Nutritional and Therapeutic Interventions for Diabetes and Metabolic Syndrome

By Debasis Bagchi

Nutritional and Therapeutic Interventions for Diabetes and Metabolic Syndrome, Second Edition, provides an overview of the current diabetes epidemic, outlines the consequences of this crisis, and lays out strategies to forestall and prevent diabetes, obesity and other intricate issues of metabolic syndrome. Contributing experts provide up-to-date global approaches to the critical consequences of metabolic syndrome and make the book an important reference for those working with the treatment, evaluation or public health planning for the effects of metabolic syndrome and diabetes.

Completely revised with 15 new chapters, the book includes coverage of the roles of gut microbiome in obesity and diabetes, macrovascular and microvascular complications, diabetes, metabolic syndrome and kidney disease, aspects of diabetic cardiomyopathy, diabetes, Alzheimer’s and neurodegenerative diseases, roles of SGLT2 inhibitors in the treatment of type 2 diabetes, novel biomarkers in diabetes, roles of Trigonella foenum-graecumseed extract in type 2 diabetes, beneficial effects of chromium (III) and vanadium supplements in diabetes, prevention of type 1 diabetes, novel drugs in the therapeutic intervention of type 2 diabetes, eHealth and mobile apps for self-management, artificial pancreatic transplantation, non-invasive glucose monitoring, and the app for glucose regulation.

• Contains a scientific discussion of the epidemiology and pathophysiology of the relationship between diabetes and metabolic syndrome
• Includes coverage of Pre-diabetes conditions, plus both Type I and Type II Diabetes
• Presents both prevention and treatment options

• Language: English
• Publisher: Academic Press
• Release date: May 25, 2018
• ISBN: 9780128120088

Book preview

Nutritional and Therapeutic Interventions for Diabetes and Metabolic Syndrome

Second Edition

Editors

Debasis Bagchi

University of Houston College of Pharmacy, Houston, TX, United States

Cepham Research Center, Piscataway, NJ, United States

Sreejayan Nair

University of Wyoming, School of Pharmacy, Laramie, WY, United States

Table of Contents

Cover image

Title page

Copyright

Dedication

List of Contributors

Preface

Section I. Epidemiology and Overview

Chapter 1. Type 1 Diabetes Mellitus: An Overview

Introduction

Definition

Epidemiology

Pathophysiology

Diagnosis

Clinical Presentation

Management

Comorbidities

Complications

Prevention and Intervention Trials

Chapter 2. Prediabetes: Prevalence, Pathogenesis, and Recognition of Enhanced Risk

Background

Prevalence

Results

Pathogenesis

Recognition of Enhanced Risk

Means for Cardiometabolic Risk Factors

Discussion

Conclusion

Chapter 3. Targeting Prediabetes to Preempt Diabetes

Introduction

Global Burden of Diabetes and Prediabetes

Contributing Factors

Prevention and Treatment of Diabetes

Conclusion

Chapter 4. Obesity and Type 2 Diabetes in Youths: New Challenges to Overcome

Obesity: The 21st Century Epidemic

Metabolic Complications of Obesity in Children and Adolescents

Type 2 Diabetes in Children and Adolescents: A New Frightening Epidemic?

Pathogenesis of Type 2 Diabetes in Obese Children and Adolescents

Role of Ectopic Fat Deposition in the Pathogenesis of Insulin Resistance

The β-Cell in the Storm of Insulin Resistance

Therapy of Type 2 Diabetes in Youths

Conclusions and Future Perspectives

Chapter 5. Roles of Environmental Pollution and Pesticides in Diabetes and Obesity: The Epidemiological Evidence

Introduction

Dioxins, Furans, and Polychlorinated Biphenyls

Pesticides

Bisphenol A and Phthalates

Air Pollution

Toxic Heavy Metals

Summary and Future Research

Chapter 6. An Overview of the Roles of the Gut Microbiome in Obesity and Diabetes

Background

Mechanisms by Which the Gut Microbiome can Influence Metabolism and Weight Gain

Colonization of the Human Gastrointestinal Tract

Microbes in Obesity and Diabetes: Are There Differences in Colonization?

Effects of Antibiotics

Bariatric Surgery

Conclusion

Section II. Types of Diabetes and its Correlation with Other Diseases

Chapter 7. Role of Peripheral Neuropathy in the Development of Foot Ulceration and Impaired Wound Healing in Diabetes Mellitus

Introduction

Diabetic Neuropathy

Diabetic Foot Ulcers

Wound Healing

Conclusions

Chapter 8. The Association of Diabetes in the Onset of Dementia in the Elderly Population: An Overview

Introduction

Epidemiology

Population at Risk

Diabetes, Associative Factors, and Dementia

Inflammatory Mediators

Potential Mechanism of Action

Nutrition and Dementia

Conclusion

Chapter 9. The Role of Insulin Resistance in the Cardiorenal Syndrome

Introduction

Population-Level Evidence

Pathophysiologic Links Between Insulin Resistance, Obesity, and the Cardiorenal Syndrome

Microalbuminuria in the Cardiorenal Syndrome

Insulin Resistance in the Cardiorenal Syndrome

Oxidative Stress and Endoplasmic Stress in the Cardiorenal Syndrome

Inappropriate Activation of the Renin–Angiotensin–Aldosterone System

Conclusions and Perspectives

Chapter 10. An Overview on Diabetic Nephropathy

Introduction

Clinical Features of Diabetic Nephropathy

Involvement of Metabolic Factors in Diabetic Nephropathy

Role of RAS in Diabetic Nephropathy

Conclusion

Chapter 11. An Overview of Diabetic Retinopathy

Introduction

Epidemiology/Risk Factor

Classification

Pathophysiology

Molecular Mechanism of Diabetic Retinopathy

Therapy

Conclusion

Chapter 12. An Overview of Gestational Diabetes

Pathophysiology

Epidemiology

Screening and Diagnosis

Effects of Untreated Gestational Diabetes

Effectiveness of Treatment

Glucose Monitoring

Lifestyle Modification: Diet and Exercise

Insulin Therapy

Oral Hypoglycemic Agents

Fetal Surveillance

Timing and Mode of Delivery

Follow-Up Testing and Long- Term Implications

Summary

Chapter 13. Diabetes, a Potential Threat to the Development and Progression of Tumor Cells in Individuals

Diabetes Mellitus Arises From Defects in Insulin Production and Utilization

Section III. Molecular Insights of Diabetes and Metabolic Syndrome

Chapter 14. Lipid-Induced Insulin Resistance: Molecular Mechanisms and Clinical Implications

Introduction

Free Fatty Acids Adversely Impact Glucose Oxidation and Utilization

Diacylglyerols

Fatty Liver Disease

Fetuin-A and Lipid Induced Insulin Resistance

Interleukin-1 and Lipid Induced Insulin Resistance

Interleukin-1 Receptor Antagonists

Interleukin-6 and Lipid-Induced Insulin Resistance

TNF-α and Lipid-Induced Insulin Resistance

Toll-Like Receptors and Nucleic Acids in Lipid-Induced Insulin Resistance

Plasmacytoid Dendritic Cell-Derived Type I Interferons in Metabolic Syndrome

Pharmacologic Interventions

Conclusions

Chapter 15. Gene–Environment Interaction in the Pathogenesis of Type 2 Diabetes

Introduction

The Genetic Component

The Environmental Component

Epigenetics

Conclusion

Chapter 16. Renal Sodium-Glucose Transporter-2 Inhibitors as Antidiabetic Agents

Diabetes and Its Complications and Disease Burden

Renal Sodium-Glucose Cotransporters

Therapeutic Role of SGLT2 Inhibitors in Diabetes

SGLT2 Inhibitors and Body Weight

SGLT2 Inhibitors in Heart Failure and Chronic Kidney Disease

Safety of SGLT2 Inhibitors

SGLT2 Inhibitors From Natural Products

Conclusion

Chapter 17. Emerging Role of MicroRNA in Diabetes Mellitus

Introduction

Conclusion

Section IV. Pathophysiology

Chapter 18. Insulin Resistance Syndrome: A Crucial Example Where a Physiological Continuum of Risks Needs Attention

Background: The Continuum Principle

Blood Pressure as a Continuum

Insulin Resistance (FBG) as a Continuum

Conclusions

Chapter 19. Sleep Disturbances, Hypertension, and Type 2 Diabetes

Background and Introduction

Sleep and Hypertension

Sleep and Pulmonary Arterial Hypertension

Mechanisms

Sleep Glucose Metabolism and Type 2 Diabetes

Mechanisms

Sleep, Pregnancy-Induced Hypertension, Preeclampsia, and Gestational Diabetes

Prevention and Public Health Importance

Conclusions

Chapter 20. Roles of Pancreatic Cell Function, Liver, Skeletal Muscle, and Adipose Tissue in Diabetes and the Metabolic Syndrome

Introduction

Adipose Tissue

Why Is Visceral Fat More Metabolically Dangerous?

Adipose Tissue Inflammation

Liver

Skeletal Muscle

Pancreas

The Role of Inflammation

Summary

Key Concepts (Fig. 20.5)

Chapter 21. Glycemic Variability and Its Clinical Implications

Introduction

Microvascular and Macrovascular Complications

Hyperglycemia: Type 1 and Type 2 Diabetes

Glycemic Variability and the Molecular Markers

Diverse Antidiabetic Drugs and Their Functions

Conclusion

Chapter 22. Diabetic Wound Inflammation

Diabetes Mellitus

Wound Healing

Diabetes and Chronic Wounds

Diabetic Wound Infections

Dysregulated Wound Inflammation During Diabetes

Nutritional Interventions of Diabetic Wound Infection

Nutritional Interventions of Diabetic Inflammation

Conclusion

Chapter 23. Sarcopenia, Diabetes, and Nutritional Intervention

Introduction

Pathophysiology and Diagnosis

Prevalence of Sarcopenia in Diabetes Mellitus

Nutritional Management and Treatments for Sarcopenia

Conclusion

Section V. Prevention and Treatment 1:diet, Exercise, Supplements and Alternative Medicines

Chapter 24. Dietary Polyphenols, Gut Microbiota, and Intestinal Epithelial Health

Introduction

Intestinal Epithelium in Obesity and Metabolic Disease

Polyphenols

Gut Microbiota and Epithelial Health

Health Implications and Conclusion

Chapter 25. Reducing the Risk of Diabetes and Metabolic Syndrome With Exercise and Physical Activity

Diabetes

Prediabetes

Insulin Resistance

Evidence on the Role of Lifestyle Interventions in the Prevention of Type 2 Diabetes

The Effect of Exercise on Insulin Resistance

The Role of Aerobic and Resistive Exercise in Preventing Diabetes

Metabolic Syndrome

Evidence on the Role of Exercise and Physical Activity in the Prevention of Metabolic Syndrome

Exercise Prescription

Summary

Chapter 26. Nutraceutical Impact on the Pathophysiology of Diabetes Mellitus

Introduction

Pathophysiology

Diabetes Pathology

Nutraceutical Effects on Diabetes Pathology

Chapter 27. Therapeutic Effect of Fucoxanthin on Metabolic Syndrome and Type 2 Diabetes

Introduction

Fucoxanthin and Its Absorption Mechanism

Antiobesity Effect of Fucoxanthin

Lowering Effect of Fucoxanthin on Blood Glucose

Regulatory Effect of Fucoxanthin on Adipokines

Effect of Fucoxanthin on GLUT4 Expression in Muscle

Conclusion

Chapter 28. Safety and Antidiabetic Efficacy of a Novel Trigonella foenum-graecum Seed Extract

Introduction

Ethnobotany of Fenugreek (Trigonella foenum-graecum)

Fenfuro, a Novel Fenugreek Seed Extract

Toxicological Assessment and Safety of Fenfuro16

Antidiabetic Efficacy of Fenfuro in Type 2 Diabetic Rats16

Conclusion

Chapter 29. Beneficial Effects of Chromium(III) and Vanadium Supplements in Diabetes

Introduction

Chromium

Vanadium

Chapter 30. Protective Role of Alpha-Tocopherol in Diabetic Nephropathy

Introduction

Effect of Vitamin E and Its Derivatives on DN and Identification of DGK Subtype Involved in the Vitamin E-Induced Improvement of DN

Mechanism of VtE-Mediated Improvement of DN

Prospective

Chapter 31. Antidiabetic Activity of Curcumin: Insight Into Its Mechanisms of Action

Introduction

Molecular Mechanisms and Therapeutic Potential of Curcumin in Type 2 Diabetes and Its Complications

Conclusions

Chapter 32. Meal Plans for Diabetics: Caloric Intake, Calorie Counting, and Glycemic Index

Introduction

Adipose Tissue

Carbohydrates

Calorie Counting, Caloric Intake

Energy Density

Energy Balance

Pancreatic β-Cell Burden Index of Food

Conclusions

Section VI. Prevention and Treatment 2: Drugs and Pharmaceuticals

Chapter 33. Evolution of Glucose-Lowering Drugs for Type 2 Diabetes: A New Era of Cardioprotection

Introduction

Pre-CVOT Era Drugs for Type 2 Diabetes

CVOT Era Drugs for Type 2 Diabetes: Benefits and Risks

Conclusions

Chapter 34. Current Antidiabetic Drugs: Review of Their Efficacy and Safety

Introduction

Insulin

Sulfonylureas

Thiazolidinediones

Biguanide

Meglitinides

Alpha-Glucosidase Inhibitors

Dipeptidyl Peptidase-4 Inhibitors

Glucagon-Like Peptide-1 Inhibitors

Sodium Glucose Cotransporter 2 Inhibitors

Dopamine Agonist

Conclusion

Chapter 35. HDACs in Diabetes: A New Era of Epigenetic Drug

Introduction

Diabetes Mellitus Characterization

Histone Deacetylation

Histone Deacetylation and Diabetes

HDAC Inhibitors and Diabetes

Conclusion

Section VII. Novel Innovations

Chapter 36. Noninvasive Blood Glucose Measurement

Technologies Employed for Noninvasive Glucose Sensors

Noninvasive Devices

Conclusions

Section VIII. Diabetes in Animals and Treatment

Chapter 37. Diabetes Mellitus in Animals: Diagnosis and Treatment of Diabetes Mellitus in Dogs and Cats

Introduction

Diabetes in Dogs and Cats

Commentary

Index

Copyright

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Dedication

Dedicated to my late beloved friend and ex-colleague, Jairaj Hegde. I always see him in his smiling face, and asking me to stay away from my favorite sweets.

Debasis Bagchi

List of Contributors

Saleh Adi,     University of California, San Francisco, CA, United States

Debasis Bagchi

University of Houston College of Pharmacy, Houston, TX, United States

Cepham Research Center, Piscataway, NJ, United States

Manashi Bagchi,     Cepham Research Center, Piscataway, NJ, United States

Pradipta Banerjee,     Visva-Bharati, Kolkata, India

Gillian M. Barlow,     Cedars-Sinai Medical Center, Los Angeles, CA, United States

Dawn Blatt,     Stony Brook University, Stony Brook, NY, United States

Meghan Brashear,     Louisiana State University System, Baton Rouge, LA, United States

Angela I. Calderon,     Auburn University, Auburn, AL, United States

Francesco P. Cappuccio,     University of Warwick, Coventry, United Kingdom

Sonia Caprio,     Yale School of Medicine, New Haven, CT, United States

Esperanza J. Carcache de Blanco,     The Ohio State University, Columbus, OH, United States

Scott Chaffee,     The Ohio State University, Columbus, OH, United States

Jayson Chen,     Product Safety Labs, Dayton, NJ, United States

Mahua Choudhury,     Texas A&M Health Science Center, College Station, TX, United States

Amitava Das,     The Ohio State University, Columbus, OH, United States

Stabak Das,     Institute of Pharmacy, Govt. of West Bengal, Jalpaiguri, India

Deep Dutta,     Venkateshwar Hospitals, Dwarka, India

Charles J. Everett,     Medical University of South Carolina, Charleston, SC, United States

Christopher Federico,     Tulane University School of Medicine, New Orleans, LA, United States

Ivar L. Frithsen,     Medical University of South Carolina, Charleston, SC, United States

Kei Fukami,     Kurume University School of Medicine, Fukuoka, Japan

Dipyaman Ganguly,     CSIR-Indian Institute of Chemical Biology, Kolkata, India

Andrea Gerard-Gonzalez,     University of Colorado Denver, Aurora, CO, United States

Cosimo Giannini,     Yale School of Medicine, New Haven, CT, United States

Kian-Peng Goh,     Saint-Julien Clinic for Diabetes and Endocrinology, Singapore

Cheri L. Gostic,     Stony Brook University, Stony Brook, NY, United States

Deborah S. Greco,     Nestle Purina PetCare, St. Louis, MO, United States

Alok K. Gupta,     The Permanente Medicine Group, Inc., Oakland, CA, United States

Daiki Hayashi,     Kobe University, Kobe, Japan

Masashi Hosokawa,     Hokkaido University, Hakodate, Japan

Md. Akil Hossain,     Veterinary Drugs and Biologics Division, Animal and Plant Quarantine Agency, Gimcheon-si, South Korea

Akifumi Ikehata,     Food research Institute, NARO, Tsukuba, Japan

William D. Johnson,     Louisiana State University System, Baton Rouge, LA, United States

Lee Koetzner,     Product Safety Labs, Dayton, NJ, United States

Michal Krawczyk,     Medical University of Lodz, Lodz, Poland

Andrew J. Krentz,     Senior Research Fellow, ProSciento, Chula Vista, CA, United States

Abhai Kumar,     Banaras Hindu University, Varanasi, India

Teresa E. Lehmann,     University of Wyoming, School of Pharmacy, Laramie, WY, United States

Eugenia A. Lin,     Cedars-Sinai Medical Center, Los Angeles, CA, United States

Gail B. Mahady,     University of Illinois at Chicago, Chicago, IL, United States

Sayantan Maitra,     Institute of Pharmacy, Govt. of West Bengal, Jalpaiguri, India

Ruchi Mathur,     Cedars-Sinai Medical Center, Los Angeles, CA, United States

Danira Medunjanin,     Medical University of South Carolina, Charleston, SC, United States

Odete Mendes,     Product Safety Labs, Dayton, NJ, United States

Ajay Menon,     University of Washington, Seattle, WA, United States

Michelle A. Miller,     University of Warwick, Coventry, United Kingdom

Kazuo Miyashita,     Hokkaido University, Hakodate, Japan

Paulin Moszczyński,     Tarnowska College, Tarnów, Poland

Beverly S. Mühlhäusler,     The University of Adelaide, Adelaide, SA, Australia

Satinath Mukhopadhyay,     Institute of Post Graduate Medical Education & Research (IPGMER) and SSKM Hospital, Kolkata, India

Anand S. Nair,     University of Wyoming, School of Pharmacy, Laramie, WY, United States

Sreejayan Nair,     University of Wyoming, School of Pharmacy, Laramie, WY, United States

Shintaro Nakao,     Kyushu University, Fukuoka, Japan

Show Nishikawa,     Hokkaido University, Hakodate, Japan

Sreedharan N,     Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India

Min Hi Park,     Texas A&M Health Science Center, College Station, TX, United States

Rokeya Pervin,     Kyungpook National University, Daegu, South Korea

Harry G. Preuss,     Georgetown University Medical Center, Washington, DC, United States

Gabriella Pridjian,     Tulane University School of Medicine, New Orleans, LA, United States

Mahadev Rao,     Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India

Sashwati Roy,     The Ohio State University, Columbus, OH, United States

Ivan Salamon,     University of Presov, Presov, Slovakia

Nicola Santoro,     Yale School of Medicine, New Haven, CT, United States

Suman Santra,     The Ohio State University, Columbus, OH, United States

Luís F. Schütz,     Texas A&M Health Science Center, College Station, TX, United States

Sonal Sekhar M,     Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India

Yasuhito Shirai,     Kobe University, Kobe, Japan

Smita Singh,     Banaras Hindu University, Varanasi, India

Koh-hei Sonoda,     Kyushu University, Fukuoka, Japan

James R. Sowers,     University of Missouri School of Medicine, Columbia, MO, United States

Anand Swaroop,     Cepham Research Center, Piscataway, NJ, United States

Zbigniew Tabarowski,     Jagiellonian University, Institute of Zoology and Biomedical Research, Kraków, Poland

Francesco Tecilazich,     Diabetes Research Institute, IRCCS San Raffaele, Milan, Italy

Yasuhiro Uwadaira,     Food research Institute, NARO, Tsukuba, Japan

Narsingh Verma,     King George’s Medical University, Lucknow, India

Aristidis Veves

Harvard Medical School, Boston, MA, United States

Center for Regenerative Therapeutics, Boston, MA, United States

Joslin-Beth Israel Deaconess Foot Center, Beth Israel Deaconess Medical Center, Boston, MA, United States

John B. Vincent,     The University of Alabama, Tuscaloosa, AL, United States

Adam Whaley-Connell,     University of Missouri School of Medicine, Columbia, MO, United States

Sheila M. Wicks,     Rush University, Chicago, IL, United States

Marzena Wojcik,     Medical University of Lodz, Lodz, Poland

Lucyna A. Wozniak,     Medical University of Lodz, Lodz, Poland

Sho-ichi Yamagishi,     Kurume University School of Medicine, Fukuoka, Japan

Shigeo Yoshida,     Kyushu University, Fukuoka, Japan

Mei-Jun Zhu,     Washington State University, Pullman, WA, United States

Preface

Diabetes mellitus is a metabolic disorder in which the pancreas either does not produce enough insulin and/or the body’s cells do not effectively respond to insulin due to insulin resistance or other dysfunctions.¹,² Environmental pollution, sedentary lifestyle, genetic factors, and overindulgence of unhealthy and fatty foods impair glucose homeostasis in humans, resulting in insulin resistance and diabetes.¹–⁵ Diabetes is an alarming public health problem, which can lead to diverse health complications, including macrovascular and microvascular complications leading to cardiomyopathy, obesity, neuropathy, retinopathy, dermatological and podiatric problems, atherosclerosis, hearing impairment, stroke, and peripheral circulatory disorder. It is important to mention that the majority of people afflicted with diabetes have type 2 diabetes.¹–⁶

The 2017 Diabetes Statistics Report released by the Centers for Disease Control and Prevention has provided⁷ a detailed estimate of the prevalence and incidence of diabetes, prediabetes, risk factors for complications, acute and long-term complications, deaths, and costs. Approximately 9.4% of the total US population, a total of 30.3 million people, is suffering from diabetes, of which 23.1 million are diagnosed, while 7.2 million are undiagnosed. It is alarming to note that an estimated 84.1 million adults, 33.9% of the adult US population, are prediabetic. This includes 23.1 million adults aged 65  years or older. Among these diabetics, only 5% suffer from type 1 diabetes in the United States.⁷

Now, let us look at the global picture. According to the World Health Organization (WHO), 422 million adults were diagnosed with diabetes in 2014 as compared to 108 million people in 1980, thus diabetes is now a global epidemic.¹ This means that the number of adults with diabetes has quadrupled. In 2012, 1.5 million deaths were reported due to diabetes, while higher-than-optimal blood glucose caused an additional 2.2 million deaths due to cardiovascular and other allied diseases. The WHO also reported that deaths attributable to diabetic subjects below age 70 were in low- and middle-income countries.¹ In 2010, approximately 10.9 million people or 26.9% of the population 65  years or older had diabetes, approximately 215,000 people less than 20  years had either type 1 or type 2 diabetes, and 1.9 million people over 20  years were newly diagnosed with diabetes in the United States alone.⁸,⁹ The World Diabetes Foundation estimates that there will be 438 million people with diabetes in 2030.¹⁰

What is more worrying is that a significant amount of people remain undiagnosed until they develop a major complication such as stroke, neuropathy, nephropathy, amputation, or blindness, which further adds to the economic burden of diabetes on society. Understanding the nature of the disease and its complications will help in designing effective therapeutic interventions to curb this epidemic. This book is aimed at providing a comprehensive approach to understanding molecular insights into the pathophysiology of diabetes, its complications, and the various strategies for its prevention, treatment, and cure. The diverse topics covered in this book will be of interest to patient care-givers, physicians, health professionals, researchers, nurses, students, and anybody interested in learning about diabetes and metabolic syndrome, and therapeutic and nutritional interventions for this disease.

Section I discusses the epidemiology and gives a general overview of type 1 and type 2 diabetes. Type 1 diabetes is an autoimmune disease wherein the pancreatic beta cells do not produce insulin, whereas type 2 diabetes, the more prevalent one, results when the body becomes resistant to the effects of insulin or does not produce sufficient insulin. In addition, this section also deals with prediabetes, a condition associated with insulin resistance that precedes classification as frank diabetes and affects about 79 million people in the United States. It is believed that some of the vascular complications attributed to diabetes begin during the prediabetic stage and therefore addressing prediabetes may help preempt the development to full-blown diabetes. This section also has a chapter on childhood diabetes, which as per the Centers for Disease Control and Prevention affects about 215,000 individuals in the United States who are younger than 20  years of age. The rising incidence of obesity and type 2 diabetes in youths, and the roles of environmental pollution, pesticides, and gut microbiome in the pathogenesis of diabetes are also addressed in this section.

Poorly controlled diabetes can lead to a variety of macrovascular and microvascular complications (retinopathy, nephropathy, and neuropathy). Atherosclerosis is the major macrovascular complication of diabetes, as well as the leading cause of morbidity and mortality in the advanced world, resulting in heart disease, stroke, and peripheral circulatory disorders.⁸ Diabetic retinopathy is the most frequent cause of new cases of blindness among adults aged 20–74 and about 28.5% of diabetic individuals >40  years of age are afflicted with diabetic retinopathy. Diabetes is the leading cause of nephropathy and end-stage renal disease and accounts for 44% of new cases of kidney failure. Diabetes is also the major cause of neuropathy, retinopathy, vasculopathy, foot ulceration, and impaired wound healing, all of which account for more than 60% of nontraumatic lower-limb amputation. Section II deals with the aforementioned devastating complications associated with diabetes and discusses various measures of prevention and management. This section also includes a chapter on gestational diabetes, its complications, and management.

Section III alludes to the molecular insights of diabetes and metabolic syndrome. Diabetes is a polygenic disorder and the pathogenesis of diabetes involves a multitude of factors involving both genetic and environmental ones that adversely affect insulin secretion and tissue response to insulin. Genome-wide association studies have attempted to identify genetic variants that contribute to the development of diabetes.¹¹ Evidence suggests that an epigenetic phenomenon plays a major role in the development of diabetes.¹² In recognition of the role of inflammation in the pathogenesis of diabetes and its complications, the chapters that deal with targeting inflammatory response in diabetes have also been included in this section. Additionally, given the emerging drugs that target renal sodium glucose transporter-2 (SGLT-2) we have included a chapter on SGLT-2 inhibitors as antidiabetic agents in this section.

In continuing with this theme, Section IV moves into the pathophysiology of various complications associated with diabetes, metabolic syndrome, pancreatic cell function, skeletal muscle, and adipose tissue. Glycemic variability and its clinical implications are emphasized in a chapter. Additionally, a chapter that highlights the role of sleep and hypertension in the pathogenesis of diabetes has also been included in this section.

Sections V and VI comprise a critical appraisal of various nonpharmacological and pharmacological modalities of management of diabetes, which includes exercise and diet, nutraceuticals, fucoxanthin, curcumin, herbal medicines, phytochemicals, fiber, omega-3 and omega-6 polyunsaturated fatty acids, mineral supplements, Ayurveda, and pharmacological agents that target different mechanisms in the underlying pathogenesis of diabetes. In addition to preclinical data, these chapters also discuss some of the key clinical studies that have formed the basis of therapeutic guidelines for treating diabetes. Because caloric input and diabetic diet play a critical role in the management of diabetes, a chapter describing the diabetic meal plan has also been included in this section. In addition, three extensive reviews of antidiabetic drugs for the adult population, which takes into consideration the requirements of the elderly population, have been added. The role of histone deacetylase inhibition (modulation of epigenetics) in diabetes has also been extensively discussed in a chapter. Section VI provides a detailed chapter on both pre-CVOT (cardiovascular outcome trials) drugs and CVOT era drugs for type 2 diabetes. Section VII provides a detailed insight into novel innovation in noninvasive blood glucose measurement. Finally, Section VIII provides an overview of diabetes in animals, especially in cats and dogs, and treatment.

In summary, this book covers a broad range of topics related to diabetes and its complications, including epidemiology, pathophysiology, complications, management, and various treatment options, rendering it an invaluable resource for professionals interested in diabetes.

Our sincere thanks to all our eminent contributors and Timothy J. Bennett for his continued support, cooperation, and assistance.

Debasis Bagchi, PhD, MACN, CNS, MAIChE,     University of Houston College of Pharmacy, Houston, TX, United States,     Cepham Research Center, Piscataway, NJ, United States

Sreejayan Nair, MPharm, PhD, FACN, FAHA,     University of Wyoming, School of Pharmacy, Laramie, WY, United States

References

1. World Health Organization. Diabetes fact sheet updated November 2017. http://www.who.int/mediacentre/factsheets/fs312/en/.

2. Diseases and conditions. Type 2 diabetes. http://www.mayoclinic.org/diseases-conditions/type-2-diabetes/basics/complications/con-20031902.

3. Diabetes: facts and figures. International Diabetes Federation. https://www.idf.org/about-diabetes.

4. Taylor S.R, Meadowcraft L.M, Willamson B. Prevalence, pathophysiology, and management of androgen deficiency in men with metabolic syndrome, type 2 diabetes mellitus, or both. Pharmacotherapy. 2015;35(8):780–792.

5. Sepehri Z, Kiani Z, Afshari M, Kohan F, Dalvand A, Ghavami S. Inflammasomes and type 2 diabetes: an updated systematic review. Immunol Lett. October 24, 2017 doi: 10.1016/j.imlet.2017.10.010 pii: S0165–2478(17)30506-0.

6. Type 1 diabetes and type 2 diabetes grow in prevalence. Available at: http://www.endocrineweb.com/news/type-1-diabetes/6222-type-1-diabetes-type-diabetes-grow-prevalence.

7. National Diabetes Statistics Report. Estimates of diabetes and its Burden in the United States. 2017. https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf.

8. National Institute of Diabetes and Digestive and Kidney Diseases. National diabetes statistics. National diabetes information clearinghouse. 2007 Available at:. http://diabetes.niddk.nih.gov/dm/pubs/statistics/.

9. Pharma Times Online. One in three diabetes patients don’t adhere to treatment. http://www.pharmatimes.com/Article/11-06-28/One_in_three_diabetes_patients_don_t_adhere_to_treatment.aspx.

10. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States. 2011 Available at:. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf.

11. Park K.S. The search for genetic risk factors of type 2 diabetes mellitus. Diabetes Metab J. 2011;35:12e22.

12. Cooper M.E, El-Osta A. Epigenetics: mechanisms and implications for diabetic complications. Circ Res. 2010;107:1403–1413.

Section I

Epidemiology and Overview

Outline

Chapter 1. Type 1 Diabetes Mellitus: An Overview

Chapter 2. Prediabetes: Prevalence, Pathogenesis, and Recognition of Enhanced Risk

Chapter 3. Targeting Prediabetes to Preempt Diabetes

Chapter 4. Obesity and Type 2 Diabetes in Youths: New Challenges to Overcome

Chapter 5. Roles of Environmental Pollution and Pesticides in Diabetes and Obesity: The Epidemiological Evidence

Chapter 6. An Overview of the Roles of the Gut Microbiome in Obesity and Diabetes

Chapter 1

Type 1 Diabetes Mellitus

An Overview

Saleh Adi¹ and Andrea Gerard-Gonzalez²     ¹University of California, San Francisco, CA, United States     ²University of Colorado Denver, Aurora, CO, United States

Abstract

Diabetes mellitus (DM) is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. By far the most common forms of DM are type 1 and type 2 diabetes. Type 1 DM is caused by autoimmune destruction of the insulin-producing β cells, and type 2 DM is caused by severe insulin resistance and subsequent β-cell failure, due primarily to obesity and lack of adequate physical activity. Other forms of DM include gestational DM and various monogenic types of DM that are caused by single gene defects that lead to deficiencies in β-cell development, insulin production, and/or secretion. This chapter focuses on type 1 DM and provides an overview of current trends and recommendations for diagnosis, management, and prevention of complications.

Keywords

Autoimmunity; HbA1c; Hyperglycemia; T1D; T1DM; Type 1 diabetes; Type 1 DM

Outline

Introduction

Definition

Epidemiology

Pathophysiology

Diagnosis

Clinical Presentation

Management

Comorbidities

Complications

Prevention and Intervention Trials

References

Further Reading

Introduction

Diabetes mellitus (DM) is a group of heterogeneous disorders with distinct genetic, etiologic, and pathophysiologic mechanisms with the common elements of glucose intolerance and hyperglycemia, due to insulin deficiency, impaired insulin action, or both. The World Health Organization (WHO) estimates that more than 400  million people worldwide have DM. The majority of these cases have type 2 DM. Currently, DM is classified on the basis of etiology and clinical presentation into four major types¹:

1. Type 1 DM: characterized by a gradual loss of insulin-producing β cells, due to autoimmune destruction.

2. Type 2 DM: caused predominantly by severe insulin resistance and subsequent β-cell failure.

3. Gestational DM: defined as hyperglycemia with onset or first recognition during pregnancy.

4. Other specific types: including monogenic forms of DM (neonatal DM and maturity onset diabetes of the young) and DM that is attributable to diseases of exocrine pancreas, other endocrinopathies, and drug-induced DM.

This overview will focus on the autoimmune type 1 DM: definition and criteria for diagnosis, epidemiology, pathophysiology, clinical presentation, management, comorbidities, and new developments in the treatment and prevention of type 1 DM.

Definition

Type 1 DM results from deficiency of insulin secretion due to a gradual autoimmune, primarily T-cell-mediated destruction of the β cells in people with genetic predisposition to this disease. More evidence has accumulated that B-cell autoimmunity also has a major role in the pathogenesis of type 1 DM.² In 85%–95% of cases of type 1DM, at least one serum marker of autoimmunity is detected in the form of autoantibodies against insulin, islet cells, the protein tyrosine phosphatase IA2, the 65-kD form of glutamate decarboxylase (GAD-65), and the zinc transporter 8 (ZnT8).³ This subgroup of type 1 DM (with positive antibodies) is designated as type 1A, while the remaining 5%–15% of cases of phenotypic type 1 DM but no detectable antibodies are referred to as idiopathic or type 1b.²–⁵ This does not necessarily mean that individuals with type 1b DM do not manifest markers of autoimmunity, but rather reflects our lack of knowledge of what these antibodies might be. Future discoveries of yet unidentified islet autoantigens may prove that in fact all cases of type 1 DM are autoimmune in nature. There is now increasing effort to further understand the pathophysiology behind this particular group of antibody-negative patients, with some data suggesting an increased incidence in individuals with African or Asian ancestry. This group tends to demonstrate a tendency for recurrent episodes of diabetic ketoacidosis (DKA) with varying degrees of insulin deficiency between episodes. This type of diabetes is strongly inherited and does not appear to have a genetic human leukocyte antigen (HLA)-type association.⁶ There are also reports of a more fulminant form of β-cell destruction primarily in Japanese patients, with T-cell infiltration of the islets but no measurable autoantibodies.⁷–⁹

Type 1 DM is generally thought of as childhood or juvenile diabetes, although it can be diagnosed at any age, with a peak incidence in the early teen years, around the time of puberty.¹⁰ Worldwide, the incidence of type 1 DM has been steadily increasing at an average annual rate of 3%–4%.¹¹,¹²

Epidemiology

Worldwide, it is estimated that approximately 8.5%, or 422  million, of adults had diabetes in 2014. These estimates are expected to continue to increase steadily, particularly in the developing countries.¹³

In the United States, the National Diabetes Fact Sheet estimated that 30.3  million children and adults had diabetes in 2017, accounting for 9.4% of the population. Of those, around 5.7  million were undiagnosed, making DM one of the most prevalent chronic diseases that carry an economic burden of around US$200 billion per year.¹⁴ However, type 1 DM accounts for only 5%–15% of these cases.

In the United States, approximately 30,000 new cases of type 1 DM are diagnosed each year; about two-thirds of them are in children under the age of 19  years.¹²,¹⁵

Pathophysiology

As noted above, the autoimmune trigger in type 1 DM is the result of certain environmental exposures in genetically susceptible individuals. This genetic susceptibility is strongly linked to specific HLA genes that encode the major histocompatibility complex proteins. These proteins play a critical role in regulating immune responses and recognition of self versus non-self cells. Certain HLA types are associated with much higher risk for developing type 1 DM, with the HLA-DR3 and DR4, and HLA-DQ being the most common in people with type 1 DM, while other types (e.g., HLA-DR2) appear to be protective against developing autoimmunity against β cells.⁴,¹⁶ The inheritance of particular HLA alleles can account for over half of the genetic risk for developing type 1 DM.¹⁶,¹⁷ Other genetic loci have also been identified.

While the genetics of type 1 DM continue to be carefully examined, identifying the environmental triggers involved in developing type 1 DM remain largely uncertain.¹⁸,¹⁹ The increasing incidence of type 1 DM over the past few decades adds further evidence that environmental factors are of importance, because genetic changes could not take place in such a short period of time. Most of the findings in this field have been based on strong associations between the incidence of type 1 DM and certain environmental elements, but no definitive studies have clearly demonstrated a cause and effect with any of these factors.¹⁸,¹⁹ Examples of these associations have linked type 1 DM to dietary habits, vitamin deficiencies, exposure to certain viruses, and the so-called hygiene hypothesis.¹⁸–²⁸ Population-based observational studies have found that children who were breastfed have a lower risk of type 1 DM than those who were not, and that exposure to cow’s milk before the age of 6  months doubles the risk of developing type 1 DM, particularly in individuals with high-risk HLA types.²⁸,²⁹ However, a report from Finland concluded that early exposure to cow’s milk is not a risk factor for developing type 1 DM.³⁰ The EURODIAB Substudy-2 group suggested that rapid growth, rather than cow’s milk or early introduction of solid foods, may explain the increased risk for type 1 DM.³¹ Similar associations (although also controversial) have been found with intake of glutens, and foods rich in proteins, carbohydrates, and nitrosamine compounds.³²–³⁴

In animals, a number of viruses can cause a diabetes-like syndrome. In humans, epidemics of mumps, rubella, and coxsackie viral infections have been associated with increases in the incidence of type 1 DM.²²–²⁵,²⁷,³⁵,³⁶ The viruses may act directly to destroy the β cells, or by triggering a widespread immune response against several endocrine tissues including the β cells.³⁵–³⁹ Some investigators postulate that this is an example of molecular mimicry between these viruses and the antigenic determinants on the surface of the β cells.⁴⁰

There is increasing evidence that inadequate vitamin D increases the risk for type 1 and type 2 DM and other autoimmune conditions.⁴¹–⁴⁵ This is supported by epidemiological findings of higher incidence of type 1 DM at higher latitudes and in other conditions with decreased sun exposure,⁴¹,⁴⁶ and by the fact that vitamin D receptors are expressed in β cells and in immune cells.⁴¹,⁴⁷–⁴⁹ Furthermore, certain polymorphisms within the vitamin D receptor gene are associated with development of type 1 DM, at least in some populations.⁵⁰,⁵¹ In animal models, pharmacological doses of the active form, 1,25-dihydroxyvitamin D3, have been shown to modulate the immune system and delay the onset of diabetes²²,⁵²; however, no human studies have demonstrated a benefit for increasing vitamin D intake in preventing type 1 DM.

The hygiene hypothesis suggests that improved living conditions are associated with avoidance of pathogen exposure, which leads to inadequate maturation of the immune system. The hypothesis is based on the increased incidence of diseases like asthma or other atopic disorders in children, in addition to the fact that type 1 DM is more prevalent in developed societies.²⁷,⁵³

Diagnosis

In general, DM is diagnosed when one or more of the following criteria are met¹,⁵³:

1. Symptoms of diabetes plus casual plasma glucose concentration ≥200mg/dL (11.1mmol/L).

    Or

2. Fasting plasma glucose ≥126mg/dL (7.0mmol/L). Fasting is defined as no caloric intake for at least 8h.

    Or

3. Two-hour postload glucose ≥200mg/dL (11.1mmol/L) during an oral glucose tolerance test. The test should be performed as described by the WHO,⁵⁴ using a glucose load containing the equivalent of 75g anhydrous glucose dissolved in water or 1.75g/kg of body weight to a maximum of 75g.

Both the WHO and the American Diabetes Association have added the fourth criteria of hemoglobin A1c (HbA1c) ≥6.5% as being diagnostic of DM.¹

As noted earlier, the presence of diabetes-related autoantibodies confirms the classification of type 1 DM, while the presence of obesity, acanthosis nigricans, family history of type 2 DM, and other risk factors for insulin resistance such as the lack of physical activity or the ethnicity of Hispanic or African American origin strongly point toward type 2 DM. However, type 1 DM can occur in obese individuals with one or more risk factors for insulin resistance, therefore screening for markers of autoimmunity is recommended in all cases of new onset DM, particularly in children.

Clinical Presentation

Type 1 DM has four major clinical phases: preclinical diabetes, overt diabetes, partial remission phase (honeymoon), and the chronic phase.

In general, autoimmune destruction of the β cells is a slow process that can take years before causing sufficient β-cell loss to cause insulin deficiency. Under normal physiological conditions, it is estimated that less than 50% of the β-cell mass is sufficient to maintain euglycemia in humans. Typically, in individuals who are developing type 1 DM, a transient state of insulin resistance occurs, mostly due to a viral or bacterial illness, leading to increased requirements for insulin production that cannot be met because of the ongoing loss of β cells. This leads to hyperglycemia, which itself has a detrimental effect on β-cell function leading to further hyperglycemia and its manifestations, leading eventually to the diagnosis of DM. It is estimated that only between 10% and 40% of the insulin-producing β cells are still functioning by the time someone develops clinical manifestations of DM.⁵⁵,⁵⁶

The symptoms and signs are related to the presence of hyperglycemia and the resulting effects of water and electrolyte imbalance. They generally include polyuria, polydipsia, polyphagia, weight loss, and blurry vision. Onset of symptoms can be very variable from insidious to acute.⁵⁷

It is also not uncommon that new onset diabetes presents with a more serious and life-threatening DKA with severe dehydration. The occurrence of DKA is more commonly seen in children younger than 4  years of age, and is less common in adolescents and young adults.⁵⁶–⁵⁸ Despite the increased awareness of diabetes in the public and among general practitioners, the incidence of initial DKA at diagnosis remains relatively high and varies between 15% and 29%.⁵⁶–⁶⁰ Typically, the patient is acidotic with acetone fruity odor, respiratory distress, abdominal pain, nausea, vomiting, and polyuria and polydipsia. Laboratory findings include hyperglycemia, glucosuria, ketonemia, and ketonuria. Without timely management, severe fluid and electrolyte depletion develops with signs of hypoperfusion and altered mental status that may lead to coma and death.⁵⁸,⁵⁹

Once the diagnosis is made, fluid resuscitation and insulin replacement can begin immediately. This reverses the metabolic derangements and hyperglycemia, which together with the recovery from the precipitating infectious process leads to relative recovery of β-cell function and return to near adequate insulin production to maintain euglycemia, heralding the honeymoon period. This remission phase can last from several months to 2  years in some cases.⁶¹ However, the process of β-cell destruction continues, eventually resulting in a gradual decrease in insulin secretion and ensuing hyperglycemia, marking the chronic phase of type 1 DM.

Management

The cornerstone of type 1 DM management is providing insulin at all times. This can be achieved by administration of 1–2 doses of long acting insulin and frequent prandial rapid acting insulin. A series of modified human insulins with altered dynamics of absorption after subcutaneous injection has been introduced since 1996 and is now standard in clinical care including the long acting insulins Glargine and Detemir, and the rapid acting insulins Lispro, Aspart, and Glulisine.⁶²–⁶⁶ These custom-designed insulins provide excellent tools to try to mimic the physiologic patterns of endogenous insulin secretion and action, while minimizing the range of blood glucose (BG) excursions and the risk of hypoglycemia, two of the main obstacles to achieving more aggressive and optimal glucose control in patients with diabetes.⁶²,⁶⁴,⁶⁶

In most practices, newly diagnosed patients are started on a multiple daily injection (MDI) regimen of subcutaneous insulin, while those who present with DKA are treated initially with intravenous insulin infusion then switched to MDI. It is widely accepted that replacement of insulin in all patients with type 1 DM should consist of a combination of basal and bolus insulin. Typically, the dose of long acting, basal insulin is unchanged from day to day and should provide about one-quarter to one-third of the total daily insulin requirements in young children, and increasing gradually to about half of total daily insulin in adolescents and young adults. However, the dosing of rapid acting insulin is different for each time, and follows certain formulas to calculate the insulin dose for each meal based on the BG value and the carbohydrate content in each meal (and snack). Alternatively, a continuous subcutaneous insulin infusion pump is used to provide frequent small doses of rapid acting insulin as basal insulin in lieu of the long acting insulin, and user-administered boluses of rapid acting insulin for meals and high BG. Because of this, management of type 1 DM requires self-monitoring of BG and a certain degree of competency in carbohydrate counting. Type 1 DM is recognized as a primarily self-managed disease, and to achieve the recommended glycemic targets patients need to receive ongoing nutritional counseling and training in self-management of their insulin regimen. In most practices, clinic visits with a team of physicians, diabetes educators, and nutritionists are recommended every 2–3  months.

In addition, a series of devices is now available for the continuous measurement of glucose concentration in the subcutaneous interstitial fluids, which reflects, with some time lag, the glucose concentration in the blood. These continuous glucose monitors (CGMs) can be operated alone or can be integrated with an insulin pump. The current devices provide predictive alarms for high and low BG, as well as continuous readings of glucose concentrations. Intense studies are ongoing for the development of the closed loop in which a CGM controls the operation of an insulin pump in response to changes in BG levels. The first of these systems has been recently approved for use in patients. Several studies have shown improved glycemic control with the use of CGMs in type 1 DM.⁶⁷–⁷² Using these tools, the goals of diabetes management in adults is to achieve an HbA1c of <7.0% with a preprandial BG of 70–130  mg/dL (3.9–7.2  mmol/L) and a peak postprandial BG of <180  mg/dL (<10.0  mmol/L).¹ These goals should be individualized in all patients and must be less stringent in children with type 1 DM.¹

Comorbidities

The same genetic factors that predispose patients to type 1 DM make them more likely to develop other autoimmune diseases.⁷³–⁷⁵ The most common of these are thyroid autoimmunity, celiac disease, gastric autoimmunity, and Addison’s disease.

Autoimmune thyroid disease occurs in 17%–30% of patients with type 1 DM. It is more common in females and is often associated with the presence of antithyroperoxidase (aTPO) and antithyroglobulin (aTG) antibodies.⁷⁴–⁷⁶ The current recommendations are for screening for aTPO and aTG at or shortly after diagnosis of type 1 DM, and measurement of thyroid stimulating hormone (TSH) concentrations after metabolic control has been established. If normal, TSH should be rechecked every 1–2  years, or if the patient develops symptoms of thyroid dysfunction, thyromegaly, or an abnormal growth rate.¹

Celiac disease is an autoimmune enteropathy with a variable reported incidence of 1%–10% in patients with type 1 DM, and is more common in children, with the risk of developing celiac disease being about 10 times higher than the general population, especially in the first 5  years after diagnosis with type 1 DM.⁷⁷ Celiac disease can manifest with nongastroenterologic signs, including poor growth, delayed puberty, amenorrhea, erratic BG concentrations, and even psychiatric problems.⁷⁸–⁸⁰ Therefore a high index of suspicion must be kept and periodic screening for serum levels of tissue transglutaminase or antiendomysial antibodies is recommended along with screening for thyroid disease in patients with type 1 DM.¹,⁷⁶,⁷⁸,⁸¹ Some studies suggest that celiac disease is more likely to develop in the first 5  years after diagnosis of type 1 DM⁸¹ and is more likely in children diagnosed with type 1 DM before the age of 4  years than in those diagnosed as teenagers.⁸²

Also associated with type 1 DM is antigastric parietal cell and antiadrenal autoimmunity. These, however, are more rare than thyroid and celiac disease, such that routine screening is not currently recommended. However, because of the potential higher risk of developing pernicious anemia and gastric carcinoid tumors and adenocarcinomas,⁸² De Block et al. recommended periodic screening for antiparietal cell antibodies especially in adolescents with longer duration of diabetes, positive GAD-65 antibodies, and anti-TPO antibodies.⁸³,⁸⁴

Complications

Chronic hyperglycemia and suboptimal control of type 1 DM can lead to several long-term complications including hyperlipidemia, cardiovascular disease, peripheral neuropathy, retinopathy, and renal disease. These complications are similar to those seen in type 2 DM and are discussed in other chapters in this book.

Prevention and Intervention Trials

The pathophysiology of type 1 DM encompasses several stages, beginning with activation of the immune system in genetically susceptible individuals, which leads to β-cell injury, impaired insulin secretion, and eventually frank hyperglycemia and clinical diabetes. This process is relatively slow and can take up to 2  years or more. By the time the diagnosis of type 1 DM is made, only 10%–50% of islet cell mass remains intact but continues to be gradually destroyed over time.⁸⁵–⁸⁹ Therefore the principal challenge in any effort toward prevention of type 1 DM is the identification of at risk individuals well before they lose a substantial β-cell mass. Currently, the best predictor of type 1 DM development is the presence of β-cell-directed autoantibodies, combined with carrying high-risk HLA alleles.⁹⁰ In such individuals, several interventions have been tried, with little success in preventing the progression to overt diabetes. However, in the past few years, significant efforts have shifted toward strategies that aim at modulating the autoimmune response to halt the destruction of pancreatic islets and preserving the remaining β cells immediately after diagnosis of type 1 DM.⁸⁵–⁸⁹ Such strategies fall into two main categories, the first is antigen specific, with interventions aimed at inducing tolerance to the specific antigen that is targeted, and the second is nonantigen specific, which aims at altering the function of components of the immune system, specifically T cells and B cells.⁸⁶,⁸⁹ Preliminary results have shown decreased insulin dependence at least in the first year after treatment but long-term insulin independence remains to be further confirmed.⁹¹–⁹³ Once these studies have shown sufficient safety and efficacy in newly diagnosed patients, they will then be tested in at risk individuals before they lose significant β-cell mass and become clinically hyperglycemic.

The role of vitamin D in regulating the immune system has gained much attention.²¹,⁴¹,⁹⁴,⁹⁵ A metaanalysis of published results suggested that vitamin D supplement given to children may reduce the risk for type 1 DM, particularly with doses of 2000  IU/day.⁹⁶

In the meantime, much effort is focusing on stem cell therapy by generating new β cells from autologous umbilical cord blood cells and gene-engineered dendritic cells.⁹⁷,⁹⁸

Other, more tertiary interventions such as whole-organ pancreatic transplant and transfer of isolated islet cells, combined with ongoing immune suppression, have both proven to be successful in terms of restoring glycemic level and insulin independence,⁹⁹,¹⁰⁰ but they remain limited by the availability of viable donor organs.

In parallel, there is continued strong interest in further developing closed loop systems to function as true artificial pancreases with minimal patient effort.

References

1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2017;40:S11–S24.

2. O’Neill S.K, Liu E, Cambier J.C. Change you can B(cell)eive in: recent progress confirms a critical role for B cells in type 1 diabetes. Curr Opin Endocrinol Diabetes Obes. 2009;16(4):293–298.

3. Wenzlau J.M, Juhl K, Yu L, Moua O, Sarkar S.A, Gottlieb P, Rewers M, Eisenbarth G.S, Jensen J, Davidson H.W, Hutton J.C. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci USA. October 23, 2007;104(43):17040–17045.

4. Zeitler P. Update on nonautoimmune diabetes in children. J Clin Endocrinol Metab. 2009;94(7):2215–2220.

5. Concannon P, Rich S.S, Nepom G.T. Genetics of type 1A diabetes. N Engl J Med. 2009;360(16):1646–1654.

6. Pörksen S, Laborie L.B, Nielsen L, Louise Max Andersen M, Sandal T, de Wet H, Schwarcz E, Aman J, Swift P, Kocova M, Schönle E.J, de Beaufort C, Hougaard P, Ashcroft F, Molven A, Knip M, Mortensen H.B, Hansen L, Njølstad P.R, Hvidøre Study Group on Childhood Diabetes. Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies. BMC Endocr Disord. 2010;23(10):16.

7. Hanafusa T, Imagawa A. Fulminant type 1 diabetes: a novel clinical entity requiring special attention by all medical practitioners. Nat Clin Pract Endocrinol Metab. 2007;3(1):36–45.

8. Imagawa A, Hanafusa T. Fulminant type 1 diabetes as an important exception to the new diagnostic criteria using HbA(1c)–response to the International Expert Committee. Diabetologia. 2009;52(11):2464–2465.

9. Zheng C, Zhou Z, Yang L, Lin J, Huang G, Li X, Zhou W, Wang X, Liu Z. Fulminant type 1 diabetes mellitus exhibits distinct clinical and autoimmunity features from classical type 1 diabetes mellitus in Chinese. Diabetes Metab Res Rev. 2011;27(1):70–78.

10. Lévy-Marchal C, Patterson C, Green A. Variation by age group and seasonality at diagnosis of childhood IDDM in Europe. The EURODIAB ACE Study Group. Diabetologia. 1995;38(7):823–830.

11. Onkamo P, Vaananen S, Karvonen M, Tuomilehto J. Worldwide increase in incidence of type 1 diabetes-the analysis of the data on published incidence trends. Diabetologia. 1999;42:1395–1403.

12. DIAMOND Project Group. Incidence and trends of childhood Type 1 diabetes worldwide 1990–1999. Diabet Med. 2006;23:857–866. .

13. International Diabetes Federation. Diabetes atlas. 3rd ed. 2006:29–30.

14. https://www.cdc.gov/diabetes/data/statistics/statistics- report.html.

15. Writing Group for the SEARCH for Diabetes in Youth Study Group, Dabelea D, Bell R.A, et al. Incidence of diabetes in youth in the United States. J Am Med Assoc. 2007;297(24):2716–2724.

16. Pociot F, Akolkar B, Concannon P, Erlich H.A, Julier C, Morahan G, Nierras C.R, Todd J.A, Rich S.S, Nerup J. Genetics of type 1 diabetes: what’s next? Diabetes. 2010;59(7):1561–1571.

17. Todd J.A, Bell J.I, McDevitt H.O, et al. HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature. 1987;329:599.

18. Knip M, Veijola R, Virtanen S.M, Hyöty H, Vaarala O, Akerblom H.K. Environmental triggers and determinants of type 1 diabetes. Diabetes. 2005;54(Suppl. 2):S125–S136.

19. Peng H, Hagopian W. Environmental factors in the development of type 1 diabetes. Rev Endocr Metab Disord. 2006;7(3):149–162.

20. Fronczak C.M, Baron A.E, Chase H.P. In utero dietary exposures and risk for islet autoimmunity in children. Diabetes Care. 2003;26:3237–3242.

21. Mathieu C, Bandenhoop K. Vitamin D and type 1 diabetes mellitus, state of the art. Trends Endocrinol Metab. 2005;16:261–266.

22. Nejentsev S, Cooper J.D, Godfrey L. Analysis of vitamin D receptor gene sequence variants in type 1 diabetes. Diabetes. 2004;53:2709–2712.

23. Hyoty H. Enterovirus infections and type 1 diabetes. Ann Med. 2002;34:138–147.

24. Ginsber Fellner F, Witt M.E, Fedun B. Diabetes mellitus and autoimmunity in patients with congenital rubella syndrome. Rev Infect Dis. 1985;7(Suppl. 1):s170–s176.

25. Viskari H, Ludvigsson J, Uibo R. Relationship between the incidence of type 1 diabetes and maternal enterovirus antibodies: time trends and geographical variation. Diabetologia. 2005;48:1280–1287.

26. Gale E.A. A missing link in the hygiene hypothesis? Diabetologia. 2002;45:588–594.

27. Bach J.F. Infections and autoimmune diseases. J Autoimmun. 2005;25:74–80.

28. Knip M, Virtanen S.M, Seppä K, Ilonen J, Savilahti E, Vaarala O, Reunanen A, Teramo K, Hämäläinen A.M, Paronen J, Dosch H.M, Hakulinen T, Akerblom H.K, Finnish TRIGR Study Group. Dietary intervention in infancy and later signs of beta-cell autoimmunity. N Engl J Med. 2010;363(20):1900–1908.

29. Rosenbauer J, Herzig P, Kaiser P, Giani G. Early nutrition and risk of type 1 diabetes mellitus – a nationwide case-control study in preschool children. Exp Clin Endocrinol Diabetes. 2007;115(8):502–508.

30. Savilahti E, Saarinen K.M. Early infant feeding and type 1 diabetes. Eur J Nutr. 2009;48(4):243–249.

31. EURODIAB Substudy 2 Study Group. Rapid early growth is associated with increased risk of childhood type 1 diabetes in various European populations. Diabetes Care. 2002;25(10):1755–1760.

32. Mueller D.B, Koczwara K, Mueller A.S, Pallauf J, Ziegler A.G, Bonifacio E. Influence of early nutritional components on the development of murine autoimmune diabetes. Ann Nutr Metab. 2009;54(3):208–217.

33. Visser J, Rozing J, Sapone A, Lammers K, Fasano A. Tight junctions, intestinal permeability, and autoimmunity: celiac disease and type 1 diabetes paradigms. Ann NY Acad Sci. May 2009;1165:195–205.

34. Frisk G, Hansson T, Dahlbom I, Tuvemo T. A unifying hypothesis on the development of type 1 diabetes and celiac disease: gluten consumption may be a shared causative factor. Med Hypotheses. 2008;70(6):1207–1209.

35. Cooke A. Infection and autoimmunity. Blood Cells Mol Dis. 2009;42(2):105–107.

36. Richer M.J, Horwitz M.S. Coxsackievirus infection as an environmental factor in the etiology of type 1 diabetes. Autoimmun Rev. 2009;8(7):611–615.

37. Richer M.J, Horwitz M.S. Viral infections in the pathogenesis of autoimmune diseases: focus on type 1 diabetes. Front Biosci. 2008;13:4241–4257.

38. Hober D, Sauter P. Pathogenesis of type 1 diabetes mellitus: interplay between enterovirus and host. Nat Rev Endocrinol. 2010;6(5):279–289.

39. Dotta F, Galleri L, Sebastiani G, Vendrame F. Virus infections: lessons from pancreas histology. Curr Diabetes Rep. 2010;10(5):357–361.

40. Christen U, Hintermann E, Holdener M, von Herrath M.G. Viral triggers for autoimmunity: is the ‘glass of molecular mimicry’ half full or half empty? J Autoimmun. 2010;34(1):38–44.

41. Bikle D.D. Vitamin D regulation of immune function. Vitam Horm. 2011;86:1–21.

42. Hyppönen E. Vitamin D and increasing incidence of type 1 diabetes-evidence for an association? Diabetes Obes Metab. September 2010;12(9):737–743.

43. Takiishi T, Gysemans C, Bouillon R, Mathieu C. Vitamin D and diabetes. Endocrinol Metab Clin North Am. 2010;39(2):419–446.

44. Holick M.F. Vitamin D: extraskeletal health. Endocrinol Metab Clin North Am. 2010;39(2):381–400.

45. Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C, Vitamin D. Modulator of the immune system. Curr Opin Pharmacol. 2010;10(4):482–496.

46. Staples J.A, Ponsonby A.L, Lim L.L, McMichael A.J. Ecologic analysis of some immune-related disorders, including type 1 diabetes, in Australia: latitude, regional ultraviolet radiation, and disease prevalence. Environ Health Perspect. 2003;111(4):518–523. .

47. Bruce D, Cantorna M.T. Intrinsic requirement for the vitamin D receptor in the development of CD8alphaalpha-expressing T cells. J Immunol. 2011;186(5):2819–2825.

48. Bhalla A.K, Amento E.P, Clemens T.L, Holick M.F, Krane S.M. Specific high-affinity receptors for 1, 25-dihydroxyvitamin D3 in human peripheral blood mononuclear cells: presence in monocytes and induction in T lymphocytes following activation. J Clin Endocrinol Metab. 1983;57:1308–1310.

49. Lee S, Clark S.A, Gill R.K, Christakos S. 1,25-Dihydroxyvitamin D3 and pancreatic beta-cell function: vitamin D receptors, gene expression, and insulin secretion. Endocrinology. 1994;134:1602–1610.

50. Maestro B, Davila N, Carranza M.C, Calle C. Identification of a vitamin D response element in the human insulin receptor gene promoter. J Steroid Biochem Mol Biol. 2003;84:223–230.

51. Mimbacas A, Trujillo J, Gascue C, Javiel G, Cardoso H. Prevalence of vitamin D receptor gene polymorphism in a Uruguayan population and its relation to type 1 diabetes mellitus. Genet Mol Res. 2007;6(3):534–542.

52. Zella J.B, McCary L.C, Deluca H.F. Oral administration of 1,25-dihydroxyvitamin D3 completely protects NOD mice from insulin-dependent diabetes mellitus. Arch Biochem Biophys. 2003;417:77–80.

53. Craig M.E, Hattersley A, Donaghue K.C. Definition, epidemiology and classification of diabetes in children and adolescents. Pediatr Diabetes. 2009;10(Suppl. 12):3–12.

54. World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. WHO/NCD/NCS/99.2 Geneva. Ref Type: Report. 1999.

55. Knip M, Korhonene S, Kulmala P, Veijola R. Prediction of type 1 diabetes in the general population. Diabetes Care. 2010;6:1206–1212.

56. Hekkala A, Knip M, Veijola R. Ketoacidosis at diagnosis of type 1 diabetes in children in northern Finland, temporal changes over 20 years. Diabetes Care. 2007;30:861–866.

57. Maniatis A.K, Goehrig S.H, Gao D, Rewers A, Walravens P, Klingensmith G.J. Increased incidence and severity of diabetes ketoacisosis among uninsured children with newly diagnosed type 1 diabetes. Pediatr Diabetes. 2005;6:79–83.

58. Neu A, Willasch A, Ehehalt S, Hub R, Ranke M.B, DIARY Group Baden-Wuerttemberg. Ketoacidosis at onset of type 1 diabetes mellitus in children–frequency and clinical presentation. Pediatr Diabetes. 2003;4(2):77–81.

59. Sundaram P.C, Day E, Kirk J.M. Delayed diagnosis in type 1 diabetes mellitus. Arch Dis Child. 2009;94(2):151–152.

60. Rewers A, Klingensmith G, Davis C, Petitti D.B, Pihoker C, Rodriguez B, Schwartz I.D, Imperatore G, Williams D, Dolan L.M, Dabelea D. Presence of diabetic ketoacidosis at diagnosis of diabetes mellitus in youth: the SEARCH for Diabetes in Youth Study. Pediatrics. 2008;121(5) e1258–6.

61. Bowden S.A, Duck M.M, Hoffman R.P. Young children (<5 yr) and adolescents (>12 yr) with type 1 diabetes mellitus have low rate of partial remission: diabetic ketoacidosis is an important risk factor. Pediatr Diabetes. 2008;9:197–201.

62. Eckardt K, Eckel J. Insulin analogues: action profiles beyond glycaemic control. Arch Physiol Biochem. 2008;114(1):45–53.

63. Hartman I. Insulin analogs: impact on treatment success, satisfaction, quality of life, and adherence. Clin Med Res. 2008;6(2):54–67.

64. Freeman J.S. Insulin analog therapy: improving the match with physiologic insulin secretion. J Am Osteopath Assoc. 2009;109(1):26–36.

65. Jensen M.G, Hansen M, Brock B, Rungby J. Differences between long-acting insulins for the treatment of type 2 diabetes. Expert Opin Pharmacother. 2010;11(12):2027–2035.

66. Brunton S.A. Nocturnal hypoglycemia: answering the challenge with long-acting insulin analogs. MedGenMed. 2007;9(2):38.

67. Currie C.J, Poole C.D, Papo N.L. An overview and commentary on retrospective, continuous glucose monitoring for the optimisation of care for people with diabetes. Curr Med Res Opin. 2009;25(10):2389–2400.

68. Chetty V.T, Almulla A, Odueyungbo A, Thabane L. The effect of continuous subcutaneous glucose monitoring (CGMS) versus intermittent whole blood finger-stick glucose monitoring (SBGM) on hemoglobin A1c (HBA1c) levels in Type I diabetic patients: a systematic review. Diabetes Res Clin Pract. 2008;81(1):79–87.

69. Carchidi C, Holland C, Minnock P, Boyle D. New technologies in pediatric diabetes care. MCN Am J Matern Child Nurs. 2011;36(1):32–39.

70. Davey R.J, Jones T.W, Fournier P.A. Effect of short-term use of a continuous glucose monitoring system with a real-time glucose display and a low glucose alarm on incidence and duration of hypoglycemia in a home setting in type 1 diabetes mellitus. J Diabetes Sci Technol. 2010;4(6):1457–1464.

71. Cooke D, Hurel S.J, Casbard A, Steed L, Walker S, Meredith S, Nunn A.J, Manca A, Sculpher M, Barnard M, Kerr D, Weaver J.U, Ahlquist J, Newman S.P. Randomized controlled trial to assess the impact of continuous glucose monitoring on HbA(1c) in insulin-treated diabetes (MITRE Study). Diabet Med. 2009;26(5):540–547.

72. Garg S.K, Voelmle M.K, Beatson C.R, Miller H.A, Crew L.B, Freson B.J, Hazenfield R.M. Use of continuous glucose monitoring in subjects with type 1 diabetes on multiple daily injections versus continuous subcutaneous insulin infusion therapy: a prospective 6-month study. Diabetes Care. 2011;34:574–579. .

73. Triolo T.M, Armstrong T.K, McFann K, Yu L, Rewers M.J, Klingensmith G.J, Eisenbarth G.S, Barker J.M. One-third of patients have evidence for an additional autoimmune disease at type 1 diabetes diagnosis. Diabetes Care. March 23, 2011 [Epub ahead of print].

74. Barker J.M. Clinical review: Type 1 diabetes-associated autoimmunity: natural history, genetic associations, and screening. J Clin Endocrinol Metab. 2006;91(4):1210–1217.

75. De Block C.E, De Leeuw I.H, Vertommen J.J, Rooman R.P, Du Caju M.V, Van Campenhout C.M, Weyler J.J, Winnock F, Van Autreve J, Gorus F.K, Belgian Diabetes Registry. Beta-cell, thyroid, gastric, adrenal and coeliac autoimmunity and HLA-DQ types in type 1 diabetes. Clin Exp Immunol. 2001;126(2):236–241.

76. Kordonouri O, Maguire A.M, Knip M, Schober E, Lorini R, Holl R.W, Donaghue K.C. Other complications and conditions associated with diabetes in children and adolescents. Pediatr Diabetes. 2009;10(Suppl. 12):204–210.

77. Collin P, Kaukinen K, Valimaki M, Salmi J. Endocrinological disorders and celiac disease. Endocr Rev. 2002;23:464–483.

78. Holmes G.K. Screening for coeliac disease in type 1 diabetes. Arch Dis Child. 2002;87(6):495–498.

79. Mohn A, Cerruto M, Lafusco D, Prisco F, Tumini S, Stoppoloni O, Chiarelli F. Celiac disease in children and adolescents with type I diabetes: importance of hypoglycemia. J Pediatr Gastroenterol Nutr. 2001;32:37–40.

80. Barker J.M, Liu E. Celiac disease: pathophysiology, clinical manifestations, and associated autoimmune conditions. Adv Pediatr. 2008;55:349–365.

81. Larsson K, Carlsson A, Cederwall E, Jönsson B, Neiderud J, Jonsson B, Lernmark A, Ivarsson S.A, Skåne Study Group. Annual screening detects celiac disease in children with type 1 diabetes. Pediatr Diabetes. 2008;9:354–359.

82. Cerutti F, Bruno G, Chiarelli F, Lorini R, Meschi F, Sacchetti C, Diabetes Study Group of the Italian Society of Pediatric Endocrinology and Diabetology. Younger age at onset and sex predict celiac disease in children and adolescents with type 1 diabetes: an Italian multicenter study. Diabetes Care. 2004;27(6):1294–1298.

83. De Block C.E, De Leeuw I.H, Van Gaal L.F. Autoimmune gastritis in type 1 diabetes: a clinically oriented review. J Clin Endocrinol Metab. 2008;93(2):363–371.

84. De Block C.E, De Leeuw I.H, Rooman R.P, Winnock F, Du Caju M.V, Van Gaal L.F. Gastric parietal cell antibodies are associated with glutamic acid decarboxylase-65 antibodies and the HLA DQA1∗0501-DQB1∗0301 haplotype in Type 1 diabetes mellitus. Belgian Diabetes Registry. Diabet Med. 2000;17(8):618–622.

85. Zhang L, Eisenbarth G.S. Prediction and prevention of Type 1 diabetes mellitus. J Diabetes. March 2011;3(1):48–57.

86. Cernea S, Dobreanu M, Raz I. Prevention of type 1 diabetes: today and tomorrow. Diabetes Metab Res Rev. 2010;26(8):602–605.

87. Rewers M, Gottlieb P. Immunotherapy for the prevention and treatment of type 1 diabetes: human trials and a look into the future. Diabetes Care. 2009;32:1769–1782.

88. Haller M.J, Atkinson M.A, Schatz D. Type 1 diabetes mellitus: etiology, presentation, and management. Pediatr Clin North Am. 2005;52:1553–1578.

89. Sherr J, Sosenko J, Skyler J.S, Herold K.C. Prevention of type 1 diabetes: the time has come. Nat Clin Pract Endocrinol Metab. 2008;4:334–343.

90. Verge C.F, Gianani R, Kawasaki E, et al. Number of autoantibodies (against insulin, GAD or ICA512/IA2) rather than particular autoantibody specificities determines risk of type I diabetes. J Autoimmun. 1996;9:379–383.

91. Herold K.C, Gitelman S.E, Masharani U, et al. A single course of anti-CD3 monoclonal antibody hOKT3γ1 (Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes. 2005;54:1753–1769.

92. Keymeulen B, Vandemeulebroucke E, Ziegler A.G, et al. Insulin needs after CD3- antibody therapy in new-onset type 1 diabetes. N Engl J Med. 2005;352:2598–2608.

93. Herold K.C, Gitelman S, Greenbaum C, Immune Tolerance Network ITN007AI Study Group, et al. Treatment of patients with new onset type 1 diabetes with a single course of anti-CD3 mAb teplizumab preserves insulin production for up to 5 years. Clin Immunol. 2009;132:166–173.

94. Borges M.C, Martini L.A, Rogero M.M. Current perspectives on vitamin D, immune system, and chronic diseases. Nutrition. 2011;27(4):399–404.

95. Mathieu C, Gysemans C, Giulietti A, Bouillon R. Vitamin D and diabetes. Diabetologia. 2005;48(7):1247–1257.

96. Zipitis C.S, Akobeng A.K. Vitamin D supplementation in early childhood and risk of type 1 diabetes: a systematic review and meta-analysis. Arch Dis Child. 2008;93(6):512–517.

97. Madsen O.D. Stem cells and diabetes treatment. APMIS. 2005;113:858–875.

98. Zhao Y, Mazzone T. Human cord blood stem cells and the journey to a cure for type 1 diabetes. Autoimmun Rev. 2010;10(2):103–107.

99. Wen Y, Chen B, Ildstad S.T. Stem cell-based strategies for the treatment of type 1 diabetes mellitus. Expert Opin Biol Ther. 2011;11(1):41–53.

100. Krishna K.A, Rao G.V, Rao K.S. Stem cell-based therapy for the treatment of Type 1 diabetes mellitus. Regen Med. 2007;2(2):171–177.

Further Reading

1. Wasmuth H.E, Kolb H. Cow’s milk and immune-mediated diabetes. Proc Nutr Soc. 2000;59(4):573–579.

2. Norris J.M. Infant and childhood diet and type 1 diabetes risk: recent advances and prospects. Curr Diab Rep. 2010;10(5):345–349.

3. Mathieu C, Van Etten E, Decallonne B, et al. Vitamin D and 1,25-dihydroxyvitamin D(3) as modulators in the immune system. J Steroid Biochem Mol Biol. 2004;89–90:449–452.

4. Hypponen E, Laara E, Reunanen A, Jarvelin M.R, Virtanen S.M. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet. 2001;358:1500–1503.

5. Chiu K.C, Chu A, Go V.L, Saad M.F. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr. 2004;79:820–825.

6. Eerligh P, Koeleman B.P, Dudbridge F, Jan B.G, Roep B.O, Giphart M.J. Functional genetic polymorphisms in cytokines and metabolic genes as additional genetic markers for susceptibility to develop type 1 diabetes. Genes Immun. 2004;5:36–40.

7. Mathieu C, Waer M, Laureys J, Rutgeerts O, Bouillon R. Prevention of autoimmune diabetes in NOD mice by 1,25 dihydroxyvitamin D3. Diabetologia. 1994;37:552–558.

8. D’Angeli M.A, Merzon E, Valbuena L.F, Tirschwell D, Paris C.A, Mueller B.A. Environmental factors associated with childhood-onset type 1 diabetes mellitus: an exploration of the hygiene and overload hypotheses. Arch Pediatr Adolesc Med. 2010;164(8):732–738.

9. Kordonouri O, Klinghammer A, Lang E.B, Grüters-Kieslich A, Grabert M, Holl R.W. Thyroid autoimmunity in children and adolescents with type 1 diabetes: a multicenter survey. Diabetes Care. 2002;25(8):1346–1350.

10. Kordonouri O, Hartmann R, Deiss D, Wilms M, Grüters-Kieslich A. Natural course of autoimmune thyroiditis in type 1 diabetes: association with gender, age, diabetes duration, and puberty. Arch Dis Child. 2005;90(4):411–414.

11. Kakkola A, Sjöblom S.M, Haapiainen R, Sipponen P, Puolakkainen P, Jarvinen H. The risk of gastric carcinoma and carcinoid tumours in patients with pernicious anemia: a prospective follow-up study. Scand J Gastroenterol. 1998;33:88–92.

Chapter 2

Prediabetes

Prevalence, Pathogenesis, and Recognition of Enhanced Risk

Alok K. Gupta¹, Ajay Menon², Meghan Brashear³ and William D. Johnson³     ¹The Permanente Medicine Group, Inc., Oakland, CA, United States     ²University of Washington, Seattle, WA, United States     ³Louisiana State University System, Baton Rouge, LA, United States

Abstract

Keywords

Adiposity; Blood pressure; Cardiovascular risk; Healthy Adult US population; Prediabetes; Prevention; Risk factors

Outline

Background

Prevalence

Methods

Study Sample

Sample Methods

Diagnosis of Prediabetes

Sample Description

Statistical Analysis

Results

Epidemiology of Prediabetes

United States (1999–2006: NHANES Study)

Australia (2002: ADOL Study)

Europe (1999: DECODE Study)

Hong Kong (1998)

Mauritius (1999)

Pima Indians in the United States (2000)

Sweden (1998)

United States (1997)

Pathogenesis

Diagnosis

Pathophysiology

Adiposity Influences Prediabetes

Prediabetes Alters Serum Lipoprotein Patterns, Glycemia, and Resting Blood Pressure

Recognition of Enhanced Risk

Means for Cardiometabolic Risk Factors

Discussion

Conclusion

References

Elucidating the prevalence and pathogenesis and recognizing the enhanced risk for prediabetes are important for the development of strategies to prevent or delay the development of full-blown type 2 diabetes. Using data from a representative sample of the US population, we highlight the high prevalence of prediabetes in otherwise healthy adults. We describe the pathogenesis of prediabetes, due to a multitude of subtle derangements in the adipose tissue, pancreas, gastrointestinal tract, kidneys, liver, muscle, and brain. Prediabetes entails an expansion of the visceral adipose tissue compartment accompanied by adipocyte dysfunction, a disruption in action of pancreatic alpha and beta cells, gastrointestinal tract incretin-secreting cells, increased renal glucose reabsorption, and a resistance to the action of insulin in liver, muscle, and the brain. The measurable clinical and laboratory changes in prediabetes by themselves constitute early correlates for an adverse cardiometabolic profile. Interventions designed to prevent progression from prediabetes to type 2 diabetes can attenuate this enhanced cardiovascular disease (CVD) risk, and may even provide primary prevention for CVD.

Background

Type 2 diabetes, hypertension, dyslipidemia, and overweight or obese status are universally recognized chronic conditions that are, without reservation, afflicting an ever-increasing proportion of the population at large.¹,² All of these conditions individually, and in a variety of combinations with each other, also tend to increase the absolute risk for sudden catastrophic adverse cardiovascular events.³–⁹ The treatment of each of these diseased states—glycemic control for diabetes, reduction in blood pressure for hypertension, appropriate correction of the disordered lipoprotein fraction in dyslipidemia, and weight loss for the overweight and obese—substantially decrease the risks for a sudden catastrophic adverse cardiovascular event.¹⁰,¹¹ Despite rapid and meaningful strides made with the treatments for these chronic conditions (with the exception of obesity), the prevalence of these chronic conditions and the consequent occurrence of cardiovascular adverse events are still alarmingly high.¹²

There is also a curious phenomenon: two out of three of the sudden catastrophic cardiovascular adverse events that result in death (myocardial infarction and cerebrovascular accident) occur in apparently healthy individuals with no known overt heart disease.¹³,¹⁴ Thus to prevent sudden death in healthy individuals, a more appropriate response would be to recognize the risk for developing chronic disease. It would also be prudent to intervene with the predisease states—prediabetes, prehypertension, or coexisting prediabetes and prehypertension—and prevent their progression into full-blown disease(s): type 2 diabetes and/or hypertension. A high prevalence of prediabetes, prehypertension,¹⁵ and coexisting prediabetes and prehypertension¹⁶ among healthy adults in the United States has been recognized. These predisease states, besides being at risk for conversion into a higher CVD risk state due to full-blown chronic disease,¹⁷–²⁰ are by themselves being recognized as being on a pathway toward accelerated cardiovascular events.¹⁵,¹⁶ Prediabetes, which converts into type 2 diabetes at a variable rate of