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.
Ebooka przeczytasz w aplikacjach Legimi na:
Liczba stron: 3965
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.
RICHARD I.G. HOLT MA, MB BChir, PhD, FRCP, FHEA
Professor in Diabetes & Endocrinology Human Development and Health Academic Unit University of Southampton Faculty of Medicine Southampton, UK
CLIVE S. COCKRAM MBBS, BSc, MD (Lond), FRCP, FRACP, FHKAM (Med)
Emeritus Professor of Medicine Chinese University of Hong Kong Hong Kong SAR People’s Republic of China
ALLAN FLYVBJERG MD, DMSc
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
BARRY J. GOLDSTEIN MD, PhD, FACP, FACE
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
Previous editions: 1991, 1997, 2003, 2010
Registered office: John Wiley & Sons, Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK
Editorial offices: 9600 Garsington Road, Oxford, OX4 2DQ, UK The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 111 River Street, Hoboken, NJ 07030-5774, USA
For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com/wiley-blackwell
The right of the author to be identified as the author of this work has been asserted in accordance with the UK Copyright, Designs and Patents Act 1988.
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher.
Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought.
The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by health science practitioners for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom.
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
The 17th and 18th centuries
The 19th century
The 20th century
Causes and natural history of diabetes
Chronic diabetic complications
Management of diabetes
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
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
IRS-proteins coordinate insulin and insulin-like growth factor signaling
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?
Medications and toxins
Neuroendocrine and behavioral regulation of energy homeostasis and the gut microbiome
Part 3 Pathogenesis of Diabetes
10 Autoimmune Type 1 Diabetes
11 Other Disorders with Type 1 Phenotype
Atypical diabetes: heterogeneous etiologies of young-onset 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
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
Little common genetic basis for T1DM and T2DM
A holistic view – systems genetics
15 Metabolic Disturbances in Diabetes
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
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 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 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
(transcription factor MODY)
Other transcription factor MODY
Neonatal diabetes and diabetes diagnosed within 6 months of life
Diabetes with extrapancreatic features
Insulin receptor gene mutations
Other monogenic conditions associated with insulin resistance
19 Drug-Induced Diabetes
Oral contraceptive agents
Menopause hormone therapy
HMG CoA reductase inhibitors
Anti-retroviral therapy for human immunodeficiency virus (HIV)
Prevention and treatment strategies
20 Endocrine Disorders that Cause Diabetes
Pheochromocytoma and paraganglioma
Other endocrine conditions causing disturbance of glucose tolerance
Endocrine disorders that associate with diabetes
21 Pancreatic Diseases and Diabetes
Tropical chronic pancreatitis
Pancreatic surgery and diabetes
Part 5 Managing the Patient with Diabetes
22 Clinical Presentations of Diabetes
Clinical considerations at presentation
Types of diabetes
Thirst, polydipsia, and polyuria
Hyperosmolar hyperglycemic syndrome
23 The Aims of Diabetes Care
St. Vincent's Declaration
The diabetes care team
Improving the outcome of the consultation
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
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
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
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
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
31 Oral Glucose-Lowering Agents
Guidelines and algorithms
Meglitinides (short-acting prandial insulin releasers)
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
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
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
TNF-related apoptosis-inducing ligand and osteoprotegerin
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
How can cardiovascular risk be reduced in persons with diabetes?
45 Congestive Heart Failure
Symptoms and diagnosis
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
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
51 Diabetes and Non-Alcoholic Fatty Liver Disease
Definition and epidemiology
NAFLD and the metabolic syndrome
NAFLD and diabetes
Why does NASH occur?
Extrahepatic-associations of NAFLD
Natural history of NAFLD
Diagnosis and assessment
52 The Skin in Diabetes
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
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
58 Social Aspects of Diabetes
Prison and custody
Part 11 Diabetes in Special Groups
59 Diabetes in Childhood
Spectrum of diabetes in children
Manifestation, diagnosis, and initial treatment
Pediatric ambulatory diabetes care
Monitoring and goals of diabetes management
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
Changes in family involvement
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
Labor and delivery
62 Diabetes in Old Age
Diabetes phenotype in old age
Special considerations in old age
Management of Diabetes
63 Diabetes at the End of Life
Dying with diabetes
End of life
The management of diabetes at the end of life
Medicines management during the last year of life
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
Continuity, access, coordination, and teamwork
A family and community orientation
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
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
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
Early human studies
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
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
The Ebers papyrus.
(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.
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 .
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.”
Claude Bernard (1813–1878).
Oskar Minkowski (1858–1931).
Paul Langerhans (1847–1888).
Jaeger's Atlas of the Optic Fundus
, 1869 . 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.
Elliott P. Joslin (1869–1962), arguably the most famous diabetes specialist of the 20th century and the frontispiece to his 1916 textbook .
(a) Georg Zuelzer (1840–1949) and (b) the title page from his paper (1907) reporting that a pancreatic extract reduced glycosuria in pancreatectomized dogs  (top). (c) Nicolas Paulesco (1869–1931).
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).
Leonard Thompson, the first person to receive insulin, in January 1922.
Nodular glomerulosclerosis. Figure from the paper by Kimmelstiel and Wilson, 1936 .
Knud Lundbæk (1912–1995).
Frederick Sanger (1918–2013) and Dorothy Hodgkin, née Crowfoot (1910–1994).
Solomon Berson and Rosalyn Yalow.
Hans Christian Hagedorn (1888–1971) from the Hagedorn Medal.
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.
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.
Ernesto Roma (1887–1978) and (right) Robin D. Lawrence (1892–1968).
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 . Reproduced with permission of Springer.
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 . Reproduced with permission of John Wiley & Sons.
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 , Harjutsalo et al. 2008 , Harjutsalo et al. 2013 , Hussen et al. 2013 , Joner & Søvik 1989 , Skrivarhaug 2014 , and Ehehalt et al. 2012 . 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.
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  and Harron et al. 2011 . 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.
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 . Reproduced with permission of Springer.
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 . Reproduced with permission of Springer.
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 . 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.
Risk factors in the development of T2DM. HDL, high-density lipoprotein cholesterol; PCOS, polycystic ovarian syndrome; TG, triglycerides.
Diabetes epidemiological model. Factors directly affecting the prevalence of diabetes included in the present analysis. Source: Adapted from Colagiuri et al. 2005 
Global prevalence of diabetes. Source: Adapted from
IDF Diabetes Atlas
, International Diabetes Federation 2015 , Chapter 3, Map 3.1.
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 ).
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.
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.
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.
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.
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.
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.
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.
Glucose-induced insulin release
. 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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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
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.
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 (•).
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 .
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].
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.
Schematic presentation of the early natural history of T1DM divided into three different disease stages.
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 .
Putative genetic factors and proposed function for non-HLA type 1 diabetes genes determined by the Type 1 Diabetes Genetics Consortium.
Probability of progression to symptomatic T1DM in relation to number of β-cell autoantibodies analyzed from birth. Source: Data from .
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.
(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 . (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.
Mechanisms of nutrient stimulus–secretion coupling in the pancreatic β cell. Source: Newsholme et al. 2014 .
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 . Reproduced with permission of the American Physiological Society.
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  (this is an open-access article distributed under the Creative Commons Attribution License [CC BY]).
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 . Reproduced with permission of Springer.
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 , Figure 4. Reproduced with permission of Springer.
(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).
-test for unpaired data). Source: Marchetti et al. 2007 , Figure 3. Reproduced with permission of Springer.
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 .
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 , Figure 2B. Reproduced with permission of John Wiley & Sons.
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 .
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  and Szendroedi et al. 2007  and 2009 .
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 . Copyright © 2014 Massachusetts Medical Society. Reprinted with permission.
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
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 . Copyright © 2014 Massachusetts Medical Society. Reprinted with permission.
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 . Copyright 2015 Elsevier.
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 . Copyright © 2014 Massachusetts Medical Society. Reprinted with permission.
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 . Copyright © 2014 Massachusetts Medical Society. Reprinted with permission.
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]).
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]).
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]).
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.
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).
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 . Copyright 2007 Elsevier.
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.
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.
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 . Reproduced with permission from the American Society for Clinical Investigation.
Nutrition and obesity-induced inflammation and development of systemic insulin resistance. Source: De Luca C, Olefsky JM. Stressed out about obesity and insulin resistance.
:41–42. Reproduced with permission from Nature Publishing Group.
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 . Copyright 2014 Elsevier.
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.
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.
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.
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.
Tysiące ebooków i audiobooków
Ich liczba ciągle rośnie, a Ty masz gwarancję niezmiennej ceny.
Napisali o nas:
Nowy sposób na e-księgarnię
Czytelnicy nie wierzą
Legimi idzie na całość
Projekt Legimi wielkim wydarzeniem
Spotify for ebooks