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1 Chapter 1Figure 1.1 Estimated comparative raw prevalence of diabetes and impaired glu...Figure 1.2 Rates of major complications of diabetes for the US population de...Figure 1.3 Age standardised mortality rates from diabetes‐related complicati...Figure 1.4 Estimated global diabetes-related healthcare costs for adults age...

2 Chapter 2Figure 2.1 The Ebers papyrus. The Wellcome Institute Library, London, UK.Figure 2.2 Thomas Willis. The Wellcome Institute Library, London, UK.Figure 2.3 Claude Bernard. The Wellcome Institute Library, London, UK.Figure 2.4 Paul Langerhans. The Wellcome Institute Library, London, UK.Figure 2.5 Charles Best and Frederick Banting in Toronto in 1922 (the dog is...Figure 2.6 Schematic amino acid sequence of human insulin; porcine and bovin...

3 Chapter 3Figure 3.1 Prevalence of diabetes‐specific retinopathy (moderate or more sev...Figure 3.2 The relationship between 2‐hour plasma glucose and survival in pa...Figure 3.3 Diagnosis of diabetes and IGT by the oral glucose tolerance test....Figure 3.4 The prevalence of retinopathy in type 2 diabetes relative to the ...Figure 3.5 High‐risk patients who should be screened annually for type 2 dia...Figure 3.6 Classification of diabetes.Figure 3.7 Using C‐peptide to confirm type 1 diabetes based on residual beta...Figure 3.8 Five replicable clusters of patients with diabetes.Figure 3.9 Clinical features of type 1 and type 2 diabetes.Figure 3.10 Other specific types of diabetes.

4 Chapter 4Figure 4.1 Rising numbers of people with diabetes worldwide. IDF Atlas, 2017...Figure 4.2 There are estimated to be 425 m patients with diabetes worldwide ...Figure 4.3 An alarming trend in the USA with increasing numbers of patients....Figure 4.4 Mortality rates due to diabetes‐related complications. IDF Atlas,...Figure 4.5 Premature mortality affects low‐, medium‐ and high‐income countri...Figure 4.6 The relationship between Body Mass Index and the hazard ratio for...Figure 4.7 Healthcare expenditure on diabetes is rising steeply. IDF Atlas, ...Figure 4.8 In the USA the costs of providing diabetes care are enormous. Bas...Figure 4.9 Factors affecting the numbers of patients with type 2 diabetes.Figure 4.10 The shift towards using new, expensive analogue insulins. IMS He...Figure 4.11 A structured lifestyle modification program (aimed at delivering...

5 Chapter 5Figure 5.1 A section of normal pancreas stained with haematoxylin and eosin....Figure 5.2 The localisation of pancreatic hormones in human islets. (a) Insu...Figure 5.3 Potential interactions between the secretory products of the majo...Figure 5.4 Structure of a pancreatic islet, showing the anatomical relations...Figure 5.5 A hypothetical model for postnatal pancreatic β cell growth in hu...Figure 5.6 The primary structure (amino acid sequence) of human insulin. The...Figure 5.7 The double zinc insulin hexamer composed of three insulin dimers ...Figure 5.8 Insulin biosynthesis and processing. Proinsulin is cleaved on the...Figure 5.9 (a) Electron micrograph of insulin secretory granules in a pancre...Figure 5.10 The regulated (normal) and constitutive (active in type 2 diabet...Figure 5.11 (a) The biphasic glucose‐stimulated release of insulin from panc...Figure 5.12 The mechanism of glucose‐stimulated insulin secretion from the β...Figure 5.13 The classic experiment illustrating the incretin effect in norma...Figure 5.14 (a) The incretin effect is greatly diminished in patients with t...Figure 5.15 The insulin receptor and its structural domains. Many mutations ...Figure 5.16 The insulin signalling cascade. Insulin binding and autophosphor...Figure 5.17 (a) The structure of a typical glucose transporter (GLUT). (b) T...Figure 5.18 Insulin regulation of glucose transport into cells.Figure 5.19 Profiles of plasma glucose and insulin concentrations in individ...Figure 5.20 Overview of carbohydrate metabolism. cats, catecholamines; cort,...

6 Chapter 6Figure 6.1 Age and sex standardised incidence rates per 100,000 population p...Figure 6.2 Incidence rates (1999–2003) of type 1 diabetes in 0–14‐year‐olds ...Figure 6.3 Seasonal variation of type 1 diabetes among Finnish children (a) ...Figure 6.4 Insulitis. There is a chronic inflammatory cell infiltrate centre...Figure 6.5 ICA demonstrated by indirect immunofluorescence in a frozen secti...Figure 6.6 Progression to symptomatic Type 1 Diabetes in 585 children with t...Figure 6.7 Potential mechanisms of viral aetiology of autoimmune and non‐aut...Figure 6.8 Proposed mechanisms of β cell death. β cells die through a proces...Figure 6.9 Stages of Type 1 Diabetes as proposed by the Juvenile Diabetes Re...Figure 6.10 Lifetime risk of developing Type 1 diabetes (left axis) compared...

7 Chapter 7Figure 7.1 The relationship between body mass index (BMI) and risk of type 2...Figure 7.2 Rising obesity rates in the USA (2008‐2015) based on self‐reporte...Figure 7.3 The rising Prevalence of type 2 diabetes parallels the rising inc...Figure 7.4 Age‐adjusted prevalence rates of type 2 diabetes in different geo...Figure 7.5 The IDF atlas also monitors the rising prevalence of prediabetes ...Figure 7.6 A league table of countries showing widely different prevalence r...Figure 7.7 Deaths attributable to diabetes are highest in low‐ and middle‐in...Figure 7.8 The relationship between HbA1c and the incidence of cardiovascula...Figure 7.9 Varying prevalence rates of type 2 diabetes by ethnicity/region a...Figure 7.10 Weight gain is a particularly strong driver of type 2 diabetes r...Figure 7.11 Insulin resistance (as assessed by glucose infusion rate (GIR) t...Figure 7.12 Age‐adjusted risk of type 2 diabetes among 5990 men. The figure ...Figure 7.13 The natural history of type 2 diabetes development often begins ...Figure 7.14 Mechanisms of insulin resistance in type 2 diabetes.Figure 7.15 The ‘thrifty phenotype’ hypothesis.Figure 7.16 β‐cell function as measured by the homeostasis model assessment ...Figure 7.17 Plasma concentrations of glucose and insulin in subjects with ty...Figure 7.18 The stages of glucose tolerance and associated β cell function a...Figure 7.19 Pathogenesis of type 2 diabetes. Both genetic and environmental ...

8 Chapter 8Figure 8.1 Rabson–Mendenhall syndrome in a 12‐year‐old boy, showing growth r...Figure 8.2 Acanthosis nigricans on the nape of the neck of a 26–year–old wom...Figure 8.3 Optic atrophy (note white optic disc) in a patient with Wolfram’s...Figure 8.4 Acute pancreatitis. CT scan of the abdomen, showing marked oedema...Figure 8.5 Pancreatic calculi, showing characteristic patterns in alcoholic ...Figure 8.6 A patient with glucagonoma, showing characteristic necrolytic mig...

9 Chapter 9Figure 9.1 Correlation in patients with type 1 diabetes between blood glucos...Figure 9.2 Example of combined blood glucose and blood ketone meter together...Figure 9.3 Urine ketone testing strips. NOTE these detect urinary acetoaceta...Figure 9.4 Continuous Glucose Sensor and Transmitter and associated Meter. T...Figure 9.5 Flash (intermittent) glucose monitoring system. Sensor and transm...Figure 9.6 Clarke error grid showing the density of paired FreeStyle Navigat...Figure 9.7 Computer download of 14 days’ data from continuous glucose monito...Figure 9.8 Computer download of 14 days’ data from flash monitoring device i...Figure 9.9 CGM Target Ranges for different groups of patients as agreed by i...

10 Chapter 10Figure 10.1 Normal plasma glucose and insulin profiles. Shaded areas represe...Figure 10.2 Basal‐bolus insulin regimen.Figure 10.3 Schematic amino acid sequence of native human insulin; porcine a...Figure 10.4 What happens in the subcutaneous tissue after subcutaneous injec...Figure 10.5 Suitable sites for subcutaneous insulin injection.Figure 10.6 Suprapubiclipohypertrophy at habitually used insulin injection s...Figure 10.7 Example of disassembled insulin pen. Insulin dose is selected us...Figure 10.8 Insulin infusion pump, fillable insulin cartridge (left), subcut...Figure 10.9 Insulin infusion pump and glucose sensor fitted on a patient wit...Figure 10.10 Meta regression analysis of mean effect size of insulin pump th...

11 Chapter 11FIGURE 11.1 Management of type 2 diabetes: the initial measures.FIGURE 11.2 Change in weight during energy restriction is similar with high ...FIGURE 11.3 Effect of Orlistat in obese patients with type 2 diabetic.Figure 11.4 Effect of Mysimba in obese patients with type 2 diabetes.FIGURE 11.5 Practical food recommendations for patients with diabetes.FIGURE 11.6 The progressive rise in median HbA1c with time in the convention...Figure 11.7 Pharmacologic Approaches to Glycemic Treatment in type 2 diabete...Figure 11.8 Approach to individualising Hba1c target in people with type 2....Figure 11.9 Mechanism by which glucose and sulfonylureas stimulate insulin s...Figure 11.10 Mechanism of action of TZDs. These agents stimulate the peroxis...Figure 11.11 Mechanism of action of SGLT‐ 2 inhibitor.Figure 11.12 LEADER STUDY. (available free online from https://tracs.unc.edu...Figure 11.13 Summary of glucose lowering therapy in type 2 diabetes.Figure 11.14 (a) Different types of common bariatric surgery procedures (b) t...

12 Chapter 12Figure 12.1 (a) Age distribution of 746 episodes of diabetic ketacidosis (ex...Figure 12.2 Mechanisms of ketacidosis. NEFA, non‐esterified fatty acids.Figure 12.3 Flowchart for the investigation of diabetic ketoacidosis.Figure 12.4 Guide to the initial treatment of diabetic ketacidosis in adults...

13 Chapter 13Figure 13.1 Some consequences of hypoglycaemia in diabetes.Figure 13.2 Major components of the counter‐regulatory and sympathetic nervo...Figure 13.3 Glycemic thresholds for secretion of counterregulatory hormones ...Figure 13.4 In the Diabetes Control and Complications Trial (DCCT, a landmar...Figure 13.5 Risks of severe hypoglycaemia associated with different diabetes...Figure 13.6 Glycaemic thresholds for the release of epinephrine and activati...Figure 13.7 Impairment of counter‐regulatory responses in type 1 diabetes. (...Figure 13.8 The vicious circle of repeated hypoglycaemia.Figure 13.9 Proposed mechanism of linking hypoglycaemia and arrhythmias in p...Figure 13.10 Algorithm for treating acute hypoglycaemia in patients with dia...

14 Chapter 14Figure 14.1 Schematic showing interaction of haemodynamic and cellular facto...Figure 14.2 Prevalence of diabetic neuropathy as a function of duration of d...Figure 14.3 Progression of proliferative retinopathy is related to glycated ...Figure 14.4 Effect of intensive treatment on the onset of retinopathy. Cumul...Figure 14.5 Risk of retinopathy progression and mean glycated haemoglobin in...Figure 14.6 Effect of intensive blood glucose control on microvascular compl...Figure 14.7 The relationship between glycated haemoglobin percentage and car...Figure 14.8 Kaplan–Meier plots of proportions of patients who developed micr...Figure 14.9 Cumulative incidence of a three‐step change in ETDRS retinopathy...Figure 14.10 The polyol pathway. (Left) The pathway is normally inactive, bu...Figure 14.11 Formation of reversible, early, non‐enzymatic glycation product...Figure 14.12 Possible mechanisms of cell damage by interactions of advanced ...Figure 14.13 Activation of protein kinase C by de novo synthesis of diacylgl...Figure 14.14 The hexosamine pathway. Glucosamine‐6‐phosphate, generated from...Figure 14.15 Superoxide links glucose and diabetic complications.

15 Chapter 15Figure 15.1 Structure of the retinal microvasculature. The endothelial cells...Figure 15.2 Microaneurysms, the earliest sign of diabetic retinopathy appear...Figure 15.3 Fluorescein angiogram, showing microaneurysms as small white dot...Figure 15.4 Retinal haemorrhages: red ‘blots’.Figure 15.5 Focal diabetic maculopathy with circinate (ring‐shaped) exudate....Figure 15.6 Cotton wool spots around the optic disc. Note also flame and blo...Figure 15.7 Intraretinal microvascular abnormalities (IRMAs) appearing as a ...Figure 15.8 Venous irregularity or ‘beading’ (centre of field) and new vesse...Figure 15.9 More extensive new vessels on the disc, occupying more than half...Figure 15.10 Extensive neovascularisation above the disc, with widespread si...Figure 15.11 Preretinal haemorrhage. Note the settling of the uncoagulated b...Figure 15.12 Fibrous bands that are exerting traction on the retina. The ret...Figure 15.13 Rhegmatogenous retinal detachment: a large retinal tear (red le...Figure 15.14 B‐scan ultrasound image of the eye, showing a retinal detachmen...Figure 15.15 Diffuse macular oedema, with a macular ‘star’. This requires la...Figure 15.16 Left eye of a patient with diffuse diabetic macular oedema. (a)...Figure 15.17 New vessels (arrows) on the iris (rubeosis iridis). There is al...Figure 15.18 Diabetic cataract appearing as pale opacification of the lens....Figure 15.19 Recent panretinal (scatter) laser photocoagulation burns for tr...Figure 15.20 Focal laser photocoagulation scars around the macula following ...

16 Chapter 16Figure 16.1 Classification and prognosis for end stage renal disease based u...Figure 16.2 Hyperfiltration in diabetes and its correction by SGLT‐2 (sodium...Figure 16.3 Relative mortality of patients with diabetes with and without pe...Figure 16.4 Nodular glomerulosclerosis in a patient with type 1 diabetes and...Figure 16.5 Nodular glomerulosclerosis (Kimmelstiel–Wilson lesions) in a pat...Figure 16.6 Electron micrograph of the glomerulus from a patient with diabet...Figure 16.7 Schematic to show how metabolic and haemodynamic factors combine...Figure 16.8 Schematic of changes in selectivity of glomerular capillary to a...Figure 16.9 Prevalence of parental hypertension in type 1 patients with norm...Figure 16.10 (a) Prevalence and (b) cumulative incidence of moderate albumin...Figure 16.11 Effects of antihypertensive treatment on (a) mean arterial bloo...Figure 16.12 Meta‐analysis of the effects of angiotensin‐converting enzyme (...Figure 16.13 (a) Cumulative incidence of death in 160 moderately albuminuric...Figure 16.14 Frequency of monitoring (number of clinic visits per year) base...Figure 16.15 Reciprocal serum creatinine plotted against date for the case h...

17 Chapter 17Figure 17.1 Diabetic neuropathy is common and associated with a complex mix ...Figure 17.2 Classification of diabetic neuropathy.Figure 17.3 Mechanisms of diabetic neuropathy.Figure 17.4 Clinical pattern of distal symmetrical neuropathies.Figure 17.5 Staging the severity of diabetic neuropathy.Figure 17.6 Positive sensory symptoms; painful neuropathy.Figure 17.7 A 10g monofilament is simple, easy to use in the clinic and is m...Figure 17.8 Increased blood flow (distended veins) on the dorsum of the foot...Figure 17.9 Clinical pattern of pressure palsies in patients with diabetes....Figure 17.10 Generalised wasting of the interossei (and hypothenar eminence)...Figure 17.11 Diabetic amyotrophy, showing marked quadriceps wasting, and cli...Figure 17.12 Histological changes associated with diabetic amyotrophy. In pa...Figure 17.13 Clinical and subclinical features of diabetic autonomic neuropa...Figure 17.14 Effects of intensified insulin therapy and strict glycaemic con...

18 Chapter 18Figure 18.1 Features of Diabetic dyslipidaemia. In the German PROCAM study, ...Figure 18.2 The pathogenesis of diabetic dyslipidaemia involves increased re...Figure 18.3 Eruptive xanthomata. This young patient with type 1 diabetes pre...Figure 18.4 The MRFIT screening study enrolled >360,000 men in the 1960s‐70s...Figure 18.5 The importance of LDL cholesterol lowering to reduce major vascu...Figure 18.6 Circulating cholesterol is derived from two sources: de novo syn...Figure 18.7 A meta‐analysis of cholesterol‐lowering therapy in 18 686 patien...Figure 18.8 The mechanism of action of statins and PCSK9 monoclonal antibodi...

19 Chapter 19Figure 19.1 Suggested mechanisms linking insulin resistance to the developme...Figure 19.2 Additive effects of diabetes and hypertension on deaths from cor...Figure 19.3 World Health Organisation/International Society for Hypertension...Figure 19.4 Schematic diagram of the renin‐angiotensin system. Dotted lines ...Figure 19.5 Summary of antihypertensive drug management in people with diabe...

20 Chapter 20Figure 20.1 Relationships between systolic BP (a) and serum cholesterol (b) ...Figure 20.2 Among patients with diabetes, those who develop nephropathy and ...Figure 20.3 Arteriolar changes in diabetes in the myocardium of a woman who ...Figure 20.4 Medial calcification of the digital arteries in a diabetic patie...Figure 20.5 New Zealand cohort study showing the relationship between CVD mo...Figure 20.6 DAG‐mediated activation of protein Kinase C‐β results in phospho...Figure 20.7 Advanced glycation end products (AGEs) have a number of unwanted...Figure 20.8 A meta‐analysis of five prospective randomised controlled trials...Figure 20.9 Cardiovascular and death from any course with Empagliflozin comp...Figure 20.10 Primary and exploratory outcomes with Liraglutide vs Placebo in...Figure 20.11 The ADVANCE study randomised approximately 20,000 high‐risk pat...Figure 20.12 Age‐adjusted prevalence of previous stroke among type 2 diabete...Figure 20.13 From the Antithrombotic Trialists Collaboration, there is no cl...Figure 20.14 Age‐adjusted prevalence of intermittent claudication in patient...Figure 20.15 Diffuse coronary artery disease in a 49‐year‐old woman with typ...

21 Chapter 21Figure 21.1 The ‘diabetic foot’ refers to a mix of pathologies.Figure 21.2 Major components in the aetiology of foot ulceration.Figure 21.3 Risk factors for diabetic foot complications.Figure 21.4 Annual foot review for everyone with diabetes above 12 years old...Figure 21.5 Typical neuropathic ulcer with surrounding callus.Figure 21.6 Neuroischaemic damage caused by tightly fitting shoes.Figure 21.7 Principles of ulcer treatment, in addition to providing educatio...Figure 21.8 Critical ischaemia, ulceration and gangrene affecting the extrem...Figure 21.9 Bilateral Charcot neuroarthropathy in the cuneiform‐metatarsal a...Figure 21.10 Plain X‐ray of a Charcot foot demonstrates gross destruction, d...Figure 21.11 Total contact plaster cast for ‘offloading’ a neuropathic ulcer...Figure 21.12 The following clinical scenario and anti‐microbial agents that ...

22 Chapter 22Figure 22.1 The most common symptoms of sexual dysfunction in men and women ...Figure 22.2 Sexual Health Inventory for Men (SHIM).Figure 22.3 Pathways that lead to the relaxation of vascular and corpus cave...Figure 22.4 Major pathways contributing to ED in diabetic men.Figure 22.5 Treatment options for diabetic men with ED.Figure 22.6 Intracavernosal injection of alprostadil, self‐injected.Figure 22.7 A vacuum device with constriction rings.Figure 22.8 Gynaecological factors relevant to women with diabetes or IGT.Figure 22.9 Genitourinary infections in diabetic women.Figure 22.10 Patterns of contraceptive use in women with type 1 diabetes in ...

23 Chapter 23Figure 23.1 Motility disorders associated with diabetes at various levels of...Figure 23.2 Dose‐dependent effect of hyperglycaemia on postprandial gallblad...Figure 23.3 Effect of insulin‐induced hypoglycaemia on gastric emptying (50%...Figure 23.4 Wet swallow‐induced oesophageal peristalsis in a healthy subject...Figure 23.5 Effect of gut microbiota in liver disease, insulin resistance, a...

24 Chapter 24Figure 24.1 Child‐Pugh score.Figure 24.2 Multiple hit model in the pathogenesis of NAFD, NASH and cirrhos...Figure 24.3 Simple non‐invasive tests for fibrosis.

25 Chapter 25Figure 25.1 Global cancer cases in 2012 due to diabetes and BMI ≥ 25 kg/m² s...Figure 25.2 Immortality bias with metformin treatment. Cancer rates recorded...

26 Chapter 26Figure 26.1 Diabetic dermopathy or ‘shin spots’.Figure 26.2 Necrobiosis lipoidica diabeticorum (NLD). (a) An early lesion on...Figure 26.3 In children, acanthosis nigricans is associated with obesity (+ ...Figure 26.4 Diabetic bullae – blistering of the foot.Figure 26.5 Granuloma annulare. Taken from http://healthool.com/granuloma‐an...Figure 26.6 Garrod’s knuckle pads.Figure 26.7 The ‘prayer sign’, another feature of cheiroarthropathy.Figure 26.8 Dupuytren’s contractors.Figure 26.9 Trigger finger in a diabetic patient.Figure 26.10 Tinea manus, showing the characteristic erythematous, scaly mar...Figure 26.11 Chronic paronychia caused by Candida albicans.

27 Chapter 27Figure 27.1 The impairment of cognitive ability in 125 adolescents with type...

28 Chapter 28Figure 28.1 Changes in plasma glucose and insulin concentrations during prol...Figure 28.2 Progressive resistance exercise training, supervised over 12 wee...Figure 28.3 Proportion of men who died during a 7‐year follow‐up period amon...Figure 28.4 Necrotizing (‘malignant’) otitis externa. This magnetic resonanc...Figure 28.5 Rhinocerebral mucomycosis. Typical appearance, in a 45‐year‐old ...Figure 28.6 Suggested modifications of existing insulin regimens for people ...Figure 28.7 Suggested VRIII rates in patients undergoing surgery or prolonge...

29 Chapter 29Figure 29.1 Impact of maternal diabetes on the foetus and neonate by gestati...Figure 29.2 (Left) A macrosomic baby born to a mother with diabetes. (Right)...

30 Chapter 30Figure 30.1 Trends and cyclical variation in the incidence of childhood type...Figure 30.2 Predicted numbers of newly diagnosed cases of childhood‐onset ty...Figure 30.3 Algorithm for the management of DKA.Figure 30.4 Type 1 diabetes has a preclinical phase of varying duration when...Figure 30.5 Meta‐analysis of CSII versus Multiple dose injection in T1D. Poz...Figure 30.6 Component of a closed loop insulin delivery system. Interstitia...Figure 30.7 Risk factors for type 2 diabetes in youth –Figure 30.8 Result from the TODAY Trial.

31 Chapter 31Figure 31.1 Trends in the number of adults with diabetes by region (A) and d...Figure 31.2 Estimated number of adults with diabetes in developed countries ...Figure 31.3 The various ways in which diabetes may present in the elderly.Figure 31.4 Diabetes in the elderly: key points to consider when individuali...Figure 31.5 Proposed framework when considering treatment goals for glycaemi...

32 Chapter 32Figure 32.1 Deleterious effects of smoking and disease on 10‐year mortality....Figure 32.2 Scheme for adjusting insulin doses during flights that cross tim...

33 Chapter 33Figure 33.1 There are many different dimensions to effective diabetes servic...Figure 33.2 This diagram summarises the key components of integration. In pa...Figure 33.3 The Care Planning house model. This model was developed to illus...Figure 33.4 The ‘commissioning windmill’. A model that illustrates key eleme...Figure 33.5 What needs to be commissioned?Figure 33.6 A framework for increasing the effectiveness of self‐management....

34 Chapter 34Figure 34.1 (a) Numbers of simultaneous pancreas kidney (SPK), pancreas afte...Figure 34.2 Simultaneous kidney and whole‐organ pancreas transplantation sho...Figure 34.3 Schematic representation of the pancreas gland showing the anato...