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Textbook of Diabetes ebook

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Now in its fifth edition, the Textbook of Diabetes has established itself as the modern, well-illustrated, international guide to diabetes. Sensibly organized and easy to navigate, with exceptional illustrations, the Textbook hosts an unrivalled blend of clinical and scientific content. Highly-experienced editors from across the globe assemble an outstanding set of international contributors who provide insight on new developments in diabetes care and information on the latest treatment modalities used around the world. The fifth edition features an array of brand new chapters, on topics including: * Ischaemic Heart Disease * Glucagon in Islet Regulation * Microbiome and Diabetes * Diabetes and Non-Alcoholic Fatty Liver Disease * Diabetes and Cancer * End of Life Care in Diabetes as well as a new section on Psychosocial aspects of diabetes. In addition, all existing chapters are fully revised with the very latest developments, including the most recent guidelines from the ADA, EASD, DUK and NICE. Includes free access to the Wiley Digital Edition providing search across the book, the full reference list with web links, illustrations and photographs, and post-publication updates Via the companion website, readers can access a host of additional online materials such as: * 200 interactive MCQ's to allow readers to self-assess their clinical knowledge * every figure from the book, available to download into presentations * fully searchable chapter pdfs Once again, Textbook of Diabetes provides endocrinologists and diabetologists with a fresh, comprehensive and multi-media clinical resource to consult time and time again.

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We dedicate this book to all people living with diabetes and the healthcare professionals who look after them. We would also like to dedicate this book to our families without whose support and encouragement the book would never have been finished.

Textbook of Diabetes



Professor in Diabetes & Endocrinology Human Development and Health Academic Unit University of Southampton Faculty of Medicine Southampton, UK


Emeritus Professor of Medicine Chinese University of Hong Kong Hong Kong SAR People’s Republic of China


CEO at Steno Diabetes Center Copenhagen (SDCC) The Capital Region of Denmark Professor of Clinical Endocrinology Faculty of Health and Medical Sciences University of Copenhagen, Copenhagen, Denmark


Vice President and Global Therapeutic Area Head Cardiovascular, Metabolic, Endocrine and Renal Medical and Scientific Affairs Covance Clinical Development Services Princeton, NJ, USA


This edition first published 2017 © 2017 by John Wiley & Sons Ltd

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Library of Congress Cataloging-in-Publication Data

Names: Holt, Richard I. G., editor. | Cockram, Clive S., editor. | Flyvbjerg,    Allan, editor. | Goldstein, Barry J., editor. Title: Textbook of diabetes / edited by Richard I.G. Holt, Clive S. Cockram,    Allan Flyvbjerg, Barry J. Goldstein. Other titles: Textbook of diabetes (Pickup) Description: Fifth edition. | Chichester, West Sussex, UK; Hoboken, NJ :    Wiley-Blackwell, 2016. | Preceded by Textbook of diabetes / edited by    Richard I.G. Holt … [et al.]. 4th ed. 2010. | Includes bibliographical    references and index. Identifiers: LCCN 2016014428| ISBN 9781118912027 (cloth) | ISBN 9781118924860    (epub) | ISBN 9781118924877 (Adobe PDF) Subjects: | MESH: Diabetes Mellitus Classification: LCC RC660 | NLM WK 810 | DDC 616.4/62–dc23 LC record available at https://lccn.loc.gov/2016014428

A catalogue record for this book is available from the British Library.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.

Cover images: Left inset: Gettyimages/AndreyPopov; Right inset: Gettyimages/SCIEPRO


List of Contributors

Preface to the Fifth Edition

List of Abbreviations

About the Companion Website and Companion Digital Edition

Part 1 Diabetes in its Historical and Social Context

1 The History of Diabetes Mellitus

Ancient times

The 17th and 18th centuries

The 19th century

The 20th century

Causes and natural history of diabetes

Chronic diabetic complications


Management of diabetes

Diabetic ketoacidosis

Diabetic pregnancy




Further reading

2 Classification and Diagnosis of Diabetes



Classification of diabetes

Methods and criteria for diagnosing diabetes [5, 6]

Glycated hemoglobin (HbA


) for diagnosis of diabetes

Type 1 diabetes (T1DM) [5, 6]

Type 2 Diabetes (T2DM)

Other specific types

Gestational diabetes (GDM)

Intermediate hyperglycemia or impaired glucose regulation (prediabetes)



3 Epidemiology of Type 1 Diabetes


Occurrence of T1DM by age, sex, place, and time

Familial clustering and twin studies

Environmental risk factors for T1DM: clues from epidemiological studies





4 Epidemiology of Type 2 Diabetes


Risk factors for T2DM

Recent emerging risk factors

Methodological issues in the epidemiology of T2DM

Regional and ethnic patterns of T2DM worldwide

Impact of diabetes

Prevention of T2DM




5 The Global Burden of Diabetes



Major burdens

Economic costs of diabetes

Gaps and future directions


Part 2 Normal Physiology

6 Islet Function and Insulin Secretion


Islet structure and function

Regulation of insulin secretion



7 Glucagon in Islet and Metabolic Regulation


α-Cell anatomy and development

Proglucagon gene transcription, translation and peptide processing

Regulation of α-cell secretion

Glucagon actions: hepatic glucose and lipid metabolism

Non-hepatic effects of glucagon

Other α-cell peptides

Abnormalities of glucagon secretion and action in diabetes

Pharmacology based on glucagon action


8 Mechanism of Insulin Action


Insulin receptor

IRS-proteins coordinate insulin and insulin-like growth factor signaling

PI3K→AKT cascade

AKT→mTORC1 cascade

AKT→mTORC2→AKT cascade

AKT→FOXO cascade

Heterologous regulation and dysregulation of the insulin and insulin-like growth factor signaling cascade

Post-translational regulation of insulin and insulin-like growth factor signaling

IRS2 as a gateway to β-cell function


9 Control of Weight: How Do We Get Fat?


Genetic factors

Environmental factors

Medications and toxins

Neuroendocrine and behavioral regulation of energy homeostasis and the gut microbiome



Part 3 Pathogenesis of Diabetes

10 Autoimmune Type 1 Diabetes






Humoral autoimmunity



11 Other Disorders with Type 1 Phenotype


Atypical diabetes: heterogeneous etiologies of young-onset diabetes

Monogenic diabetes

Latent autoimmune diabetes in adults (LADA)

Other subtypes of diabetes with type 1 phenotype



12 Abnormalities of Insulin Secretion and β-Cell Defects in Type 2 Diabetes


Physiological insulin secretion

Natural history of β-cell failure

Genetic predisposition

Abnormalities of β-cell function precede overt diabetes

Insulin secretion progressively worsens after development of T2DM

β-Cell dysfunction: exhaustion or insufficient mass?



13 Insulin Resistance in Type 2 Diabetes

Definition and measurement of insulin resistance in humans

Insulin resistance as a risk factor for type 2 diabetes mellitus (T2DM)

Insulin resistance in skeletal muscle

Insulin resistance in the liver

Insulin resistance in adipose tissue

Stepwise development of tissue-specific insulin resistance




14 Genetic Architecture of Type 2 Diabetes

The diabetes epidemic

The diabetes spectrum

Heritability of T2DM

The genetic architecture of T2DM

Difficulties in assigning functions to associated genes

Genotype-based treatment

Little common genetic basis for T1DM and T2DM

A holistic view – systems genetics



15 Metabolic Disturbances in Diabetes


Carbohydrate metabolism

Carbohydrate metabolism in type 1 diabetes

Carbohydrate metabolism in type 2 diabetes

Lipid metabolism in type 1 and type 2 diabetes

Protein metabolism in type 1 and type 2 diabetes

Counter-regulatory hormones

Diabetic ketoacidosis


16 Obesity and Diabetes


Definition of obesity and the body fat distribution pattern

Obesity is the most potent risk factor for type 2 diabetes

Genetic predisposition for obesity and type 2 diabetes

Developmental programming of obesity and diabetes

Pathophysiology of obesity

Environmental factors promoting obesity and type 2 diabetes

Pathophysiologic links between obesity and type 2 diabetes

Treatment of obesity in the context of the metabolic syndrome and type 2 diabetes



17 The Microbiome and Diabetes

The microbiome

The intestinal microbiome is associated with body mass

Composition of the intestinal microbiome is altered in T2DM

The intestinal microbiome can influence intestinal permeability

Metabolic endotoxemia

Metabolic endotoxemia in T2DM

Modulation of the intestinal microbiome is associated with improvements in insulin sensitivity

The microbiome contributes to T2DM risk via innate immune pathways

The microbiome contributes to T2DM risk via modulation of enteroendocrine cell function

The microbiome contributes to T2DM risk via modulation of bile acids

Type 1 diabetes

Conclusions and perspectives


Part 4 Other Types of Diabetes

18 Monogenic Causes of Diabetes


Maturity-onset diabetes of the young

Prevalence of MODY mutations

Strategies to improve case-finding

Use of diagnostic and predictive molecular testing in monogenic diabetes

Glucokinase MODY




(transcription factor MODY)

Other transcription factor MODY

Neonatal diabetes and diabetes diagnosed within 6 months of life

Diabetes with extrapancreatic features

Insulin resistance

Insulin receptor gene mutations

Inherited lipodystrophies

Other monogenic conditions associated with insulin resistance



19 Drug-Induced Diabetes



Second-generation antipsychotics

Oral contraceptive agents

Menopause hormone therapy

Thiazide diuretics

Beta-adrenoceptor antagonists

HMG CoA reductase inhibitors

Anti-retroviral therapy for human immunodeficiency virus (HIV)



Calcineurin inhibitors


Prevention and treatment strategies


20 Endocrine Disorders that Cause Diabetes



Cushing syndrome

Pheochromocytoma and paraganglioma

Other endocrine conditions causing disturbance of glucose tolerance

Endocrine disorders that associate with diabetes


21 Pancreatic Diseases and Diabetes


Acute pancreatitis

Chronic pancreatitis

Tropical chronic pancreatitis

Hereditary hemochromatosis

Pancreatic neoplasia

Pancreatic surgery and diabetes

Cystic fibrosis




Part 5 Managing the Patient with Diabetes

22 Clinical Presentations of Diabetes


Clinical considerations at presentation

Types of diabetes

Thirst, polydipsia, and polyuria

Weight loss

Blurred vision


Diabetic ketoacidosis

Hyperosmolar hyperglycemic syndrome

Macrovascular presentations

Microvascular presentations

Neuropathic syndromes



Other presentations



23 The Aims of Diabetes Care


St. Vincent's Declaration

The diabetes care team

Improving the outcome of the consultation

Following diagnosis

Ongoing clinic visits

Inpatient diabetes care

Involving people with diabetes in the planning of healthcare and service development




24 Educating the Person with Diabetes


Theory underlying diabetes education

Identification and use of theory to guide method

Health education methods

Modalities of education

Educator skills in group-based diabetes education

Dialogue and participation in diabetes education—practical examples

Psychosocial support in diabetes education

Family perspectives in diabetes education

Evaluation of diabetes education



25 Lifestyle Issues: Diet


Energy balance and body weight

Carbohydrate and diabetes

Dietary fat



Salt or sodium

Sterols and stanols


Diet in special circumstances


26 Lifestyle Issues: Exercise

Defining exercise, type of exercise and intensity

Type 1 diabetes and exercise

Exercise and type 2 diabetes

Gestational diabetes and exercise

Exercise advice in type 1 and type 2 diabetes


27 Monitoring Diabetes

Why monitor?

Tests and their characteristics

Monitoring in clinical practice

The future of monitoring in diabetes



28 Drug Therapy: Special Considerations in Diabetes


Drugs that raise blood glucose concentrations

Drugs that lower blood glucose concentration

Drug interactions that affect blood glucose concentrations

Hazards of general drugs when used in people with diabetes

Special precautions in diabetic complications

Drug interference with monitoring of diabetic control



Part 6 Treatment of Diabetes

29 Insulin and Insulin Treatment

Life (and death) before insulin

The discovery of insulin

The first insulins

Modifying the duration of action of insulin without altering its molecular structure

Modifying the duration of insulin action through altering its molecular structure

Biosimilar insulins

Different insulin concentrations

Reproducing physiological insulin delivery—the size of the problem

Oral, inhaled, intraperitoneal and intramuscular routes of insulin administration

Technique for subcutaneous injection of insulin

Complications of subcutaneous insulin therapy

Insulin regimens

Selecting the most appropriate insulin regimen

Declaration of interest


30 New Technologies for Glucose Monitoring and Insulin Administration


Episodic blood glucose monitoring

Real-time continuous glucose monitoring

Continuous subcutaneous insulin infusion pumps

Closed-loop insulin delivery: the artificial pancreas

Insulin pens

Inhaled insulin


31 Oral Glucose-Lowering Agents


Pathophysiological considerations

Guidelines and algorithms



Meglitinides (short-acting prandial insulin releasers)


DPP-4 inhibitors

SGLT-2 inhibitors

α-Glucosidase inhibitors



Antiobesity therapies

Fixed-dose combinations



32 Non-Insulin Parenteral Therapies


Glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonists (GLP-1RAs)

Amylin and amylin analogs


33 How to Use Type 2 Diabetes Treatments in Clinical Practice: Combination Therapies


Pathophysiological rationale for using multiple therapies

Individual glucose-lowering drug classes

Combination therapy: uses and evidence

Combination therapy: specific strategies


Future research needs



34 In-Hospital Treatment and Surgery in People with Diabetes


Pathophysiology of hyperglycemia in acute illness

Evidence of harm from in-hospital hyperglycemia and effect of glucose lowering

Glycemic targets for hospitalized inpatients

Current recommended standards of care for hospital inpatients with diabetes

Management of in-hospital hyperglycemia

Avoiding and treating in-hospital hypoglycemia

Surgery in people with diabetes

Glucocorticoid use

Foot care



35 Hypoglycemia in Diabetes

Overview of the clinical problem

Physiology of glucose counter-regulation

Pathophysiology of glucose counter-regulation in diabetes

Risk factors for hypoglycemia in diabetes

Magnitude of the clinical problem of hypoglycemia in diabetes

Prevention and treatment of hypoglycemia in diabetes

The clinical problem of hypoglycemia in children

Perspective on hypoglycemia in diabetes




36 Acute Metabolic Complications of Diabetes: Diabetic Ketoacidosis and the Hyperosmolar Hyperglycemic State


Diabetic ketoacidosis

Hyperosmolar hyperglycemic state


Part 7 Microvascular Complications in Diabetes

37 Pathogenesis of Microvascular Complications

Diabetic angiopathy: definition and clinical features

Pathogenesis of microvascular complication: the role of hyperglycemia

Pathogenesis of microvascular complication: beyond hyperglycemia




38 Diabetic Retinopathy









Exploration of diabetic retinopathy


39 Diabetic Nephropathy



Screening for and classification of chronic kidney disease

Natural history and histopathology

Changing epidemiology of kidney disease in diabetes

Risk factors and markers for chronic kidney disease in diabetes

Investigation of kidney disease in diabetes

Prevention and management of diabetic kidney disease

Further management of chronic kidney disease stage 3 or poorer

Organization of care

Pregnancy in women with diabetes and chronic kidney disease


40 Diabetic Peripheral and Autonomic Neuropathy

Diabetic peripheral neuropathy

Diabetic autonomic neuropathy


Part 8 Macrovascular Complications in Diabetes

41 Pathogenesis of Macrovascular Complications in Diabetes

Epidemiology of diabetic macrovascular complications

Pathogenesis of diabetic macrovascular disease

Role of vasoactive hormones in diabetes-related atherosclerosis

The endothelin system

Urotensin II

TNF-related apoptosis-inducing ligand and osteoprotegerin

Complement activation

Interventions to reduce diabetes-associated macrovascular complications


42 Cardiovascular Risk Factors: Hypertension


43 Diabetic Dyslipidemia and Risk of Cardiovascular Disease


CVD risk factors in diabetes

Guidelines and lipids in diabetes

Future drug developments and drug targets



44 Ischemic Heart Disease in Diabetes


Pathophysiological perspective

How can cardiovascular risk be reduced in persons with diabetes?



45 Congestive Heart Failure


Symptoms and diagnosis





Gender aspects


46 Cerebrovascular Disease

Epidemiology of stroke in general

Diabetes as a risk factor for stroke

Stroke in people with diabetes

Prediabetes and other risk factors

Pathophysiology of ischemic stroke in diabetes

Primary prevention of stroke in persons with diabetes

Treatment of acute stroke in persons with diabetes

Secondary Prevention of Stroke in Diabetes



47 Peripheral Vascular Disease


Peripheral arterial disease

Carotid artery disease


Part 9 Other Complications of Diabetes

48 Foot Problems in People with Diabetes


Epidemiology and economic aspects of diabetic foot disease

Etiopathogenesis of diabetic foot lesions

Prevention of diabetic foot ulcers

Foot ulcers: diagnosis and management

Charcot neuroarthropathy



49 Sexual Function in Men and Women with Diabetes

Male erectile dysfunction

Female sexual dysfunction


Hormone replacement therapy


50 Gastrointestinal Manifestations of Diabetes




Pathophysiology of diabetic enteropathy in humans

Clinical manifestations

Diagnostic tests




51 Diabetes and Non-Alcoholic Fatty Liver Disease


Definition and epidemiology

NAFLD and the metabolic syndrome

NAFLD and diabetes

Histologic subtypes

Why does NASH occur?

Clinical features

Extrahepatic-associations of NAFLD

Natural history of NAFLD

Diagnosis and assessment



52 The Skin in Diabetes


Metabolic manifestations

Vascular changes


Associated conditions



53 Bone and Rheumatic Disorders in Diabetes

Musculoskeletal disease in diabetes


54 Diabetes and Cancer: Evidence for Risk, Methodology and Implications


Diabetes and cancer risk: the epidemiological evidence

Interpretation of the epidemiological evidence

Hyperglycemia versus hpyerinsulinemia hypotheses

Pharmaco-epidemiology: glucose-lowering agents and cancer risk

Impact of diabetes on outcome after cancer diagnosis

Clinical implications


Conflict of interest


55 Diabetes and Infections


Diabetes, the immune system and host factors

Specific infections either strongly associated with diabetes or in which the presence of diabetes is important

Respiratory tract infections and tuberculosis

Infections of the urinary tract

Intra-abdominal infections other than those within the urinary tract

Skin and superficial soft tissue infections

Principles of treatment, prevention, and general care


Part 10 Psychosocial Aspects of Diabetes

56 Psychological Factors and Diabetes Mellitus


Psychological risk factors for the development of diabetes

The psychological impact of diabetes and its complications

The impact of psychological factors on diabetes management

The impact of behavioral factors (“adherence”) on diabetes management

Interventions to reduce psychological distress and improve quality of life, self-care, and glycemic control

Neuropsychological and cognitive consequences of diabetes




57 Psychiatric Disorders and Diabetes


Mood disorders

Psychotic disorders

Eating disorders



58 Social Aspects of Diabetes




Prison and custody



Recreational drugs


Leaving home


Part 11 Diabetes in Special Groups

59 Diabetes in Childhood

Spectrum of diabetes in children

Manifestation, diagnosis, and initial treatment

Pediatric ambulatory diabetes care

Insulin treatment




Sick-day management

Monitoring and goals of diabetes management

Psychological care

Screening and early treatment of risk factors for complications and associated conditions


60 Adolescence and Emerging Adulthood: Diabetes in Transition


Demographic information about diabetes

Physical changes during adolescence

Developmental stages

Changes in family involvement

Diabetes technologies

Type 2 diabetes in adolescence and transition

Acute and chronic complications in young adults diagnosed with diabetes in childhood

What is transition?

Problems with transition

Existing transition programs and interventions



61 Diabetes in Pregnancy


Changes in glucose metabolism in pregnancy

Classification of diabetes in pregnancy

Effects of diabetes on pregnancy

Management of diabetes in pregnancy

Obstetric monitoring

Labor and delivery

Gestational diabetes


62 Diabetes in Old Age




Diabetes phenotype in old age

Clinical presentation



Special considerations in old age

Management of Diabetes


Future perspectives


63 Diabetes at the End of Life

Dying with diabetes

End of life

The management of diabetes at the end of life

Glycemic targets

Medicines management during the last year of life

Other medication



Management of diabetes in those treated with glucocorticosteroids

Withdrawal of diabetes and other medication



Part 12 Delivery and Organization of Diabetes Care

64 The Role of the Multidisciplinary Team Across Primary and Secondary Care


Upskilling of primary or community care professionals in multidisciplinary teams

Support of multidisciplinary teams in structured patient education in diabetes

Multidisciplinary teams in diabetes care models

Enhancement of multidisciplinary teams through the use of information technology

Multidisciplinary teams in the management of complexities in CVD risk prevention

Multidisciplinary teams in renal disease in diabetes

Multidisciplinary teams in the care of people with diabetic retinopathy

Multidisciplinary teams in the care of people with diabetic foot problems

Multidisciplinary teams in the care of women with diabetes in pregnancy

Multidisciplinary teams in the care of young people with T2DM

Multidisciplinary teams in the care of elderly people with diabetes

The staff composition of a multidisciplinary diabetes team



65 Models of Diabetes Care Across Different Resource Settings


A comprehensive approach

Integrated healthcare

Continuity, access, coordination, and teamwork

Patient-centered care

A family and community orientation

Clinical governance

Information technology



Part 13 Future Directions

66 Future Drug Treatments for Type 1 Diabetes


New biosynthetic human insulin analogs

Alternative means of accelerating insulin absorption and action

New generation of insulins in development

Adjunctive therapies

Artificial pancreas development

Improved glucagon preparations



67 Future Drug Treatments for Type 2 Diabetes


Development of new antidiabetes agents

Modifiers of carbohydrate digestion and absorption

Supporting pancreatic β-cell function

Inhibitors of glucagon secretion and action

Insulin mimetic agents

Insulin potentiating agents

Peroxisome proliferator-activated receptor γ agonists

Vitamins and minerals

Hydroxysteroid dehydrogenase 1 inhibitors

Sodium–glucose co-transporter inhibitors

Suppression of glucose production

Antiobesity agents






68 Stem Cell Therapy in Diabetes

Why use stem cells in individuals with diabetes?

What is a stem cell?

Stem cells for insulin replacement

Healing the heart

Creating new vessels



69 Islet Transplantation


Background history

Early human studies

Pancreas transplantation

Islet transplantation and the Edmonton Protocol in the year 2000

Islet transplantation current state-of-the-art

Islet transplantation outcomes

Indications and contraindications for islet transplantation

Patient evaluation

Challenges and future directions

Summary and conclusions


70 Gene Therapy for Diabetes

Introduction to gene therapy

Gene therapy for diabetes

Conclusions and perspectives


71 Future Models of Diabetes Care


The Chronic Care Model





List of Tables

Chapter 1

Table 1.1

Table 1.2

Table 1.3

Table 1.4

Chapter 2

Table 2.1

Table 2.2

Table 2.3

Chapter 4

Table 4.1

Table 4.2

Table 4.3

Table 4.4

Table 4.5

Table 4.6

Table 4.7

Table 4.8

Table 4.9

Chapter 5

Table 5.1

Table 5.2

Table 5.3

Chapter 6

Table 6.1

Chapter 10

Table 10.1

Table 10.2

Table 10.3

Chapter 14

Table 14.1

Table 14.2

Table 14.3

Chapter 16

Table 16.1

Table 16.2

Table 16.3

Table 16.4

Table 16.5

Chapter 18

Table 18.1

Table 18.2

Table 18.3

Table 18.4

Table 18.5

Chapter 19

Table 19.1

Table 19.2

Table 19.3

Chapter 20

Table 20.1

Table 20.2

Table 20.3

Table 20.4

Table 20.5

Table 20.6

Chapter 21

Table 21.1

Table 21.2

Table 21.3

Table 21.4

Table 21.5

Table 21.6

Chapter 22

Table 22.1

Chapter 23

Table 23.1

Table 23.2

Chapter 24

Table 24.1

Table 24.2

Chapter 25

Table 25.1

Table 25.2

Chapter 26

Table 26.1

Table 26.2

Table 26.3

Table 26.4

Table 26.5

Table 26.6

Table 26.7

Chapter 27

Table 27.1

Table 27.2

Table 27.3

Chapter 28

Table 28.1

Table 28.2

Table 28.3

Table 28.4

Table 28.5

Chapter 29

Table 29.1

Table 29.2

Chapter 31

Table 31.1

Table 31.2

Table 31.3

Table 31.4

Table 31.5

Table 31.6

Table 31.7

Table 31.8

Table 31.9

Table 31.10

Table 31.11

Table 31.12

Table 31.13

Table 31.14

Chapter 32

Table 32.1

Chapter 33

Table 33.1

Table 33.2

Chapter 34

Table 34.1

Table 34.2

Table 34.3

Table 34.4

Table 34.5

Chapter 35

Table 35.1

Table 35.2

Table 35.3

Table 35.4

Table 35.5

Table 35.6

Chapter 36

Table 36.1

Chapter 38

Table 38.1

Table 38.2

Chapter 39

Table 39.1

Table 39.2

Table 39.3

Table 39.4

Chapter 40

Table 40.1

Table 40.2

Table 40.3

Table 40.4

Table 40.5

Table 40.6

Table 40.7

Chapter 42

Table 42.1

Table 42.2

Table 42.3

Table 42.4

Chapter 43

Table 43.1

Chapter 45

Table 45.1

Table 45.2

Table 45.3

Chapter 46

Table 46.1

Table 46.2

Table 46.3

Chapter 47

Table 47.1

Table 47.2

Chapter 48

Table 48.1

Table 48.2

Table 48.3

Table 48.4

Table 48.5

Chapter 49

Table 49.1

Table 49.2

Chapter 50

Table 50.1

Table 50.2

Table 50.3

Chapter 51

Table 51.1

Table 51.2

Table 51.3

Table 51.4

Table 51.5

Table 51.6

Table 51.7

Table 51.8

Table 51.9

Chapter 52

Table 52.1

Chapter 53

Table 53.1

Table 53.2

Chapter 54

Table 54.1

Table 54.2

Chapter 57

Table 57.1

Table 57.2

Table 57.3

Table 57.4

Table 57.5

Table 57.6

Chapter 58

Table 58.1

Table 58.2

Table 58.3

Table 58.4

Table 58.5

Table 58.6

Table 58.7

Chapter 59

Table 59.1

Table 59.2

Table 59.3

Table 59.4

Table 59.5

Chapter 60

Table 60.1

Chapter 61

Table 61.1

Table 61.2

Table 61.3

Table 61.4

Table 61.5

Table 61.6

Table 61.7

Table 61.8

Table 61.9

Table 61.10

Chapter 62

Table 62.1

Table 62.2

Chapter 63

Table 63.1

Table 63.2

Table 63.3

Table 63.4

Chapter 67

Table 67.1

Table 67.2

Chapter 69

Table 69.1

Chapter 70

Table 70.1

List of Illustrations

Chapter 1

Figure 1.1

The Ebers papyrus.

Figure 1.2

(a) Clinical description of diabetes by Aretaeus of Cappadocia (2nd century AD). Adapted from Papaspyros NS (1952)

The History of Diabetes Mellitus

. (b) Sushrut (Susrata), an Indian physician who wrote medical texts with Charak (Charuka) between 500 BC and 400 BC.

Figure 1.3

Frontispiece and opening page of the paper by Matthew Dobson (1776), in which he described the sweet taste of both urine and serum from a person with diabetes [2].

Figure 1.4

Extract from John Rollo's account of two cases of diabetes (1797). Rollo was well aware of the problem of non-adherence. Note that “the patient was strongly remonstrated with, and told of the consequences of repeated deviations.”

Figure 1.5

Claude Bernard (1813–1878).

Figure 1.6

Oskar Minkowski (1858–1931).

Figure 1.7

Paul Langerhans (1847–1888).

Figure 1.8

Pictures from

Jaeger's Atlas of the Optic Fundus

, 1869 [14]. Top left: Bright's disease. Top right: Jaeger's retinitis hemorrhagica is now recognized as central retinal vein occlusion. Bottom left: A 22-year-old man with suspected diabetes. Bottom right: Central retinal artery occlusion.

Figure 1.9

Elliott P. Joslin (1869–1962), arguably the most famous diabetes specialist of the 20th century and the frontispiece to his 1916 textbook [22].

Figure 1.10

(a) Georg Zuelzer (1840–1949) and (b) the title page from his paper (1907) reporting that a pancreatic extract reduced glycosuria in pancreatectomized dogs [23] (top). (c) Nicolas Paulesco (1869–1931).

Figure 1.11

The discoverers of insulin. Clockwise from top left: Frederick G. Banting (1891–1941); James B. Collip (1892–1965); J.J.R. Macleod (1876–1935); and Charles H. Best (1899–1978).

Figure 1.12

Leonard Thompson, the first person to receive insulin, in January 1922.

Figure 1.13

Nodular glomerulosclerosis. Figure from the paper by Kimmelstiel and Wilson, 1936 [41].

Figure 1.14

Knud Lundbæk (1912–1995).

Figure 1.15

Frederick Sanger (1918–2013) and Dorothy Hodgkin, née Crowfoot (1910–1994).

Figure 1.16

Solomon Berson and Rosalyn Yalow.

Figure 1.17

Hans Christian Hagedorn (1888–1971) from the Hagedorn Medal.

Figure 1.18

Robert Turner (1939–1999), instigator of the UKPDS, the first study to show that good control of blood glucose and blood pressure was beneficial in type 2 diabetes.

Figure 1.19

Jørgen Pedersen (1914–1978) and Ivo Drury (1905–1988), pioneers, with Priscilla White (1900–1989), in the management of pregnancy in women with type 1 diabetes.

Figure 1.20

Ernesto Roma (1887–1978) and (right) Robin D. Lawrence (1892–1968).

Chapter 3

Figure 3.1

 Incidence rate of type 1 diabetes per 100,000/year in Swedish males and females by age during 1983–1998. Source: Pundziute-Lyckå et al. 2002 [11]. Reproduced with permission of Springer.

Figure 3.2

 Geographic variation in childhood onset type 1 diabetes incidence rates, 1990–1999. Note that most registries were not nationwide and that several countries display within-country variation. Source: The DIAMOND Project Group 2006 [5]. Reproduced with permission of John Wiley & Sons.

Figure 3.3

 Long-term time trends in incidence rate of type 1 diabetes diagnosed before 15 years of age in Finland, Sweden, Norway, and Germany. Source: Data from Tuomilehto et al. 1999 [40], Harjutsalo et al. 2008 [7], Harjutsalo et al. 2013 [41], Hussen et al. 2013 [43], Joner & Søvik 1989 [163], Skrivarhaug 2014 [50], and Ehehalt et al. 2012 [44]. Finish data 1965–1996 are for age group 1–14 years, and thereafter 0–14 years (and data from 1997 to 2005 are averages for three calendar years); all other data are observed incidence per calendar year without smoothing of curves. Nordic data are from nation-wide registries and German data are from former Eastern Germany (GDR) and the Baden-Württemberg registry 1987–2006.

Figure 3.4

 Incidence trends in type 1 diabetes among ethnic groups in Sweden and Israel (left panel) and Yorkshire, UK (right panel). Source: Data from Hussen et al. 2013 [43] and Harron et al. 2011 [47]. Note that the data from Israel shown here are for ages below 15 years, as for the Swedish and UK data. R.C. Parslow and O. Blumenfeld kindly provided raw data for UK and Israel, respectively.

Figure 3.5

Seasonal variation in diagnosis of type 1 diabetes among >22,000 children diagnosed 1989–1998 in European centers, by age at onset.


Age (years) at first insulin injection. Source: Green and Patterson 2001 [26]. Reproduced with permission of Springer.

Figure 3.6

 Diabetes-free survival in non-diabetic monozygotic twins whose co-twin had type 1 diabetes, after several years of follow-up. Dotted lines represent 95% confidence intervals. Source: Redondo et al. 2001 [75]. Reproduced with permission of Springer.

Figure 3.7

 Standardized mortality ratios (SMRs) for people followed from diagnosis of childhood-onset type 1 diabetes. Data are from different studies, summarized by Morgan et al. 2015 [143]. Only studies with at least 10 observed deaths are shown. An SMR of 1.0 means a mortality rate among people with type 1 diabetes that is equal to that in the background population for the same age, sex, and calendar period. Studies were sorted by the earliest year of diagnosis of type 1 diabetes, and secondarily by SMR. Note that there were differences in duration of follow-up and other minor methodological differences between studies.

Chapter 4

Figure 4.1

Risk factors in the development of T2DM. HDL, high-density lipoprotein cholesterol; PCOS, polycystic ovarian syndrome; TG, triglycerides.

Figure 4.2

Diabetes epidemiological model. Factors directly affecting the prevalence of diabetes included in the present analysis. Source: Adapted from Colagiuri et al. 2005 [49]

Figure 4.3

Global prevalence of diabetes. Source: Adapted from

IDF Diabetes Atlas

, International Diabetes Federation 2015 [1], Chapter 3, Map 3.1.

Figure 4.4

Changes in prevalence of diabetes among Chinese adults aged 35–64 years. Source: Data from the 1994 Chinese National Survey and the 2000–2001 InterASIA study (Gu et al. 2003 [209]).

Chapter 5

Figure 5.1

Diagram illustrating the cyclical relationship between poverty and ill-health: poverty predisposes one to illness, and costs of illness in a system of fee-for-service care have the potential to impoverish households, further perpetuating poverty.

Chapter 6

Figure 6.1

Anatomy of the islet of Langerhans. (a) Mouse islet. The image shows a section through a mouse pancreas in which insulin and glucagon are identified by red and green immunofluorescence, respectively, demonstrating the typical β-cell core surrounded by a thin mantle of α cells. In mouse islets, β cells comprise ~80% of the endocrine cell mass. Scale bar is 10 μm. Source: image courtesy of C. Li, King's College London. (b) Human islet. The image shows a section through a human pancreas in which insulin and glucagon are identified by red and green immunofluorescence respectively, demonstrating the less organized structure of the human islet when compared with mouse islets. In human islets, β cells comprise ~50–60% of the endocrine cell mass. Scale bar is 10 μm. Source: image courtesy of V. Foot, King's College London. (c) Transmission electron micrograph of human islet cells. The image shows a transmission electron micrograph of several cells within a human islet. The two cells at the top with the electron-dense secretory granules surrounded by a clear halo are β cells. The cells in the lower part of the micrograph are α cells. Scale bar is 2 μm. Source: authors' unpublished data.

Figure 6.2

Intra-islet autocrine–paracrine interactions. The heterogeneous nature and complex anatomy of the islet permit numerous interactions between islet cells that are mediated by the release of biologically active molecules.

Figure 6.3

Structure of the human insulin gene. The coding region of the human insulin (INS) gene comprises three exons, which encode the signal peptide (SP), B chain, C-peptide, and A chain. The exons are separated by two introns (In1 and In2). Beyond the 5′ untranslated region (5′UT), upstream of the coding sequence, lies a hypervariable region in which three alleles (classes I, II and III) can be distinguished by their size.

Figure 6.4

The intracellular pathways of (pro)insulin biosynthesis, processing, and storage. The molecular folding of the proinsulin molecule, its conversion to insulin, and the subsequent arrangement of the insulin hexamers into a regular pattern are shown at the left. The time course of the various processes and the organelles involved are also shown.

Figure 6.5

Insulin biosynthesis and processing. Proinsulin is cleaved on the C-terminal side of two dipeptides, namely Arg




(by prohormone convertase 3) and Lys




(prohormone convertase 2). The cleavage dipeptides are liberated, so yielding the “split” proinsulin products and ultimately insulin and C-peptide.

Figure 6.6

Glucose-induced insulin secretion from islets of Langerhans. No stimulation is seen below a threshold value of ~5 mmol/L glucose. Potentiators amplify insulin secretion at stimulatory concentrations of glucose, but are ineffective at subthreshold glucose levels.

Figure 6.7

Glucose-induced insulin release

in vitro

. The image shows the pattern of glucose-induced insulin secretion from perfused pancreas, in response to an increase in the glucose concentration. An acute first phase, lasting a few minutes, is followed by a sustained second phase of secretion that persists for the duration of the high-glucose stimulus.

Figure 6.8

Intracellular mechanisms through which glucose stimulates insulin secretion. Glucose is metabolized within the β cell to generate ATP, which closes ATP-sensitive potassium channels in the cell membrane. This prevents potassium ions from leaving the cell, causing membrane depolarization, which in turn opens voltage-gated calcium channels in the membrane and allows calcium ions to enter the cell. The increase in cytosolic calcium initiates granule exocytosis. Sulfonylureas act downstream of glucose metabolism, by binding to the SUR1 component of the K


channel (inset). GLUT, glucose transporter.

Figure 6.9

Adenylate cyclase and the regulation of insulin secretion. Some receptor agonists (e.g. glucagon, glucagon-like peptide 1, pituitary adenylate cyclase activating polypeptide) bind to cell-surface receptors that are coupled to adenylate cyclase (AC) via the heterotrimeric GTP-binding protein Gs. Adenylate cyclase hydrolyzes ATP to generate adenosine 5′ cyclic monophosphate (cAMP), which activates protein kinase A (PKA) and exchange proteins activated by cAMP (EPACs). Both of these pathways potentiate glucose-stimulated insulin secretion. Glucose also activates adenylate cyclase, but increases in intracellular cyclic AMP levels in response to glucose are generally smaller than those obtained with receptor agonists. Some inhibitory agonists (e.g. norepinephrine, somatostatin) bind to receptors that are coupled to adenylate cyclase via the inhibitory GTP-binding protein G


, resulting in reduced adenylate cyclase activity and a decrease in intracellular cAMP.

Figure 6.10

Phospholipase C and the regulation of insulin secretion. Some receptor agonists (e.g. acetylcholine, cholecystokinin) bind to cell-surface receptors that are coupled to phospholipase C (PLC) via the heterotrimeric GTP-binding protein G


. Phospholipase C hydrolyzes phosphatidylinositol bisphosphate (PIP


), an integral component of the membrane, to generate inositol 1,4,5-trisphosphate (IP


) and diacylglycerol (DAG). IP


mobilizes calcium from the endoplasmic reticulum and DAG activates protein kinase C (PKC), both of which enhance insulin secretion. Nutrients also activate PLC in a calcium-dependent manner but the importance of IP


and DAG in nutrient-induced insulin secretion is uncertain.

Chapter 7

Figure 7.1

Islet development and anatomy. A simplified model of pancreatic islet–cell differentiation in the developing pancreas and the role of islet transcription factors during islet–cell development. Transcriptional factors such as neurogenin 3 (Ngn3) and pancreatic duodenal homeobox 1 (Pdx1) are critical for the endocrine cell fate determination, and aristaless-related homeobox (Arx) and forkhead box A2 (Foxa2) are important for the initial or terminal differentiation stages of α-cell differentiation, respectively. In mice and rats, the organization of the islet includes a mantle of α and δ cells on the periphery of the islet, surrounding a core of β cells. In humans, the major endocrine cell types are spread more diffusely throughout the islet and most β cells have contact with either α or δ cells.

Figure 7.2

Regulation of


gene expression. IGF (insulin-like growth factor), other growth factors, nutrients, and insulin are stimulatory factors for


expression. IGF, growth factors, and nutrients activate a GPCR/cAMP signaling that has multiple downstream effects including activation of PKA and subsequently CREB (cAMP response element-binding protein). cAMP either directly or indirectly (via EPAC) activates other transcription factors (beta-cat/TCF7L2, Pax6/MafB, or Foxa1 depending on whether the activation occurs in the intestine or pancreas) that bind to promoter regions of the


gene. Additionally, insulin signaling is also upstream of these transcription factors and can stimulate transcription in both the pancreas and intestine.

Figure 7.3

Regulation of glucagon secretion. Neural (SNS stimulates and PNS inhibits), paracrine (insulin and somatostatin inhibit), autocrine (glucagon stimulates its own secretion), endocrine (GIP stimulates and GLP-1 inhibits), and nutrient (low glucose stimulates) factors all regulate glucagon secretion. ADP, adenosine diphosphate; ANS, autonomic nervous system; ATP, adenosine triphosphate; EPI, epinephrine; SNS, sympathetic nervous system; TCA, tricarboxylic acid cycle.

Figure 7.4

Glucagon GPCR signaling via PKA activates glycogenolysis (via inhibition of glycogen synthase; activation of phosphorylase kinase and glycogen phosphorylase) and inhibits glycolysis (via inhibition of fructose 2,6-bisphosphatase and pyruvate kinase) via regulation of major rate-limiting enzymes in these pathways. PKA also activates CREB, which increases transcription of Pck1 and G6PC, major enzymes regulating gluconeogenesis, and also FGF21, which activates several downstream genes that increase lipid oxidation and inhibit lipid synthesis.

Figure 7.5

Pharmacological targeting of glucagon signaling. Approaches to block glucagon action to suppress the elevated hepatic glucose production (HGP) seen in T2DM has been explored for decades. However, the additional effect of inhibiting fatty acid oxidation (FAO) and increasing triglyceride synthesis may limit this therapeutic target. Newer hybrid peptides that favor glucagon's ability to suppress feeding and increase energy expenditure combined with hypoglycemic agents (such as GLP-1 agonists) have potent effects on weight loss in preclinical models. BAT, brown adipose tissue; CNS, central nervous system.

Chapter 8

Figure 8.1

A linear diagram of the insulin receptor (IR) precursor protein showing the position of important modules in the α and β subunits including leucine-rich regions (L1 and L2), a cysteine-rich region (CR), disulfide bonds , the alternative IRA/IRB splice site that generates the short CT


or long CT


, a transmembrane region (TM), the furin cleavage site, the IRS binding motif (NPEpY), the kinase activation loop autophosphorylation sites, and C-terminal tyrosine phosphorylation sites (CT).

Figure 8.2

Diagram of the mature insulin receptor composed of two extracellular α-subunits and two transmembrane β-subunits. The juxtaposed α-subunit are labeled with either black or white (L1, CR, L2, Fn


1, Fn


2, Fn


3) symbols to outline the two α-subunit. The holoreceptor is stabilized extracellularly by disulfide bonds between cysteine residues (S–S) in the α and β subunits, and also by non-covalent interactions. Two regions within the α subunit contribute to insulin binding including L1•CR (and the extra 12 amino acids encoded by exon-11 in the B form of the insulin receptor) that binds the S1 site of insulin; and the junction between Fn


1 and Fn


2 that binds the S2 site of insulin. The β subunit contains the tyrosine kinase catalytic domain with an ATP binding site (Lys


) and a number of tyrosine phosphorylation sites, including those in the juxtamembrane region (pY


), activation loop (pY

1158, 1162, 1163

), and C-terminal regions (gray box). A structure of the catalytic domain is shown. An inset shows the insulin structure with the position of some critical amino acids that compose the two binding surfaces (S1 and S2) that interact with the L1•CR•CT and Fn




2 regions of the insulin receptor, respectively. The A chain is shown in green and the B chain in blue, and some amino acids composing each binding site are shown as space-filling residues in red (S1) or orange (S2). The N- and C-terminal residues of each chain are labeled in black.

Figure 8.3

Alignments of IRS1 and IRS2 tyrosine phosphorylation sites relative to the N-terminal pleckstrin homology (PH) and phosphotyrosine-binding (PTB) domains. Conserved tyrosine phosphorylation sites—including their number in the human protein and the surrounding amino acid sequences—are color coded; white boxes indicates unique sites in IRS1 or IRS2. The relative position of serine/threonine phosphorylation sites in IRS1 or IRS2 revealed by MS/MS are indicated with red circles (•).

Figure 8.4

A canonical insulin/IGF signaling cascade. Two main branches propagate insulin signals generated via the IRS-proteins initiated by PI3K and GRB2•SOS. Activation of the receptors for insulin and IGF1 results in tyrosine phosphorylation of the IRS proteins, which bind PI3K and Grb2/SOS. The Grb2/SOS complex promotes GDP/GTP exchange on p21


, which activates the ras→raf→MEK→ERK1/2 cascade. Activated ERK stimulates transcriptional activity by direct phosphorylation of ELK1 (ETS domain-containing protein) and by indirect phosphorylation of cFOS through MAPKAPK1 (MAPK-activated protein kinase-1). MAPKAP1 also phosphorylates other proteins, including S6 (ribosomal protein S6), NFκB, PP1, and MYT1 (myelin transcription factor 1). The activation of PI3K by recruitment to IRS1 or IRS2 produces PI3,4P


, and PI(3,4,5)P


(antagonized by the action of PTEN or SHIP2), which recruits PDK1 and AKT to the plasma membrane. AKT is activated upon phosphorylation at T308 by PDK1 and at S473 by mTORC2. mTORC1 is activated by Rheb


, which accumulates upon inhibition of the GAP (GTPase-activating protein) activity of the TSC1•TSC2 complex following AKT-mediated phosphorylation of TSC2. The S6K is primed through mTORC1-mediated phosphorylation. AKT phosphorylates many cellular proteins, inactivating PGC1α, p21


, GSK3β, BAD, and AS160, and activating PDE3b and eNOS. AKT-mediated phosphorylation of forkhead proteins, including FOXO1, results in their sequestration in the cytoplasm, which inhibits their influence upon transcriptional activity. Insulin stimulates protein synthesis by altering the intrinsic activity or binding properties of key translation initiation and elongation factors (eIFs and eEFs, respectively) and also critical ribosomal proteins. Components of the translational machinery that are targets of insulin regulation include eIF2B, eIF4E, eEF1, eEF2, and the S6 ribosomal protein [215].

Figure 8.5

Schematic diagram of heterologous and feedback inhibition of insulin signaling mediated by Ser/Thr-phosphorylation and degradation of IRS1/IRS2. Various kinases in the insulin signaling cascade are implicated in this feedback mechanism, including PKB, mTOR, S6K, ERK, AKT, and atypical PKC isoforms. Other IRS kinases are activated by heterologous signals, including lipids, TNFα or other cytokines. Serine phosphorylation of IRS1 can recruit CRL7 ubiquitinylation (purple oval) complex to mediate degradation of IRSs through the 26S proteasome. Proinflammatory cytokines that cause insulin resistance also induce the expression of SOCS family members, which contain an N-terminal SH2 domain and a C-terminal SOCS box [216, 217]. SOCS1 or SOCS3 can target phosphotyrosine residues in IRS1 or IRS2 for ubiquitinylation and degradation, because the SOCS box associates with elongin BC-containing ubiquitin ligase E3 [218–220].

Figure 8.6

The integrative role of IRS2 signaling in pancreatic β-cell function. The diagram shows the relation between the IRS2 branch of the insulin signaling pathway and upstream and downstream mechanisms regulating β-cell growth and function. The production of PI(3,4,5)P


by the PI3K recruits the Ser/Thr-kinases PDK1 and AKT to the plasma membrane where AKT is activated by PDK1 and mTORC2-mediated phosphorylation. AKT phosphorylates many proteins that play important physiological roles in β cells including GSK3β (glycogen synthesis), the BAD•BCL2 heterodimer (apoptosis inhibition), TSC1/2 (protein synthesis and nutrient sensing), and FOXO (transcriptional regulation). Activation of GLP1→cAMP→PKA→CREB, glucose→Ca


→CRTC2 and calcineurin→NFAT induce IRS2 expression in β cells, revealing a mechanism that places β-cell growth, function, and survival under the control of glucose and incretins. Since insulin and IGF1R are constitutively active, IRS2 expression can act as the regulatory gateway to mTORC1, FOXO1, and p27


. Together, this integrated pathway shows how signals known to promote β-cell and islet growth and function can be integrated by the IRS2 signaling cascade into a common pathway.

Chapter 10

Figure 10.1

Schematic presentation of the early natural history of T1DM divided into three different disease stages.

Figure 10.2

Incidence of the first islet autoantibody in relation to HLA-DQ genetic risk. In all four panels the red line represents IAA as the first β-cell autoantibody, the blue as GADA and the black simultaneously GADA and IAA. The Environmental Determinants of Diabetes in the Young (TEDDY) children in (a) were HLA-DQ2/8, in (b) HLA-DQ4/8, in (c) HLA-DQ8/8 and in (d) HLA-DQ 2/2. Source: Data from [12].

Figure 10.3

Putative genetic factors and proposed function for non-HLA type 1 diabetes genes determined by the Type 1 Diabetes Genetics Consortium.

Figure 10.4

Probability of progression to symptomatic T1DM in relation to number of β-cell autoantibodies analyzed from birth. Source: Data from [11].

Chapter 11

Figure 11.1

There are considerable overlaps between the phenotypes of type 1 and type 2 diabetes due to heterogeneous genetic and autoimmune etiologies. These include maturity-onset diabetes of the young (MODY), latent autoimmune diabetes in adults (LADA), and genetic variants affecting the insulin, amylin, and mitochondrial pathways. Other rare causes include fibrocalculous pancreatic diabetes and fulminant type 1 diabetes.

Figure 11.2

(a) The cascade of transcription factors involved in pancreatic development and also neogenesis, differentiation, and maturation of pancreatic β cells. Maturity-onset diabetes of the young (MODY) includes subtypes with mutations in transcription factors, namely MODY 1 with mutations of hepatic nuclear factor (HNF-4α); MODY 3, HNF-1α; MODY 4, insulin promotion factor (IDF-1); MODY 5, HNF-1β; MODY 6, NeuroD1 (neurogenic differentiation 1); and MODY 7, carboxyl ester lipase (CEL), and also glucokinase, which is the glucose sensor of the pancreatic β cells (MODY 2). There are also involvement and interactions of glucose transporter 2 (GLUT-2) and endodermal factor, including GATA and various important genes and transcription factor governing the differentiation and maturation of pancreatic islet and β cells. These include Pax genes family and genes encoding the homeodomain transcription factors Nkx 2.2 and Nkx 6.1. In the Southern Indian population, interaction of the NeuroD1, neurogenin-3 (Neurog3), and HNF-1α genes has been observed to have a combined effect in controlling islet cell development and insulin secreting, thus contributing to the overall glucose tolerance [106]. (b) The multiple steps involved in regulation of insulin secretion commencing with sensing of ambient blood glucose level by GLUT-2, glycolysis by glucokinase (GK), and ATP production by mitochondria. The generated ATP particles then close the potassium channel, leading to membrane depolarization and opening of calcium channels. The intracellular calcium influx is associated with translocation of insulin- and amylin-containing vesicles to the cellular surface for extracytosis. During these processes, transcription factors are also activated, resulting in insulin gene transcription and production to replenish the insulin-containing vesicles and maintain continuous insulin secretion.

Chapter 12

Figure 12.1

Mechanisms of nutrient stimulus–secretion coupling in the pancreatic β cell. Source: Newsholme et al. 2014 [14].

Figure 12.2

First- and second-phase plasma insulin response during hyperglycemic clamp in healthy individuals. Plasma glucose is acutely raised +125 mg/dL above baseline and maintained for the ensuing 2 h. Plasma insulin concentration is measured at regular intervals. Source: DeFronzo et al. 1979 [7]. Reproduced with permission of the American Physiological Society.

Figure 12.3

T2DM and glycemic trait-associated variants. The variants are represented by gene names here, which could indicate that the location is present either in the gene or in the vicinity of the gene. The white circle represents T2DM and the gene names in black in that circle represent variants only associated with T2DM. The overlapping circles indicate additional reporting associations for that variant. Source: Prasad and Groop 2015 [26] (this is an open-access article distributed under the Creative Commons Attribution License [CC BY]).

Figure 12.4

Associations between the genotypes of rs7903146 polymorphism in the


gene with insulin secretion during a hyperglycemic clamp in 73 participants. Black lines, CC; red lines, CT and TT. AIR, acute insulin response. Arrow, administration of 5 g of arginine. The


values show the differences for the first- and second-phases of glucose-induced insulin secretion, first- and second-phases of GLP-1-induced insulin secretion, and acute insulin secretory response to arginine (AIR). Source: Schäfer et al. 2007 [31]. Reproduced with permission of Springer.

Figure 12.5

Relationship between the insulin secretion/insulin resistance index (ΔI/ΔG factored by the severity of insulin resistance measured with the euglycemic insulin clamp) and (a) the fasting plasma glucose (FPG) and (b) the 2-h plasma glucose (2-h PG) concentration (log–log scale). Source: Gastaldelli et al. 2004 [53], Figure 4. Reproduced with permission of Springer.

Figure 12.6

(a, b) Electron microscopy images showing the ER in (a) non-diabetic β cells and (b) T2DM β cells. The ER components (arrows) are scarcely visible in non-diabetic cells and more apparent in T2DM cells. Magnification ×10,000. IG, insulin granules; M, mitochondria; N, nucleus. (c) The ER density volume was significantly higher inT2DM β cells (red box) than non-diabetic β cells (yellow box).



<0.05 (Student's


-test for unpaired data). Source: Marchetti et al. 2007 [105], Figure 3. Reproduced with permission of Springer.

Figure 12.7

Mechanisms of β-cell damage in T2DM. Environmental factors and genetic backgrounds interact to activate stress processes that contribute to functional abnormalities and also progressive loss/dedifferentiation of β cells. Source: Adapted from Halban et al. 2014 [135].

Figure 12.8

β-Cell mass in the pancreas of people without (left) and with T2DM (right). Data are presented for individual values as scatterplots and mean values ± SD as columns. Although on average the β-cell mass is about 40% less in people with T2DM, there is some degree of overlap between the two groups. Source: Rahier et al. 2008 [138], Figure 2B. Reproduced with permission of John Wiley & Sons.

Figure 12.9

Insulin secretion rates (ISRs) during the hyperglycemic clamp studies related to the prevailing severity of insulin resistance (ISR


). On comparing control participants with healthy participants with a strong family history of T2DM (FH+), the first-phase ISR


is similar during the saline studies; with lipid infusion, the first-phase ISR


deteriorates in FH+ participants, whereas it increases in control participants. The second-phase ISR


is also reduced by lipid infusion in the FH+ group but is unchanged in healthy control.



<0.01 vs. saline; †


<0.05 vs. saline; ‡


<0.001 vs. control participants; ¶


<0.05 vs. control participants. Source: Adapted from Kashyap et al. 2003 [141].

Chapter 13

Figure 13.1

Basal and insulin-stimulated muscle and liver metabolism. In skeletal muscle (top left), insulin-stimulated glucose disposal is reduced in insulin-resistant non-obese elderly individuals and in those with type 2 diabetes mellitus (T2DM) compared with insulin-sensitive, lean, young individuals without diabetes. Both basal and insulin-stimulated ATP synthase flux show similar patterns (top middle), whereas intracellular triacylglycerols (TAGs) are frequently higher in insulin resistant persons (top right). In the liver, insulin-mediated suppression of glucose production is reduced in the insulin-resistant individuals (bottom left). ATP synthase flux is also lower only in persons with T2DM (bottom middle), whereas intracellular TAGs are markedly increased (bottom right). Source: data from Schmid et al. 2011 [138] and Szendroedi et al. 2007 [58] and 2009 [138].

Figure 13.2

Cellular mechanism of insulin resistance in human skeletal muscle. Augmented lipid availability, mainly increased fatty acid flux, raises the intramyocellular pool of the long-chain fatty acyl (CoA) pool, which fuels mitochondrial oxidation or serves to synthesize diacylglycerols (DAGs) for storage as triglyceride (TAG) lipid droplets. When fatty acid delivery and uptake exceed the rates of mitochondrial long-chain fatty acyl-CoA oxidation and incorporation of DAGs into TAGs, the intramyocellular DAG content transiently or chronically increases. Specific, mainly C


-containing, DAGs in the membrane and cytosol promote the activate novel protein kinase C (nPKC) isoforms. Translocation of the PKCθ isoform to the membrane leads to increased serine phosphorylation of insulin receptor substrate 1 (IRS-1) on critical sites (e.g. Ser 1101), which in turn blocks insulin-stimulated tyrosine phosphorylation of IRS-1 and the binding and activation of phosphatidylinositol 3-kinase (PI3K). This results in reduced recruitment of glucose transporter type 4 (GLUT-4) units to the membrane with impaired insulin-stimulated glucose uptake and phosphorylation to glucose-6-phosphate (G-6-P) and ultimately decreased insulin-stimulated glycogen synthesis. Source: Shulman 2014 [51]. Copyright © 2014 Massachusetts Medical Society. Reprinted with permission.

Figure 13.3

Cellular mechanism of insulin resistance in human liver. An imbalance of intrahepatocellular fluxes gives rise to hepatocellular diacylglyerols (DAGs), particularly when DAG synthesis, from both fatty acid re-esterification and

de novo

lipogenesis, exceeds the rates of mitochondrial oxidation of long-chain fatty acyl-coenzyme A (CoA) and/or the rates of DAG incorporation as triglycerides (TAGs) into lipid droplets. This activates the epsilon isoform of protein kinase C (PKCϵ), which likely phosphorylates the insulin receptor tyrosine kinase. In turn, phosphorylation of glycogen synthase kinase 3 (GSK3) phosphorylation increases, while that of forkhead box subgroup O (FOXO) decreases. This results in inhibition of glycogen synthase activity and thereby lower insulin-stimulated glycogen storage and in FOXO-mediated gene transcription of the gluconeogenic enzymes (e.g. phosphoenolpyruvate carboxykinase [PEP-CK] and G6P), with decreased insulin suppression of hepatic gluconeogenesis. Source: Shulman 2014 [51]. Copyright © 2014 Massachusetts Medical Society. Reprinted with permission.

Figure 13.4

Hypothesis of adaptation of hepatic energy metabolism in the pathogenesis of non-alcoholic fatty liver disease and progression of hepatic insulin resistance. (a) In states of obesity, increased fatty acid delivery upregulates hepatic mitochondrial oxidative capacity, which prevents excessive storage of triacylglycerols (TAGs) but promotes the accumulation of reactive oxygen species and lipid peroxides, which are scavenged by hepatic catalase activity. (b) During the development of non-alcoholic fatty liver disease (NAFLD), the efficiency of mitochondrial coupling fails, which accelerates the generation of hydrogen peroxide (H




) in the face of decreasing catalase activity. Finally, oxidative stress decreases mitochondrial biogenesis, but increases leakage of mitochondria and activates c-Jun N-terminal kinase (JNK), which drives cellular inflammation and progression to steatohepatitis (NASH). Source: Koliaki et al. 2015 [144]. Copyright 2015 Elsevier.

Figure 13.5

Hypothesis of macrophage-induced lipolysis in the pathogenesis of fasting hyperglycemia and insulin resistance. During the development of obesity, macrophage infiltration of white adipose tissue results in increased lipolysis by release of macrophage-derived cytokines such as interleukin-6. Increased rates of lipolysis lead to accelerated rates of hepatic gluconeogenesis by two mechanisms. (a) First, increased fatty acid delivery to the liver gives rise to hepatic acetyl-CoA levels, when its production through fat oxidation exceeds its rates of oxidation in the TCA cycle. This leads to increased pyruvate carboxylase activity. (b) Second, increased delivery of glycerol promotes its conversion to dihydroxyacetone (glyceraldehyde) 3-phosphate, which serves as precursor of glucose. Source: Shulman 2014 [51]. Copyright © 2014 Massachusetts Medical Society. Reprinted with permission.

Figure 13.6

Concept of the stepwise development of insulin resistance from skeletal muscle to atherogenic dyslipidemia and non-alcoholic fatty liver disease. In healthy, young, lean persons, selective insulin resistance in skeletal muscle results in diversion of ingested carbohydrates from muscle glycogen synthesis to the liver. Combined with compensatory hyperinsulinemia, this stimulates hepatic de novo lipogenesis, synthesis of triglycerides and secretion of very low-density lipoproteins (VLDL) resulting in hypertriglyceridemia and reduced plasma high-density lipoprotein (HDL) levels. Of note, even one bout of exercising is able to restore the abnormal pattern of energy storage after carbohydrate ingestion by stimulating glucose uptake and glycogen synthesis in muscle through insulin-independent adenosine 5′-monophosphate-activated protein kinase (AMPK) activation of glucose transporter 5 (GLUT-4) recruitment. Source: Shulman 2014 [51]. Copyright © 2014 Massachusetts Medical Society. Reprinted with permission.

Chapter 14

Figure 14.1

The spectrum of diabetes subgroups. The data are from the ANDIS project (All New Diabetics in Scania) (http://andis.ludc.med.lu.se) in April 2012, which at that time included 5800 individuals aged 0–100 years with newly diagnosed diabetes. The criteria used for diagnosis are as follows. T1DM: age at onset <35 years, C-peptide <0.2 nmol/L, and GAD antibodies >20; T1DM with relative insulin deficiency if C-peptide 0.2–0.6 nmol/L. T2DM: age at onset >35 years, C-peptide >0.6 nmol/L, GAD antibodies <10; T2DM with relative insulin deficiency C-peptide 0.2–0.6 nmol/L. LADA: age at onset >35 years, GAD antibodies >20; LADA light if GAD antibodies 10–20. The data clearly illustrate the difficulty in classifying persons with diabetes at diagnosis, with 19% unclassifiable. Source: Prasad RB, Groop L. Genetics of type 2 diabetes—Pitfalls and possibilities.




:87–123 (this is an open-access article distributed under the Creative Commons Attribution License [CC BY]).

Figure 14.2

T2DM risk variants. The


-axis shows the chromosomal location, the


-axis shows the effect sizes, and the


-axis shows the year of discovery. One risk variant was reported in 1998, two in 2002, to a total of 153 T2DM variants that we have today. Source: Prasad RB, Groop L. Genetics of type 2 diabetes—Pitfalls and possibilities.




:87–123 (this is an open-access article distributed under the Creative Commons Attribution License [CC BY]).

Figure 14.3

T2DM and glycemic trait-associated variants. The variants are represented by gene names here, which could indicate that the location is present either in the gene or in the vicinity of the gene. The black circle represents T2DM, and the gene names in black in this represent variants associated only with T2DM. The overlapping circles indicate additional reporting associations for that variant; for instance,






, etc., are associated with T2DM and also with β-cell dysfunction. An ADCY5 variant is associated with 2-h insulin adjusted for 2-h glucose, 2-h glucose/T2DM (in brown) ***Variants in TMEM163 are also associated with fasting insulin,


, associated with fasting and 2-h glucose, and


variants, associated with fasting proinsulin, fasting glucose and HOMA-B. Source: Prasad RB, Groop L. Genetics of type 2 diabetes—Pitfalls and possibilities.




:87–123 (this is an open-access article distributed under the Creative Commons Attribution License [CC BY]).

Chapter 15

Figure 15.1

Insulin dose–response curves for glucose production and utilization in individuals without diabetes. Source: Adapted from Vella A.




:1410–1415. Reproduced with permission from Springer-Verlag.

Figure 15.2

In an experiment in otherwise healthy volunteers, a non-diabetic postprandial insulin profile coupled with postprandial glucagon suppression results in a normal postprandial glucose profile (a). In the same individuals, absent postprandial glucagon suppression in the presence of a non-diabetic postprandial insulin profile resulted in a minimal increase in postprandial glucose (b). On the other hand, a diabetic insulin profile produced glucose intolerance (c), which was markedly worsened by the absence of postprandial glucagon suppression (d).

Chapter 16

Figure 16.1

Contribution of five body mass index (BMI) categories to the overall prevalence of diabetes. National Health and Nutrition Examination Survey (NHANES) samples of 1976–1980 and 1999–2004 were compared. Source: Gregg et al. 2007 [7]. Copyright 2007 Elsevier.

Figure 16.2

Hyperbolic relation between β-cell function and insulin sensitivity. IGT, impaired glucose tolerance; NGT, normal glucose tolerance; T2DM, type 2 diabetes mellitus. Source: Stumvoll M, et al. Type 2 diabetes: Principles of pathogenesis and therapy.




:1333–1346. Copyright 2005 Elsevier.

Figure 16.3

Secretory products from adipose tissue and functional relationship. SNS: sympathetic nervous system. Source: Lafontan M. Fat cells: Afferent and efferent messages define new approaches to treat obesity.

Annu Rev Pharmacol Toxicol



:119–146. Reproduced with permission from Annual Reviews.

Figure 16.4

Potential cellular mechanisms for inflammation and development of insulin resistance. AP-1, activator protein 1; ER, endoplasmic reticulum; IKK, Iκ kinase; IL, interleukin; IRS, insulin receptor substrate; JNK, c-Jun N-terminal kinase; NF-κB, nuclear transcription factor κB; PKC, protein kinase C; ROS, reactive oxygen species; TLR, toll-like receptor; TNFR, tumor necrosis factor receptor; TZD, thiazolidinedione. Source: Shoelson and Lee 2006 [55]. Reproduced with permission from the American Society for Clinical Investigation.

Figure 16.5

Nutrition and obesity-induced inflammation and development of systemic insulin resistance. Source: De Luca C, Olefsky JM. Stressed out about obesity and insulin resistance.

Nat Med



:41–42. Reproduced with permission from Nature Publishing Group.

Chapter 17

Figure 17.1

A synergistic relationship between the intestinal microbiome and host provides a number of benefits, including (1) competitive exclusion of pathogenic strains, (2) energy harvest, (3) promotion of barrier integrity, and (4) immune education. Source: Modified from Cox et al. 2014 [11]. Copyright 2014 Elsevier.

Figure 17.2

Components of the intestinal microbiota (namely lipopolysaccharide, LPS) have the potential to activate innate immune pathways. Cross-talk between TLR4 and insulin signaling pathways provide a mechanism linking the intestinal microbiota to insulin resistance.

Figure 17.3

Short-chain fatty acids (SCFAs) are produced during microbial fermentation of non-digestible dietary starches. SCFA signaling via G protein-coupled receptors (GPRs) can regulate incretin signaling, namely glucagon-like peptide 1 (GLP-1) and polypeptide YY (PYY), with downstream effects on glycemic control.

Figure 17.4

The intestinal microbiome influences the composition of the bile acid pool and metabolites. Bile acid signaling through the farnesoid X receptor (FXR) and the G protein-coupled receptor TRG5 pathways can effect transcriptional regulation of various metabolic pathways. Regulation of other signaling pathways can also contribute to alterations in glycemic control.

Chapter 18

Figure 18.1

Clinical subtypes of monogenic β-cell diabetes. To convert plasma glucose measurements to mg/dL multiply by 18. ABCC8, ATP binding cassette subfamily C;


, glucokinase gene; HNF, hepatocyte nuclear factor;


, potassium inwardly rectifying channel, subfamily J, member 11 gene; OGTT, oral glucose tolerance test.

Figure 18.2