Table Of ContentCDLINICiIAaN’S bDESKe REtFEReENCsE
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
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Contents
Preface 7 CHAPTER 3
Acknowledgments 7 Type 1 diabetes 37
Epidemiology 37
Abbreviations 8
Causes of type 1 diabetes 38
Prediction of type 1 diabetes 40
CHAPTER 1
Genetic factors 40
The nature of diabetes 11
Nongenetic factors 42
What is diabetes? 11 Development of type 1 diabetes 42
Overview 11 Pancreaticβ-cell dysfunction 42
Epidemiology 12 Insulin resistance 43
Definitions and classification 13 Mortality 43
Forms of diabetes 17 Screening for potential type 1 diabetes 44
Type 1 diabetes 17
Type 2 diabetes 17 CHAPTER 4
Maturity onset diabetes of the young Type 2 diabetes 45
(MODY) 17
Epidemiology 45
Gestational diabetes mellitus (GDM) 18
Causes of type 2 diabetes 46
Neonatal diabetes 19
Environmentalrisk factors 46
Secondary diabetes 19
Genetic factors 47
Clinical presentations of diabetes 19
Associated conditions 48
Complications of diabetes 20
Hyperinsulinemia and hyperglycemia 49
Macrovascular complications 20
Hypertension 49
Microsvascular complications 20
Abnormalities of lipid metabolism 50
Acute metabolic complications 20
The metabolic syndrome and obesity 50
Infections 21
Development of type 2 diabetes 52
Disorders of the joints, ligaments,
and skin 22 Glucoregulatory defects in type 2 diabetes 52
The cost of diabetes 23 Pancreaticβ-cell deficiency 52
Insulin resistance 53
CHAPTER 2 The role of amylin 54
Glucose, insulin, and diabetes 25 Glucotoxicity and lipotoxicity 54
Glucotoxicity 54
The role of glucose 25
Lipotoxicity 55
Glucose levels and diabetes 26
Screening and prevention 56
Normal glucose metabolism 27
Type 2 diabetes prevention studies 57
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
4
CHAPTER 5 Reducing the risk of vascular disease 81
Diabetes screening and patient care 59 Obesity and sedentary lifestyle 82
Hypertension 82
Management overview 59
Dyslipidemia 84
Risk factors 59
Smoking 85
Annual examination 60
Hyperglycemia 85
Screening for complications 60
Antithromboticagents 86
Eyes 60
Kidneys 61
CHAPTER 7
Feet 61
Diabetic neuropathy 87
Erectile dysfunction 61
Vascular disease 61 Prevalence and classification 87
Treating children 62 Diagnosis 88
Types of childhood diabetes 62 Chronic sensory polyneuropathy 89
Management of young patients 63 Acute sensory neuropathy 90
The elderly diabetes patient 65 Acute motor neuropathy 92
Management of elderly patients 65 Autonomic neuropathy 92
Controlof hypoglycemia 66 Cardiovascular system 92
Ethnic minorities 67 Gastrointestinal tract 93
Patient education and community care 68 Bladder involvement 93
Living with diabetes 69 Erectile dysfunction 93
Employment 69 Neuroendocrine disturbances 93
Finance 69 Sudomotor dysfunction 93
Sport 69 Pupillary effects 93
Holidays and travel 70 Treatment and management 94
Driving 70 Acute sensory neuropathies 94
Focal sensory mononeuropathies 94
CHAPTER 6 Acute motor neuropathies 94
Diabetes and vascular disease 73 Autonomic neuropathy 94
Macrovascular disease 73
CHAPTER 8
Pathogenesis of macrovascular complications 74
The diabetic foot 97
Treatment and management principles for
macrovascular disease 75 Overview 97
General principles 75 Pathophysiology and risk factors 97
Glucose control 75 Neuropathy 97
Lipid-lowering drugs 76 Peripheral arterial disease 98
Revascularization procedures 76 Infection 98
Pathogenesis of microvascular complications 77 Pressure 98
Hyperglycemia 78 Clinical presentation and evaluation 98
High intracellular glucose 79 Evaluation 98
Advanced glycation endproducts 79 Examination 99
Reactive oxygen species 80 Treatment and management 100
Sorbitol accumulation 80 Infection 101
Activation of protein kinase C-beta 80 Peripheral arterial disease 101
Hemodynamic changes 80 High plantar pressure 102
Treatment and management principles for Deformities 102
microvascular disease 81
The wound environment 102
Surgery 102
Charcot’s arthropathy 103
5
CHAPTER 9 Hyperosmolarnonketotic hyperglycemia 128
Diabetic eye disease 105 Clinical features 129
Investigations 129
Overview 105
Complications 129
Natural history 105
Treatment 130
Nonproliferative diabetic retinopathy 106
Prognosis 130
Proliferative diabetic retinopathy 108
Brittle diabetes mellitus 130
Diabetic maculopathy 108
Recurrent ketoacidosis 130
Cataracts 109
Lactic acidosis 130
Glaucoma 109
Ocular nerve palsies 109
CHAPTER 12
Treatment and management 109
Long-term management of
Diabetic maculopathy 110
hyperglycemia 131
Cataracts 110
Glaucoma 110 Overview 131
Targets of treatment 132
CHAPTER 10 Dietary management 132
Diabetic kidney disease 111 Calorie intake 133
Carbohydrates 134
Overview 111
Fats 134
Natural history 111
Prescribing a diet 135
Stage 1: Functional changes 112
Exercise 136
Stage 2: Structural changes 112
Bariatric surgery 138
Stage 3: Microalbuminuria 112
Stage 4: Overt clinical nephropathy 113
CHAPTER 13
Stage 5: End-stage renal disease 113
Noninsulin therapies 139
Diagnosis of nephropathy 114
Urinary tract infections 114 Tablet treatment for type 2 diabetes 139
Treatment and management 114 Metformin 141
General therapy 115 Side-effects 142
Blood glucose 116 Insulin secretagogues: sulfonylureas 143
Blood pressure 116 Drug interactions and side-effects 144
Lipids 117 Sulfonylureas and heart disease 145
Smoking 117 Other oral insulin secretagogues 145
Protein restriction 117 Side-effects 145
Renal replacement therapy 118 Thiazolidinediones 146
Continuous ambulatory peritoneal dialysis 118 Side-effects 147
Hemodialysis 118 TZDs and cardiovascular disease 148
Transplantation 119 Apha-glucosidase inhibitors 148
Pancreastransplant or islet cell implantation 119 Side-effects 148
GLP-1 analogues 149
CHAPTER 11 Side-effects 151
Severe diabetic metabolic disturbances 121 Dipeptidyl peptidase-4 inhibitors 152
Side-effects 153
Diabetic ketoacidosis 121
Other recent developments 153
Pathogenesis 122
Colesevelam 153
Clinical features 124
Bromocriptine 154
Investigations 124
Pramlintide 154
Acute managment 125
Drugs on the horizon 154
Subsequent management 127
Sodium–glucose cotransporter 2 (SGLT2)
inhibitors 154
6
CHAPTER 14 CHAPTER 15
Insulin treatment 155 Special management considerations 173
Overview 155 The diabetic inpatient 173
Therapeutic insulin 155 Diabetes and surgery 174
Regular (or soluble) insulin 155 Major surgery 175
Rapid-acting insulin analogs 155 Minor surgery 176
Insulins with prolonged action 156 Surgery and blood pressure 176
Alternative insulin delivery systems 157 Conception, contraception, and pregnancy 176
Indications for insulin treatment 158 Contraception and diabetes 178
Insulin regimen: type 1 diabetes 159 Glucose monitoring and glycemic goals
Continuous subcutaneous insulin in pregnancy 178
infusion: insulin pump treatment 160 Type 1 diabetes patients 180
Implantable glucose monitors 163 Type 2 diabetes patients 181
Insulin regimen: type 2 diabetes 163 Risks to the diabetic mother 182
General considerations 163 Gestational diabetes mellitus (GDM) 183
Basal insulin 165 Labor and delivery 184
Mealtime insulin 166 Neonatal problems 184
Premixed insulin 167
Metabolic instability on insulin 167 Further reading 187
Complications: hypoglycemia 168
Resources 191
Hypoglycemic unawareness 170
Glossary 193
Nocturnal hypoglycemia 170
Recurrentsevere hypoglycemia 170 Index 201
Treating hypoglycemia 171
Mild hypoglycemia 171
Severe hypoglycemia 171
Preventing hypoglycemia 172
Other complications or adverse effects
from insulin treatment 172
7
Preface
THEAIMOFTHISBOOKis 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 DAVIDLESLIE
M CECILIALANSANG
SIMONCOPPACK
LAURENCEKENNEDY
Acknowledgments
Drs. Leslie, Coppack, and Kennedy would especially We also thank Dr. Ernesto Lopez, Dr. Frida
like to acknowledge the major role of their co-author, Djukiadmodjo, Dr. Lily Ho-Le, Dr. Serena Chiu,
Dr. Lansang, in reviewing and updating the text and Dr. Lina Paschou for their help in preparing
during the gestation of this book. and editing the text and figures.
We would all like to thank Professor David In addition, the authors would like to thank
Hadden, Belfast, Northern Ireland, and Professor Dr Michael Tolentino and Dr. Rishi Singh for
David Bell, Birmingham, Alabama, for providing supplying the retinal photos.
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.
8
Abbreviations
AACE American Association of Clinical DAN diabetic autonomic neuropathy
Endocrinologists DNA deoxyribonucleic acid
ABX abciximab DCCT Diabetes Control and Complications Trial
ACEI angiotensin-converting enzyme inhibitor DIGAMI Diabetes Mellitus Insulin Glucose Infusion
acyl-CoA acyl-coenzyme-A in Acute Myocardial Infarction (study)
ADA American Diabetes Association DKA diabetic ketoacidosis
ADP adenosine diphosphate DPP Diabetes Prevention Program
AGE advanced glycation endproducts DPP dipeptidyl peptidase
AGI a-glucosidase inhibitor DREAM Diabetes REduction Assessment with
ALLHAT Anti-Hypertensive and Lipid-Lowering ramipril and rosiglitazone Medication
Treatment to Prevent Heart Attacks Trials (trial)
AMPK AMP-activated protein kinase DSME diabetes self-management education
ARB angiotensin-receptor blocker DVLA Driver and Vehicle Licensing Agency
ATP adenosine triphosphate
EASD European Association for the Study of
AUC area under the curve Diabetes
ECD expanded criteria donor
BARI Bypass Angioplasty Revascularization
Investigation (trial) ECG electrocardiogram
BENEDICT Bergamo Nephrologic Diabetes ED50 effective dose of insulin that produces
Complications Trial 50% of maximal effect
BMI body mass index eGFR estimated glomerular filtration rate
BP blood pressure EGIR European Group for the Study of Insulin
Resistance
BUN blood urea nitrogen
eNOS endothelial nitric oxide synthase
C4 complement 4 EPIC Evaluation of Platelet IIb/IIIa Inhibition
for Prevention of Ischemic Complications
CABG coronary artery bypass grafting
(trial)
CAD coronary artery disease
EPILOG Evaluation of PTCA to Improve Long-term
cAMP cyclic adenosine monophosphate Outcome by c7E3 GP IIb/IIIa Receptor
CAPD continuous ambulatory peritoneal dialysis Blockade (trial)
CARDS Collaborative Atorvastatin Diabetes Study EPISTENT Evaluation of Platelet IIb/IIIa Inhibitor for
CARE Cholesterol and Recurrent Events (trial) Stenting (trial)
CHF congestive heart failure ESR erythrocyte sedimentation rate
CK-MB creatine kinase, muscle–brain type ESRD end-stage renal disease
CNS central nervous system ETDRS Early Treatment Diabetic Retinopathy
Study
CRP C-reactive protein
CSF cerebrospinal fluid FDA Food and Drug Administration
CSII continuous subcutaneous insulin infusion FEV1 forced expiratory volume in 1 second
CT computed tomography FFA free fatty acids
CVD cardiovascular disease FIELD Fenofibrate Intervention and Event
Lowering in Diabetes (study)
FPG fasting plasma glucose
FSH follicle-stimulating hormone
FTO fused-toe gene
