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CLINICIAN’S DESK REFERENCE

Diabetes R David Leslie MD, FRCP

Professor of Diabetes and Autoimmunity and Consultant Physician, St. Bartholomew’s and Royal London Hospitals, and the Blizard Institute, University of London

M Cecilia Lansang MD, MPH Co-chair, Diabetes Care Committee, Cleveland Clinic, Cleveland, Ohio

Simon Coppack MD, FRCP Consultant and Reader in Diabetes and Metabolism, St. Bartholomew’s and Royal London Hospitals, and the Blizard Institute, University of London

Laurence Kennedy MD, FRCP Chairman, Department of Endocrinology, Diabetes, and Metabolism, Cleveland Clinic, Cleveland, Ohio

MANSON PUBLISHING

www.cambodiamed.blogspot.com | Best Medical Books | Chy Yong

Copyright © 2012 Manson Publishing Ltd ISBN: 978-1-84076-158-0 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 without the written permission of the copyright holder or in accordance with the provisions of the Copyright Act 1956 (as amended), or under the terms of any license permitting limited copying issued by the Copyright Licensing Agency, 33–34 Alfred Place, London WC1E 7DP, UK. Any person who does any unauthorized act in relation to this publication may be liable to criminal prosecution and civil claims for damages. A CIP catalogue record for this book is available from the British Library. For full details of all Manson Publishing titles please write to: Manson Publishing Ltd, 73 Corringham Road, London NW11 7DL, UK. Tel: +44(0)20 8905 5150 Fax: +44(0)20 8201 9233 Website: www.mansonpublishing.com Commissioning editor: Jill Northcott Project manager: Ayala Kingsley Copy editor: Joanna Brocklesby Book and diagram design: Ayala Kingsley Proof reader: John Forder Indexer: Jill Dormon Color reproduction: Tenon & Polert Colour Scanning Ltd, Hong Kong Printed by: Butler Tanner & Dennis Ltd, Frome, Somerset, UK

Contents Preface 7 Acknowledgments 7 Abbreviations 8 CHAPTER 1

The nature of diabetes 11 What is diabetes? 11 Overview 11 Epidemiology 12 Definitions and classification 13 Forms of diabetes 17 Type 1 diabetes 17 Type 2 diabetes 17 Maturity onset diabetes of the young (MODY) 17 Gestational diabetes mellitus (GDM) 18 Neonatal diabetes 19 Secondary diabetes 19 Clinical presentations of diabetes 19 Complications of diabetes 20 Macrovascular complications 20 Microsvascular complications 20 Acute metabolic complications 20 Infections 21 Disorders of the joints, ligaments, and skin 22 The cost of diabetes 23 CHAPTER 2

Glucose, insulin, and diabetes 25 The role of glucose 25 Glucose levels and diabetes 26 Normal glucose metabolism 27 Glucose transporters 28 The role of insulin 30 The structure of insulin 31 Normal insulin secretion and kinetics 32 The insulin receptor 33 The actions of insulin 34 Second messenger systems 36 Insulin-like growth factors (IGFs) 36 Abnormalities of insulin synthesis and secretion 36

CHAPTER 3

Type 1 diabetes 37 Epidemiology 37 Causes of type 1 diabetes 38 Prediction of type 1 diabetes 40 Genetic factors 40 Nongenetic factors 42 Development of type 1 diabetes 42 Pancreatic β-cell dysfunction 42 Insulin resistance 43 Mortality 43 Screening for potential type 1 diabetes 44 CHAPTER 4

Type 2 diabetes 45 Epidemiology 45 Causes of type 2 diabetes 46 Environmental risk factors 46 Genetic factors 47 Associated conditions 48 Hyperinsulinemia and hyperglycemia 49 Hypertension 49 Abnormalities of lipid metabolism 50 The metabolic syndrome and obesity 50 Development of type 2 diabetes 52 Glucoregulatory defects in type 2 diabetes 52 Pancreatic β-cell deficiency 52 Insulin resistance 53 The role of amylin 54 Glucotoxicity and lipotoxicity 54 Glucotoxicity 54 Lipotoxicity 55 Screening and prevention 56 Type 2 diabetes prevention studies 57

4 CHAPTER 5

Diabetes screening and patient care 59 Management overview 59 Risk factors 59 Annual examination 60 Screening for complications 60 Eyes 60 Kidneys 61 Feet 61 Erectile dysfunction 61 Vascular disease 61 Treating children 62 Types of childhood diabetes 62 Management of young patients 63 The elderly diabetes patient 65 Management of elderly patients 65 Control of hypoglycemia 66 Ethnic minorities 67 Patient education and community care 68 Living with diabetes 69 Employment 69 Finance 69 Sport 69 Holidays and travel 70 Driving 70 CHAPTER 6

Diabetes and vascular disease 73 Macrovascular disease 73 Pathogenesis of macrovascular complications 74 Treatment and management principles for macrovascular disease 75 General principles 75 Glucose control 75 Lipid-lowering drugs 76 Revascularization procedures 76 Pathogenesis of microvascular complications 77 Hyperglycemia 78 High intracellular glucose 79 Advanced glycation endproducts 79 Reactive oxygen species 80 Sorbitol accumulation 80 Activation of protein kinase C-beta 80 Hemodynamic changes 80 Treatment and management principles for microvascular disease 81

Reducing the risk of vascular disease 81 Obesity and sedentary lifestyle 82 Hypertension 82 Dyslipidemia 84 Smoking 85 Hyperglycemia 85 Antithrombotic agents 86 CHAPTER 7

Diabetic neuropathy 87 Prevalence and classification 87 Diagnosis 88 Chronic sensory polyneuropathy 89 Acute sensory neuropathy 90 Acute motor neuropathy 92 Autonomic neuropathy 92 Cardiovascular system 92 Gastrointestinal tract 93 Bladder involvement 93 Erectile dysfunction 93 Neuroendocrine disturbances 93 Sudomotor dysfunction 93 Pupillary effects 93 Treatment and management 94 Acute sensory neuropathies 94 Focal sensory mononeuropathies 94 Acute motor neuropathies 94 Autonomic neuropathy 94 CHAPTER 8

The diabetic foot 97 Overview 97 Pathophysiology and risk factors 97 Neuropathy 97 Peripheral arterial disease 98 Infection 98 Pressure 98 Clinical presentation and evaluation 98 Evaluation 98 Examination 99 Treatment and management 100 Infection 101 Peripheral arterial disease 101 High plantar pressure 102 Deformities 102 The wound environment 102 Surgery 102 Charcot’s arthropathy 103

5 CHAPTER 9

Diabetic eye disease 105 Overview 105 Natural history 105 Nonproliferative diabetic retinopathy 106 Proliferative diabetic retinopathy 108 Diabetic maculopathy 108 Cataracts 109 Glaucoma 109 Ocular nerve palsies 109 Treatment and management 109 Diabetic maculopathy 110 Cataracts 110 Glaucoma 110 CHAPTER 10

Diabetic kidney disease 111 Overview 111 Natural history 111 Stage 1: Functional changes 112 Stage 2: Structural changes 112 Stage 3: Microalbuminuria 112 Stage 4: Overt clinical nephropathy 113 Stage 5: End-stage renal disease 113 Diagnosis of nephropathy 114 Urinary tract infections 114 Treatment and management 114 General therapy 115 Blood glucose 116 Blood pressure 116 Lipids 117 Smoking 117 Protein restriction 117 Renal replacement therapy 118 Continuous ambulatory peritoneal dialysis 118 Hemodialysis 118 Transplantation 119 Pancreas transplant or islet cell implantation 119 CHAPTER 11

Severe diabetic metabolic disturbances 121 Diabetic ketoacidosis 121 Pathogenesis 122 Clinical features 124 Investigations 124 Acute managment 125 Subsequent management 127

Hyperosmolar nonketotic hyperglycemia 128 Clinical features 129 Investigations 129 Complications 129 Treatment 130 Prognosis 130 Brittle diabetes mellitus 130 Recurrent ketoacidosis 130 Lactic acidosis 130 CHAPTER 12

Long-term management of hyperglycemia 131 Overview 131 Targets of treatment 132 Dietary management 132 Calorie intake 133 Carbohydrates 134 Fats 134 Prescribing a diet 135 Exercise 136 Bariatric surgery 138 CHAPTER 13

Noninsulin therapies 139 Tablet treatment for type 2 diabetes 139 Metformin 141 Side-effects 142 Insulin secretagogues: sulfonylureas 143 Drug interactions and side-effects 144 Sulfonylureas and heart disease 145 Other oral insulin secretagogues 145 Side-effects 145 Thiazolidinediones 146 Side-effects 147 TZDs and cardiovascular disease 148 Apha-glucosidase inhibitors 148 Side-effects 148 GLP-1 analogues 149 Side-effects 151 Dipeptidyl peptidase-4 inhibitors 152 Side-effects 153 Other recent developments 153 Colesevelam 153 Bromocriptine 154 Pramlintide 154 Drugs on the horizon 154 Sodium–glucose cotransporter 2 (SGLT2) inhibitors 154

6

CHAPTER 14

CHAPTER 15

Insulin treatment 155

Special management considerations 173

Overview 155 Therapeutic insulin 155 Regular (or soluble) insulin 155 Rapid-acting insulin analogs 155 Insulins with prolonged action 156 Alternative insulin delivery systems 157 Indications for insulin treatment 158 Insulin regimen: type 1 diabetes 159 Continuous subcutaneous insulin infusion: insulin pump treatment 160 Implantable glucose monitors 163 Insulin regimen: type 2 diabetes 163 General considerations 163 Basal insulin 165 Mealtime insulin 166 Premixed insulin 167 Metabolic instability on insulin 167 Complications: hypoglycemia 168 Hypoglycemic unawareness 170 Nocturnal hypoglycemia 170 Recurrent severe hypoglycemia 170 Treating hypoglycemia 171 Mild hypoglycemia 171 Severe hypoglycemia 171 Preventing hypoglycemia 172 Other complications or adverse effects from insulin treatment 172

The diabetic inpatient 173 Diabetes and surgery 174 Major surgery 175 Minor surgery 176 Surgery and blood pressure 176 Conception, contraception, and pregnancy 176 Contraception and diabetes 178 Glucose monitoring and glycemic goals in pregnancy 178 Type 1 diabetes patients 180 Type 2 diabetes patients 181 Risks to the diabetic mother 182 Gestational diabetes mellitus (GDM) 183 Labor and delivery 184 Neonatal problems 184

Further reading 187 Resources 191 Glossary 193 Index 201

7

Preface THE AIM OF THIS BOOK is to provide clinicians and other health professionals with an easily readable and clinically applicable text on diabetes. The joint European and American authorship indicates the widespread international agreement on the best way to manage diabetes, both in terms of limiting the disease risk and of treating complications once they develop. The book integrates the physiology and anatomy of the disease with clinical and laboratory analysis. Summaries of key clinical trials emphasize the knowledge base underlying the practical recommendations. A range of treatment options is provided, reflecting the need for customized treatment strategies. The authors have sought to provide a clear and concise guide to the optimal treatment approach. The text is intended for clinicians with an interest in diabetes at all levels, including primary-care physicians, medical students, nurse specialists, physician assistants, diabetes educators, and those in postgraduate training. R DAVID LESLIE M CECILIA LANSANG SIMON COPPACK LAURENCE KENNEDY

Acknowledgments Drs. Leslie, Coppack, and Kennedy would especially like to acknowledge the major role of their co-author, Dr. Lansang, in reviewing and updating the text during the gestation of this book. We would all like to thank Professor David Hadden, Belfast, Northern Ireland, and Professor David Bell, Birmingham, Alabama, for providing constructive criticism and comments while we were preparing the text, and specifically acknowledge the valuable input of Professor Hadden concerning the most up-to-date views on diabetes and pregnancy.

We also thank Dr. Ernesto Lopez, Dr. Frida Djukiadmodjo, Dr. Lily Ho-Le, Dr. Serena Chiu, and Dr. Lina Paschou for their help in preparing and editing the text and figures. In addition, the authors would like to thank Dr Michael Tolentino and Dr. Rishi Singh for supplying the retinal photos.

8

Abbreviations

AACE ABX ACEI acyl-CoA ADA ADP AGE AGI ALLHAT AMPK ARB ATP AUC BARI

American Association of Clinical Endocrinologists abciximab angiotensin-converting enzyme inhibitor acyl-coenzyme-A American Diabetes Association adenosine diphosphate advanced glycation endproducts a-glucosidase inhibitor Anti-Hypertensive and Lipid-Lowering Treatment to Prevent Heart Attacks Trials AMP-activated protein kinase angiotensin-receptor blocker adenosine triphosphate area under the curve

BMI BP BUN

Bypass Angioplasty Revascularization Investigation (trial) Bergamo Nephrologic Diabetes Complications Trial body mass index blood pressure blood urea nitrogen

C4 CABG CAD cAMP CAPD CARDS CARE CHF CK-MB CNS CRP CSF CSII CT CVD

complement 4 coronary artery bypass grafting coronary artery disease cyclic adenosine monophosphate continuous ambulatory peritoneal dialysis Collaborative Atorvastatin Diabetes Study Cholesterol and Recurrent Events (trial) congestive heart failure creatine kinase, muscle–brain type central nervous system C-reactive protein cerebrospinal fluid continuous subcutaneous insulin infusion computed tomography cardiovascular disease

BENEDICT

DAN DNA DCCT DIGAMI DKA DPP DPP DREAM

DSME DVLA EASD ECD ECG ED50 eGFR EGIR eNOS EPIC

EPILOG

EPISTENT ESR ESRD ETDRS FDA FEV1 FFA FIELD FPG FSH FTO

diabetic autonomic neuropathy deoxyribonucleic acid Diabetes Control and Complications Trial Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (study) diabetic ketoacidosis Diabetes Prevention Program dipeptidyl peptidase Diabetes REduction Assessment with ramipril and rosiglitazone Medication (trial) diabetes self-management education Driver and Vehicle Licensing Agency European Association for the Study of Diabetes expanded criteria donor electrocardiogram effective dose of insulin that produces 50% of maximal effect estimated glomerular filtration rate European Group for the Study of Insulin Resistance endothelial nitric oxide synthase Evaluation of Platelet IIb/IIIa Inhibition for Prevention of Ischemic Complications (trial) Evaluation of PTCA to Improve Long-term Outcome by c7E3 GP IIb/IIIa Receptor Blockade (trial) Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (trial) erythrocyte sedimentation rate end-stage renal disease Early Treatment Diabetic Retinopathy Study Food and Drug Administration forced expiratory volume in 1 second free fatty acids Fenofibrate Intervention and Event Lowering in Diabetes (study) fasting plasma glucose follicle-stimulating hormone fused-toe gene

9 GAD GADA GBM GDM GFAT GFR GIP GIR GLP GLUT HAPO HbA1c HDL HGO HLA H/Ma HNF HONK HOT HHS IAA IA-2 IADPSG IAPP IDF IDNT IFCC IFG IGF IgG IGT IPF-1 IR IRMA IRMA-2

glutamic acid decarboxylase glutamic acid decarboxylase antibody glomerular basement membrane Gestational diabetes mellitus glutamine:fructose-6 phosphate amidotransferase glomerular filtration rate glucose-dependent insulinotrophic peptide glucose infusion rate glucagon-like peptide glucose transporter protein Hyperglycemia and Adverse Pregnancy Outcome (study) glycated hemoglobin high-density lipoprotein hepatic glucose output histocompatibility leukocyte antigen hemorrhages or microaneurysms hepatic nuclear factor hyperosmolar nonketotic hyperglycemia Hypertension Optimal Treatment (trial) hyperosmolar hyperglycemic state insulin autoantibody insulinoma-associated antigen-2 International Association of the Diabetes and Pregnancy Study Groups islet amyloid polypeptide International Diabetes Federation Irbesartan Type 2 Diabetic Nephropathy Trial International Federation of Clinical Chemistry impaired fasting glycemia insulin-like growth factor immunoglobulin G impaired glucose tolerance insulin promoter factor-1 immunoreactive (insulin) intraretinal microvascular abnormalities Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (study)

LADA LDL LDL-C LH LIFE LIPID MDI MDRD

multiple daily insulin injections Modification of Diet in Renal Disease (formula) MHC major histocompatibility complex Micro-HOPE Micro-Heart Outcomes Prevention Evaluation (study) MODY maturity onset diabetes of the young MNT medical nutrition therapy MRFIT Multiple Risk Factor Intervention Trial MRI magnetic resonance imaging NAD NADPH

nicotinamide adenine dinucleotide nicotinamide adenine dinucleotide phosphate NAVIGATOR Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (trial) NCEP National Cholesterol Education Program NDDG National Diabetes Data Group NEFA nonesterified fatty acids NFκB nuclear factor-kappa B NICE National Institute for Health and Clinical Excellence NICE-SUGAR Normoglycaemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation (study) NIDDM noninsulin-dependent diabetes mellitus NIMGU noninsulin-mediated glucose uptake NPDR nonproliferative diabetic retinopathy NPH neutral protamine Hagedorn NVD neovascularization near the optic disk NVE neovascularization elsewhere OGTT OECD OHA

KATP Km KPD

ATP-sensitive potassium (channel) Michaelis constant ketosis-prone diabetes

latent autoimmune diabetes of adults low-density lipoprotein low-density lipoprotein cholesterol luteinizing hormone Losartan Intervention for Endpoint Reduction (study) Long-Term Intervention with Pravastatin in Ischemic Disease (trial)

oral glucose tolerance test Organisation for Economic Co-operation and Development oral hypoglycemic agents

10 PARP PDE5 PDR PKC PKC-b PPAR PTCA RAGE RENAAL

RIA ROS RNA

poly(ADP-ribose) polymerase phosphodiesterase type-5 proliferative diabetic retinopathy protein kinase C protein kinase C-beta peroxisome proliferator-activated receptor percutaneous transluminal coronary angioplasty advanced glycation endproduct receptor Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (trial) radio-immunoassay reactive oxygen species ribonucleic acid

SGLT SMBG STOPNIDDM SU

sodium–glucose co-transporter self-monitored blood glucose Study to Prevent NIDDM (trial)

TRIPOD

Troglitazone in the Prevention of Diabetes (study) thiazolidinedione

TZD

sulfonylurea

UDP UGDP UKPDS

uridine diphosphate University Group Diabetes Program UK Prospective Diabetes Study

VA-HIT VB VCAM VEGF VIP VISEP

Veterans Affairs HDL Intervention Trial venous beading vascular cell adhesion molecule vascular endothelial growth factor vasoactive intestinal peptide Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (study) very low-density lipoprotein very low density lipoprotein receptor vascular smooth muscle cell

VLDL VLDLR VSMC WESDR WHO

Wisconsin Epidemiologic Study of Diabetic Retinopathy World Health Organization

XENDOS

XENical in the Prevention of Diabetes in Obese Subjects (study)

ZnT8

zinc transporter 8

11 CHAPTER 1

The nature of diabetes

What is diabetes?

Pancreas Islet of Langerhans

Overview 쏆 Diabetes mellitus is a serious chronic hormonal condition in which the body is unable to properly use the energy from food. 쏆 The name ‘diabetes mellitus’ differentiates the condition from the much rarer diabetes insipidus. Both of these conditions cause an increase in urine production; the urine in diabetes mellitus – but not diabetes insipidus – is sweet because of the glucose it contains. Diabetes mellitus will be referred to simply as diabetes in this book. 쏆 Diabetes occurs when either the pancreas does not produce enough insulin (insulin deficiency) or the insulin is ineffective (insulin resistance). The function of insulin is to enable glucose to enter the body’s cells in order to be used as energy. When glucose cannot enter the cells, its levels in the blood increase, resulting in hyperglycemia. 쏆 The cause of diabetes is not known. Genetic and environmental factors both appear to be involved. 쏆 There are two main types of diabetes: 앳 Type 1 (insulin-dependent) diabetes, where the beta (β)-cells of the pancreas (1) are damaged so that little or no insulin is produced. This type is most often diagnosed in children or young adults. Patients with type 1 diabetes have to use injectable insulin to control blood glucose levels.

Diabetes occurs as a result of insulin deficiency and/or insulin resistance.

Pancreatic acinus

Blood vessel

β cell α cell

1 Beta cells. Beta cells contained within the islets of Langerhans produce the hormone insulin that controls glucose levels in the blood.Type 1 diabetes is caused by autoimmune destruction of these cells, while in type 2 diabetes their function deteriorates over time. Alpha cells produce glucagon – a counter-regulatory hormone.

앳 Type 2 (noninsulin-dependent) diabetes,

where some insulin is produced but is not fully taken up by the tissues. Type 2 diabetes is associated with obesity and is most commonly diagnosed in adults. This type of diabetes can be controlled with diet and exercise, and sometimes medication. 앳 These two types of diabetes differ in their pathogenesis and metabolic features. 쏆 Long-term complications in blood vessels, kidneys, eyes, and nerves occur in both types of diabetes and are the major causes of morbidity and death.

12

The nature of diabetes Comparative prevalence (%) >12 9–12 7–9 5–7 4–5 6.1 (>110)

>6.1 (>110)

>7.0 (>126)

>10.0 (>180)

>11.1 (>200)

>11.1 (>200)

Fasting (if measured) and 2 h post-glucose load