelium of the small intestine. The end products of this breakdown are the monosaccharides, glucose, galactose, and fructose.4 56

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Figure 1: Mechanism along with the site of action.

These so called membrane-bound enzymes are secreted by the brush border epithelium of the maturing enterocytes in the jejunum. The enzymes included in this are sucrase, isomaltase (usually complexed together), maltase, glucoamylase, trehalase, and lactase. Collectively these enzymes are referred to as “α-glucosidases”. The terminal digestion of CHOs is achieved by α-glucosidases at the surface of the brush border epithelium. AGIs act at this level and completely block glucose absorption from starch as well as sucrose. The monosaccharides are absorbed readily via both specific (Na+-dependent active transport and facilitated diffusion) and nonspecific (passive diffusion) transport routes.5 The normal human intestine absorbs little disaccharide. If not hydrolyzed, disaccharides cause various clinical symptoms: abdominal cramps, bloating and diarrhea. This is due to osmotic effect of unabsorbed disaccharide and its fermentation by colonic bacteria. Thus, it leads to increased fluid passing to the colon, causing diarrhea and irritation of colonic mucosa.6 This mechanism, along with the site of action, has been depicted in figure 1.

PHARMACOLOGY OF Alpha-glucosidase inhibitors Mechanism of Action Alpha-glucosidase inhibitors (AGIs) behave as pseudo-CHOs in the intestine. Primarily all three of them, act by competitive inhibition of α-glucosidase enzymes found in the brush border of gut epithelium. However, there exist a few differences in their mechanisms of action that are described in table 1. 57

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Kalra and Bhutani Table 1: Mechanisms of Action of Various α-glucosidase Inhibitors (AGIs) Features

Acarbose

Miglitol

Voglibose

Remarks

Target enzymes

Most effective on glucoamylase, followed by sucrase, maltase, and dextranase

More potent inhibitor of disaccharide digesting enzymes, such as sucrase and maltase

More specific inhibitor of disaccharide digesting enzymes, such as sucrase and maltase

No effect on α-amylase

No effect on α-amylase

Acarbose is more effective in a diet rich in starch, as it is the case in Asian type of nutrition since it preferentially inhibits glucoamylase

Delays intestinal CHO absorption resulting in improvement of PPG

It also inhibits the α-amylase but has no effect on β-glucosidases, such as lactase Mechanism of action

Delays intestinal carbohydrate (CHO) absorption resulting in improvement of postprandial hyperglycemia (PPG)

Delays intestinal CHO absorption resulting in improvement of PPG

Dosage and administration

25–50 mg; TDS, oral

25–50/100 mg; 0.2–0.3 mg, TDS, oral TDS, oral

Acarbose, a pseudo-tetrasaccharide, possesses nitrogen between the first and second glucose molecule. This modification imparts to this drug a high affinity for the α-glucosidase enzymes.7 The affinity and inhibition capacity of acarbose, for various glucosidases is in the following order: glucoamylase, followed by sucrase, maltase, and dextranase. It does not inhibit β-glucosidases, such as lactase.8 Voglibose is prepared by reductive alkylation of valiolamine, a compound derived from antibiotic validamycin C. It is also a potent AGI with almost no action on α-amylase. Miglitol is derived from 1-deoxynojirimycin. In contrast to acarbose, it is a small molecule, similar to glucose. It effectively inhibits disaccharide digesting enzymes, e.g., sucrase, maltase, and isomaltase. It has no inhibitory action on α-amylase.9 It also acts on the intestinal sodium-dependent glucose transporter, but this has not been found to affect intestinal glucose absorption.10 Since AGIs affect the digestion of complex CHOs, they should be taken just before meals. Also their effectiveness and role in controlling PPG depends on the complex CHO present in the diet.11 This implies that AGIs may prove to be effective in diabetes in management in Indian scenario where the traditional Indian CHO-rich diet, especially rice-containing meals are preferred over the processed foods. The mechanisms of action of various AGIs along with their dosages have been summarized in table 1.12 58

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Pharmacokinetics and Pharmacodynamics A brief summary of pharmacokinetics and pharmacodynamics of AGIs is given in table 2 for an easier understanding and comparison.12,13

Clinical Implications From table 2, it can be inferred that voglibose is only less than 5% excreted via the renal route, thus can be used safely in patients with renal disease, while less than 5% of acarbose undergoes biliary excretion and can be used in patients with active hepatitis or any other liver disease. Miglitol, due to its long-lasting action and 96% bioavailability can be prescribed to patients consuming CHO-rich meals during the day. Table 2: Pharmacological Properties of Various α-glucosidase Inhibitors Features

Acarbose

Miglitol

Voglibose

Remarks

Extent of absorption

Low (0.5–1.7%) Poorly absorbed

Almost complete, dosedependent

Low, dosedependent Poorly absorbed

Neither acarbose nor voglibose are absorbed in their active form; whereas miglitol is almost completely absorbed in the upper part of the small intestine, it has a longlasting presence in the mucosa

Clearance

Mainly renal

Mainly renal

Mainly renal

By glomerular filtration

Bioavailability 96%