1

2 Diabetes mellitus is a clinical syndrome characterised by an increase in plasma blood glucose (hyperglycaemia). Diabetes has many causes but is most commonly due to type 1 or type 2 diabetes.

3 Type 1 diabetes is caused by autoimmune destruction of insulin-producing cells (B cells) in the pancreas, resulting in absolute insulin deficiency Type 2 diabetes is characterised by resistance to the action of insulin and an inability to produce sufficient insulin to overcome this ‘insulin resistance’.

4 Globally, diabetes caused 4Globally, diabetes caused 4.6 million deaths in 2011, and health-care expenditure attributed to diabetes was estimated to be at least US$465 billion, or 11% of total health-care expenditure. The incidence of diabetes is rising. Globally, it is estimated that 366 million people had diabetes in 2011 (approximately 8.3% of the world population, or 3 new cases every 10 seconds), and this figure is expected to reach 552 million by Type 2 Environmental factors such as greater longevity, obesity, unsatisfactory diet, sedentary lifestyle,increasing urbanisation and economic development .

5 Aetiology and pathogenesis of diabetesIn both of the common types of diabetes, environmental factors interact with genetic susceptibility to determine which people develop the clinical syndrome, and the timing of its onset.

6 Type 1 diabetes Type 1 diabetes is a T cell-mediated autoimmune disease involving destruction of the insulin-secreting β cells in the pancreatic islets 80–90% of the functional capacity Type 1 diabetes is associated with other autoimmune disorders

7 Genetic factors account for about one-third of the susceptibility to type 1 diabetes, the inheritance of which is polygenic .

8 Environmental predispositionThe concordance rate between monozygotic twins is less than 40% , and wide geographic and seasonal variations in incidence. Direct toxicity to B cells or by stimulating an autoimmune reaction directed against B cells. Potential candidates fall into three main categories: viruses, specific drugs or chemicals, and dietary constituents.

9 Type 2 diabetes Thought to be caused by resistance to insulin action. obesity is a major cause Inactivity

10 Environmental and other risk factorsDiet and obesity Tenfold in people with a body mass index (BMI) of more than 30 kg/m2 Age Type 2 diabetes is more common in the middle-aged and elderly . In the UK, it affects 10% of the population over 65, and over 70% of all cases of diabetes occur after the age of 50 years.

11 Aetiological classification of diabetes mellitusExcess endogenous production of hormonal antagonists to insulin, e.g. Growth hormone – acromegaly,Glucocorticoids – Cushing’s syndrome Glucagon – glucagonom, ,Catecholamines – phaeochromocytoma Thyroid hormones – thyrotoxicosis • Drug-induced (e.g. corticosteroids, thiazide diuretics, phenytoin) • Uncommon forms of immune-mediated diabetes (e.g. IPEX (immunodysregulation polyendocrinopathy X) syndrome) • Associated with genetic syndromes (e.g. Down’s syndrome; Klinefelter’s syndrome; Turner’s syndrome; DIDMOAD (Wolfram’s syndrome) optic atrophy, nerve deafness; Friedreich’s ataxia; myotonic dystrophy) Gestational diabetes Type 1 diabetes • Immune-mediated • Idiopathic Type 2 diabetes Other specific types • Genetic defects of β-cell function • Genetic defects of insulin action (e.g. leprechaunism, lipodystrophies) • Pancreatic disease (e.g. pancreatitis, pancreatectomy, neoplastic disease, cystic fibrosis, haemochromatosis, fibrocalculous pancreatopathy)

12 Symptoms of hyperglycaemia

13 Classical features of type 1 and type 2 diabetes

14 Investigation To make the diagnosis of diabetes, the blood glucose concentration should be estimated using an accurate laboratory method rather than a portable technique. Glucose concentrations are lower in venous than arterial or capillary (fingerprick) blood. Whole blood glucose concentrations are lower than plasma concentrations because red blood cells contain relatively little glucose. Venous plasma values are usually the most reliable for diagnostic purposes .

15 Glycated haemoglobin In diabetes, the slow non-enzymatic covalent attachment of glucose to haemoglobin (glycation) increases the amount in the HbA1 (HbA1c) fraction relative to nonglycated adult haemoglobin (HbA0). Although HbA1c concentration reflects the integrated blood glucose control over the lifespan of erythrocytes (120 days), HbA1c is most sensitive to changes in glycaemic control occurring in the month before measurement.

16 Conversion between DCCT and IFCC units for HbA1c

17 Establishing the diagnosis of diabetesGlycaemia can be classified into three categories: normal, impaired (pre-diabetes) and diabetes The glucose cut-off that defines diabetes is based upon the level above which there is a significant risk of microvascular complications (retinopathy, nephropathy, neuropathy). People categorised as having pre-diabetes have blood glucose levels that carry a negligible risk of microvascular complications but are at increased risk of developing diabetes. Also, people with pre-diabetes have increased risk of cardiovascular disease (myocardial infarction, stroke and peripheral vascular disease).

18 Diagnosis of diabetes and pre-diabetesDiabetes is confirmed by either: • Plasma glucose in random sample or 2 hrs after a 75 g glucose load ≥ 11.1 (200 mg/dL) or • Fasting plasma glucose ≥ 7.0 mmol/L (126 mg/dL) In asymptomatic patients, two diagnostic tests are required to confirm diabetes. ‘Pre-diabetes’ is classified as: • Impaired fasting glucose = fasting plasma glucose ≥ 6.0 (108 mg/dL) and < 7.0 mmol/L (126 mg/dL) • Impaired glucose tolerance = fasting plasma glucose< 7.0 mmol/L (126 m g/dL) and 2-hr glucose after 75 g oral glucose drink 7.8–11.1 mmol/L (140–200 mg/dL)

19 Criteria for Screening for T2D and Prediabetes in Asymptomatic AdultsQ1. How is diabetes screened and diagnosed? Age ≥45 years without other risk factors Family history of T2D CVD Overweight BMI ≥30 kg/m2 BMI kg/m2 plus other risk factors* Sedentary lifestyle Member of an at-risk racial or ethnic group: Asian, African American, Hispanic, Native American, and Pacific Islander Dyslipidemia HDL-C <35 mg/dL Triglycerides >250 mg/dL IGT, IFG, and/or metabolic syndrome PCOS, acanthosis nigricans, NAFLD Hypertension (BP >140/90 mm Hg or therapy for hypertension) History of gestational diabetes or delivery of a baby weighing more than 4 kg (9 lb) Antipsychotic therapy for schizophrenia and/or severe bipolar disease Chronic glucocorticoid exposure Sleep disorders† in the presence of glucose intolerance Screen at-risk individuals with glucose values in the normal range every 3 years Consider annual screening for patients with 2 or more risk factors *At-risk BMI may be lower in some ethnic groups; consider using waist circumference. †Obstructive sleep apnea, chronic sleep deprivation, and night shift occupations. BMI = body mass index; BP = blood pressure; CVD=cardiovascular disease; HDL-C = high density lipoprotein cholesterol; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; NAFLD = nonalcoholic fatty liver disease; PCOS = polycystic ovary syndrome; T2D, type 2 diabetes.

20 Diagnostic Criteria for Prediabetes and Diabetes in Nonpregnant AdultsQ1. How is diabetes screened and diagnosed? Normal High Risk for Diabetes Diabetes FPG <100 mg/dL IFG FPG ≥ mg/dL FPG ≥126 mg/dL 2-h PG <140 mg/dL IGT 2-h PG ≥ mg/dL 2-h PG ≥200 mg/dL Random PG ≥200 mg/dL + symptoms* A1C <5.5% 5.5 to 6.4% For screening of prediabetes† ≥6.5% Secondary‡ *Polydipsia (frequent thirst), polyuria (frequent urination), polyphagia (extreme hunger), blurred vision, weakness, unexplained weight loss. †A1C should be used only for screening prediabetes. The diagnosis of prediabetes, which may manifest as either IFG or IGT, should be confirmed with glucose testing. ‡Glucose criteria are preferred for the diagnosis of DM. In all cases, the diagnosis should be confirmed on a separate day by repeating the glucose or A1C testing. When A1C is used for diagnosis, follow-up glucose testing should be done when possible to help manage DM. FPG, fasting plasma glucose; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; PG, plasma glucose.

21 Diagnostic Criteria for Gestational DiabetesQ1. How is diabetes screened and diagnosed? Test Screen at weeks gestation FPG, mg/dL >92 1-h PG*, mg/dL ≥180 2-h PG*, mg/dL ≥153 *Measured with an OGTT performed 2 hours after 75-g oral glucose load. FPG, fasting plasma glucose; OGTT, oral glucose tolerance test; PG, plasma glucose.

22 Recommendations for A1C TestingQ1. How is diabetes screened and diagnosed? A1C should be considered an additional optional diagnostic criterion, not the primary criterion for diagnosis of diabetes When feasible, using traditional glucose criteria for diagnosis of diabetes A1C is not recommended for diagnosing type 1 diabetes A1C is not recommended for diagnosing gestational diabetes AACE. Endocrine Pract. 2010;16:

23 Recommendations for A1C TestingQ1. How is diabetes screened and diagnosed? Recommendations for A1C Testing A1C levels may be misleading in several ethnic populations (for example, African Americans) A1C may be misleading in some clinical settings Hemoglobinopathies Iron deficiency Hemolytic anemias Thalassemias Spherocytosis Severe hepatic or renal disease AACE. Endocrine Pract. 2010;16:

24 How to perform an oral glucose tolerance test (OGTT)Which patients to test • Fasting plasma glucose 6.1–7.0 mmol/L (110–126 mg/dL) • Uncertainty about the diagnosis of diabetes Preparation before the test • Unrestricted carbohydrate diet for 3 days • Fasted overnight for at least 8 hrs • Rest for 30 mins • Remain seated for the duration of the test, with no smoking Sampling • Measure plasma glucose before and 2 hrs after a 75 g oral glucose drink

25 Management The aims of management are to improve symptoms of hyperglycaemia and to minimise the risks of long-term microvascular and macrovascular complications. Treatment methods for diabetes include dietary/lifestyle modification, oral anti-diabetic drugs and injected therapies.

26 Management -cont Blood glucose targets vary according to individual circumstances, but, in general, Pre-meal values between 4 and 7 mmol/L (72 and 126 mg/dL) and 2-hour post-meal values between 4 and 8 mmol/L represent optimal control. HbA1c target depends on the individual patient. Early on in diabetes (i.e. patients managed by diet or one or two oral agents), a target of 48 mmol/mol (6.5%) or less may be appropriate. However, a higher target of 58 mmol/mol (7.5%) may be more appropriate in older patients with pre-existing cardiovascular disease, or those treated with insulin and therefore at risk of hypoglycaemia.

27 Therapeutic Lifestyle ChangesQ4. How are glycemic targets achieved for T2D? Therapeutic Lifestyle Changes Parameter Treatment Goal Weight loss (for overweight and obese patients) Reduce by 5% to 10% Physical activity 150 min/week of moderate-intensity exercise (eg, brisk walking) plus flexibility and strength training Diet Eat regular meals and snacks; avoid fasting to lose weight Consume plant-based diet (high in fiber, low calories/glycemic index, and high in phytochemicals/antioxidants) Understand Nutrition Facts Label information Incorporate beliefs and culture into discussions Use mild cooking techniques instead of high-heat cooking Keep physician-patient discussions informal

28 Dietary management of diabetesAims of dietary management • Achieve good glycaemic control • Reduce hyperglycaemia and avoid hypoglycaemia • Assist with weight management: Weight maintenance for type 1 diabetes and non-obese type 2 diabetes Weight loss for overweight and obese type 2 diabetes • Reduce the risk of micro- and macrovascular complications • Ensure adequate nutritional intake • Avoid ‘atherogenic’ diets or those that aggravate complications, e.g. high protein intake in nephropathy

29 Dietary constituents and recommended % of energy intakeCarbohydrate: 45–60% Sucrose: up to 10% • Fat (total): < 35% • Protein: 10–15% (do not exceed 1 g/kg body weight/day) • Fruit/vegetables: 5 portions daily

30 Healthful Eating RecommendationsQ4. How are glycemic targets achieved for T2D? Healthful Eating Recommendations Carbohydrate Specify healthful carbohydrates (fresh fruits and vegetables, legumes, whole grains); target 7-10 servings per day Preferentially consume lower-glycemic index foods (glycemic index score <55 out of 100: multigrain bread, pumpernickel bread, whole oats, legumes, apple, lentils, chickpeas, mango, yams, brown rice) Fat Specify healthful fats (low mercury/contaminant-containing nuts, avocado, certain plant oils, fish) Limit saturated fats (butter, fatty red meats, tropical plant oils, fast foods) and trans fat; choose fat-free or low-fat dairy products Protein Consume protein in foods with low saturated fats (fish, egg whites, beans); there is no need to avoid animal protein Avoid or limit processed meats Micronutrients Routine supplementation is not necessary; a healthful eating meal plan can generally provide sufficient micronutrients Chromium; vanadium; magnesium; vitamins A, C, and E; and CoQ10 are not recommended for glycemic control Vitamin supplements should be recommended to patients at risk of insufficiency or deficiency

31 Noninsulin Agents Available for T2DQ4. How are glycemic targets achieved for T2D? Noninsulin Agents Available for T2D Class Primary Mechanism of Action Agent(s) Available as -Glucosidase inhibitors Delay carbohydrate absorption from intestine Acarbose Miglitol Precose or generic Glyset Amylin analogue Decrease glucagon secretion Slow gastric emptying Increase satiety Pramlintide Symlin Biguanide Decrease HGP Increase glucose uptake in muscle Metformin Glucophage or generic Bile acid sequestrant Decrease HGP? Increase incretin levels? Colesevelam WelChol DPP-4 inhibitors Increase glucose-dependent insulin secretion Alogliptin Linagliptin Saxagliptin Sitagliptin Nesina Tradjenta Onglyza Januvia Dopamine-2 agonist Activates dopaminergic receptors Bromocriptine Cycloset Glinides Increase insulin secretion Nateglinide Repaglinide Starlix or generic Prandin DPP-4 = dipeptidyl peptidase; HGP = hepatic glucose production. Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48. Inzucchi SE, et al. Diabetes Care. 2012;35: Continued on next slide

32 Noninsulin Agents Available for T2DQ4. How are glycemic targets achieved for T2D? Noninsulin Agents Available for T2D Class Primary Mechanism of Action Agent(s) Available as GLP-1 receptor agonists Increase glucose-dependent insulin secretion Decrease glucagon secretion Slow gastric emptying Increase satiety Albiglutide Dulaglutide Exenatide Exenatide XR Liraglutide Tanzeum Trulicity Byetta Bydureon Victoza SGLT2 inhibitors Increase urinary excretion of glucose Canagliflozin Dapagliflozin Empagliflozin Invokana Farxiga Jardiance Sulfonylureas Increase insulin secretion Glimepiride Glipizide Glyburide Amaryl or generic Glucotrol or generic Diaeta, Glynase, Micronase, or generic Thiazolidinediones Increase glucose uptake in muscle and fat Decrease HGP Pioglitazone Rosiglitazone Actos Avandia GLP-1 = glucagon-like peptide; HGP = hepatic glucose production; SGLT2 = sodium glucose cotransporter 2. Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48. Inzucchi SE, et al. Diabetes Care. 2012;35: Continued from previous slide

33 Biguanides(Metformin)It is employed as first-line therapy in all patients who tolerate it, and its use is maintained when additional agents are added as glycaemia deteriorates . Metformin is usually introduced at low dose (500 mg twice daily) to minimise the risk of gastrointestinal side effects. The usual maintenance dose is 1 g twice daily.

34 Biguanides(Metformin)Metformin reduces hepatic glucose production, may also increase insulin-mediated glucose uptake, and has effects on gut glucose uptake and utilisation.

35 Sulphonylureas Promote pancreatic B-cell insulin secretion. Sulphonylureas are an effective therapy for lowering blood glucose and are often used as an add-on to metformin, if glycaemia is inadequately controlled on metformin alone . The main adverse effects of sulphonylureas are weight gain and hypoglycaemia. Glibenclamide, gliclazide ,glimepiride and glipizide.

36 Alpha-glucosidase inhibitorsThe Alpha -glucosidase inhibitors delay carbohydrate absorption in the gut by inhibiting disaccharidases. Acarbose and miglitol are available and are taken with each meal. Both lower post-prandial blood glucose and modestly improve overall glycaemic control.

37 Thiazolidinediones Enhance the actions of endogenous insulin, in part directly (in the adipose cells) and in part indirectly (by altering release of ‘adipokines’, such as adiponectin, which alter insulin sensitivity in the liver) Pioglitazone can be very effective at lowering blood glucose in some patients and appears more effective in insulin-resistant patients.

38 Incretin-based therapies: DPP-4 inhibitors and GLP-1 analoguesThe incretin effect is the augmentation of insulin secretion seen when a glucose stimulus is given orally rather than intravenously, and reflects the release of incretin peptides from the gut . The incretin hormones are primarily glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). These are rapidly broken down by the peptidase DPP-4 (dipeptidyl peptidase 4). Sitagliptin; others now available include vildagliptin, saxagliptin and linagliptin. GLP-1 receptor agonists have to be given by subcutaneous injection Delays gastric emptying and, at the level of the hypothalamus, decreases appetite. Exenatide (twice daily), exenatide MR (once weekly) and liraglutide (once daily)..

39 SGLT2 inhibitors Glucose is filtered freely in the renal glomeruli and reabsorbed in the proximal tubules. SGLT2 is involved in reabsorption of glucose. Inhibition results in approximately 25% of the filtered glucose not being reabsorbed, with consequent glycosuria. Dapagliflozin

40 Monotherapy, Dual Therapy, and Triple Therapy for T2DQ4. How are glycemic targets achieved for T2D? Monotherapy* Dual therapy* Metformin (or other first-line agent) plus Triple therapy* First- and second-line agent plus Metformin GLP1RA SGLT2I DPP4I TZD† Basal insulin† AGI Colesevelam SU/glinide† BCR-QR AGI = -glucosidase inhibitors; BCR-QR = bromocriptine quick release; Coles = colesevelam; DPP4I = dipeptidyl peptidase 4 inhibitors; GLP1RA = glucagon-like peptide 1 receptor agonists; Met = metformin; SGLT2I = sodium-glucose cotransporter 2 inhibitors; SU = sulfonylureas; TZD = thiazolidinediones. *Intensify therapy whenever A1C exceeds individualized target. Boldface denotes little or no risk of hypoglycemia or weight gain, few adverse events, and/or the possibility of benefits beyond glucose-lowering. † Use with caution.

41 Insulin therapy Insulin was discovered in 1921 Until the 1980s, insulin was obtained by extraction and purification from pancreata of cows and pigs Recombinant DNA technology enabled large-scale production of human insulin. More recently, the amino acid sequence of insulin has been altered to produce analogues of insulin, which differ in their rate of absorption from the site of injection.

42 Duration of action (in hours) of insulin preparations

43 Insulin dosing regimensThe choice of regimen depends on the desired degree of glycaemic control, the severity of underlying insulin deficiency, the patient’s lifestyle, and his or her ability to adjust the insulin dose. Most people with type 1 diabetes require two or more injections of insulin daily. In type 2 diabetes, insulin is usually initiated as a once-daily long acting insulin, either alone or in combination with oral hypoglycaemic agents.

44 Insulin dosing regimensTwice-daily administration of a short-acting and intermediate-acting insulin (usually soluble and isophane insulins), given in combination before breakfast and the evening meal, is the simplest regimen and is still used commonly in many countries. Initially, two-thirds of the total daily requirement of insulin is given in the morning in a ratio of short-acting to intermediate-acting of 1 : 2, and the remaining third is given in the evening.

45 Insulin dosing regimensMultiple injection regimens (intensive insulin therapy) are popular, with short-acting insulin being taken before each meal, and intermediate- or long-acting insulin being injected once or twice daily (basal-bolus regimen). This type of regimen allows greater freedom with regard to meal timing and more variable day-today physical activity.

46 Side-effects of insulin therapy

47 Alternative insulin therapies‘Open-loop’ systems are battery-powered portable pumps providing continuous subcutaneous (CSII), intraperitoneal or intravenous infusion of insulin. Artificial Pancreas uses glucose sensors to communicate wirelessly with the insulin pump, which would automatically adjust its rate. Alternative routes of insulin delivery have been investigated. Clinical trials with intrapulmonary (inhalation), transdermal and oral insulins are ongoing but as yet none has proven commercially viable.

48 Whole pancreas transplantationTransplantation of isolated pancreatic islets Stem cells

49 Diabetic ketoacidosisA medical emergency and remains a serious cause of morbidity, principally in people with type 1 diabetes. Mortality is low in the UK (approximately 2%) but remains high in developing countries and among non-hospitalised patients. Mortality in DKA is most commonly caused in children and adolescents by cerebral oedema and in adults by hypokalaemia, acute respiratory distress syndrome and comorbid conditions such as acute myocardial infarction, sepsis or pneumonia.

50 DKA is characteristic of type 1 diabetes and is often the presenting problem in newly diagnosed patients. DKA may be precipitated by an intercurrent illness because of failure to increase insulin dose appropriately to compensate for the stress response.

51 The hyperglycaemia causes a profound osmotic diuresis leading to dehydration and electrolyte loss, particularly of sodium and potassium. Potassium loss is exacerbated by secondary hyperaldosteronism as a result of reduced renal perfusion. Ketosis results from insulin deficiency, exacerbated by elevated catecholamines and other stress hormones, leading to unrestrained Lipolysis and supply of FFAs for hepatic ketogenesis. When this exceeds the capacity to metabolise acidic ketones, these accumulate in blood. The resulting metabolic acidosis forces hydrogen ions into cells, displacing potassium ions.

52 • hyperketonaemia (≥ 3 mmol/L) and ketonuria (more than 2+ on standard urine sticks) • hyperglycaemia (blood glucose ≥ 11 mmol/L (~200 mg/dL)) • metabolic acidosis (venous bicarbonate < 15 mmol/L and/or venous pH < 7.3).

53 Every patient in DKA is potassium-depleted, but the plasma concentration of potassium gives very little indication of the total body deficit. Plasma potassium may even be raised initially due to disproportionate loss of water, catabolism of protein and glycogen, and displacement of potassium from the intracellular compartment by H+ ions.

54 Clinical features of diabetic ketoacidosis

55 Investigations • Venous blood: for urea and electrolytes, glucose and bicarbonate (severe acidosis is indicated by a venous plasma bicarbonate < 12 mmol/L). • Urine or blood analysis for ketones • ECG. • Infection screen

56 Management Insulin Fluid replacement Potassium Bicarbonate

57 Insulin A fixed-rate intravenous insulin infusion of 0.1 U/ kg body weight/hr is recommended. Exceptionally, if intravenous administration is not feasible, soluble insulin can be given by intramuscular injection (loading dose of 10–20 U, followed by 5 U hourly), or a fast-acting insulin analogue can be given hourly by subcutaneous injection (initially 0.3 U/kg body weight, then 0.1 U/kg hourly).

58 Insulin The blood glucose concentration should fall by 3–6 mmol/L (approximately 55–110 mg/dL) per hour. When the blood glucose has fallen, 10% dextrose infusion is introduced and insulin infusion continued to encourage glucose uptake into cells and restoration of normal metabolism.

59 Fluid replacement Rapid fluid replacement in the first few hours is usually recommended . Caution is recommended in children and young adults because of the risk of cerebral oedema. Most current guidelines favour correction of the extracellular fluid deficit with isotonic saline (0.9% sodium chloride).

60 Potassium Potassium replacement is not usually recommended with the initial litre of fluid because prerenal failure may be present secondary to dehydration. Treatment with 0.9% sodium chloride with potassium chloride 40 mmol/L is recommended if the serum potassium is below 5.5 mmol/L and the patient is passing urine . If the potassium falls below 3.5 mmol/L, the potassium replacement regimen needs to be reviewed. Cardiac rhythm should be monitored in severe DKA because of the risk of electrolyte-induced cardiac arrhythmia.

61 Bicarbonate Adequate fluid and insulin replacement should resolve the acidosis. The use of intravenous bicarbonate therapy is currently not recommended. Acidosis may reflect an adaptive response, improving oxygen delivery to the tissues, and so excessive bicarbonate may induce a paradoxical increase in cerebrospinal fluid acidosis and has been implicated in the pathogenesis of cerebral oedema in children and young adults.

62 Management of diabetic ketoacidosis

63 Hyperglycaemic hyperosmolar stateCharacterised by severe hyperglycaemia (> 30 mmol/L (600 mg/ dL)), hyperosmolality (serum osmolality > 320 mOsm/ kg), and dehydration in the absence of significant hyperketonaemia (< 3 mmol/L) or acidosis (pH > 7.3, bicarbonate > 15 mmol/L).

64 There is glycosuria, leading to an osmotic diuresis, with loss of water, sodium, potassium and other electrolytes. However, in HHS, hyperglycaemia usually develops over a longer period (a few days to weeks), causing more profound hyperglycaemia and dehydration (fluid loss may be 10–22 litres in a person weighing 100 kg).

65 Common precipitating factors includeInfection, Myocardial infarction, Cerebrovascular events Drug therapy (e.g. corticosteroids). Poor prognostic signs Hypothermia, Hypotension (systolic blood pressure < 90 mmHg), Tachy- or bradycardia, Severe hypernatraemia (sodium > 160 mmol/L), Serum osmolality > 360 mOsm/kg, The presence of other serious comorbidities.

66 Principles of management of hyperglycaemic hyperosmolar state

67 Hypoglycaemia Hypoglycaemia (blood glucose < 3.5 mmol/L (63 mg/dL)) in diabetes results in most circumstances from insulin therapy, less frequently from use of oral insulin secretagogues such as sulphonylurea drugs, and rarely with other anti-diabetic drugs.

68 In health, If blood glucose falls, endogenous insulin release from pancreatic B cells is suppressed; release of glucagon from pancreatic α cells is increased; and the autonomic nervous system is activated, with release of catecholamines both systemically and within the tissues. In addition, stress hormones, such as cortisol and growth hormone, are increased in the blood. These actions reduce whole-body glucose uptake and increase hepatic glucose production, maintaining a glucose supply to the brain.

69 People with type 1 diabetes cannot regulate insulin once it is injected subcutaneously, and so it continues to act, despite developing hypoglycaemia. In addition, within 5 years of diagnosis, most patients will have lost their ability to release glucagon specifically during hypoglycaemia. This is thought to result mainly from loss of α-cell regulation by β cells. These two primary defects mean that hypoglycaemia occurs much more frequently in people with type 1 and longer duration type 2 diabetes.

70 Most common symptoms of hypoglycaemia

71 Causes of hypoglycaemia

72 Risk factors for severe hypoglycaemia

73 Nocturnal hypoglycaemia in patients with type 1 diabetes is common but often undetected, as hypoglycaemia does not usually waken a person from sleep. Patients may describe poor quality of sleep, morning headaches and vivid dreams or nightmares, or a partner may observe profuse sweating, restlessness, twitching or even seizures.

74 Exercise-induced hypoglycaemia occurs in people with well-controlled, insulin-treated diabetes because of hyperinsulinaemia. Suppression of endogenous insulin secretion to allow increased hepatic glucose production to meet the increased metabolic demand is key to the normal physiological response to exercise.

75 Emergency treatment of hypoglycaemia

76 COMPLICATIONS OF DIABETES

77 Diabetic retinopathy Microaneurysms and retinal haemorrhages. Cotton wool spots, venous beading and intra-retinal microvascular abnormalities. The disease may then progress to proliferative DR, which is characterised by Growth of new blood vessels on the retina or optic disc .The new vessels are abnormal and often bleed, leading to vitreous haemorrhage, subsequent fibrosis and scarring, and finally tractional retinal detachment.

78

79 Diabetic nephropathy Among the most common causes of end-stage renal failure in developed countries. About 30% of patients with type 1 diabetes have developed diabetic nephropathy 20 years after diagnosis, but the risk after this time falls to less than 1% per year

80 Risk factors for diabetic nephropathy

81 Natural history of diabetic nephropathy

82 Diabetic neuropathy Classification

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84

85

86 Preventing diabetes complicationsGlycaemic control Control of other risk factors Management of blood pressure Management of dyslipidaemia

87 Association between HbA1c and risk of diabetes complications