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DIABETES Arshia Panahloo Consultant Diabetologist St. George's Hospital , London

DIABETES Arshia Panahloo Consultant Diabetologist St. George's Hospital , London. www.addison.ac.uk. Topics to be covered:. Diagnosis Classification Epidemiology and Pathogenesis Complications. Diagnosis. Diagnosis. Hyperglycaemia central to the diagnosis Diagnostic confusion

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DIABETES Arshia Panahloo Consultant Diabetologist St. George's Hospital , London

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  1. DIABETES Arshia Panahloo Consultant Diabetologist St. George's Hospital , London

  2. www.addison.ac.uk

  3. Topics to be covered: • Diagnosis • Classification • Epidemiology and Pathogenesis • Complications

  4. Diagnosis

  5. Diagnosis • Hyperglycaemia central to the diagnosis • Diagnostic confusion • 1985 WHO criteria,based on an oral glucose tolerance test • American Diabetes Association set their own criteria in 1997 • WHO revised in 1998

  6. WHO 1985 Diagnostic Criteria

  7. ADA 1997 Diagnostic Criteria

  8. Diagnosis In the presence of symptoms: (polyuria, polydipsia,weight loss) • Random plasma glucose  11.1 mmol/l OR • Fasting plasma glucose  7.0 mmol/l OR • 2 hour plasma glucose  11.1 mmol/l, 2hrs after a 75g oral glucose tolerance test

  9. Diagnosis In the absence of symptoms • Diagnosis should not be based on a single sample • Two samples on separate days, either: • fasting • random • 2 hour post load

  10. Diagnosis IGT and IFG • IGT (Impaired Glucose Tolerance) • Fasting plasma glucose < 7.0 mmol and 2 hour OGT value 7.8 -11.1 • IFG (Impaired Fasting Glycaemia) • fasting plasma glucose 6.1 - 7.0 mmol/l • IGT and IFG are not clinical entities in their own right but risk categories for cardiovascular disease (IGT) and/or future diabetes (IFG)

  11. Diagnosis • The diagnosis of diabetes has important legal and medical implications • Diagnosis should NOT be made on: • Glycosuria • Finger prick blood glucose • HbA1c • A venous plasma sample is needed in an accredited laboratory

  12. Classification

  13. Type 1 b cell destruction Type 2 insulin resistance +/- insulin deficiency due to b cell dysfunction Gestational diabetes Aetiological Classification WHO 1998

  14. Classification • Other specific types • genetic defects (b cell) • genetic defects (insulin) • exocrine pancreas • endocrinopathies • drug / chemical induced • infections • immune-mediated • other genetic syndromes

  15. Classification • Diabetes due to other endocrine disease: • Cushing’s syndrome • Acromegaly • Thyrotoxicosis • Phaeochromocytoma • Hyperaldosteronism • Glucagonoma

  16. Classification • Diabetes due drugs and chemicals: • Glucocorticoids • Diuretics • B-Blockers • B2-agonists • Phenytoin • Cyclosporin • Nicotinic acid

  17. Classification • Diabetes associated with genetic syndromes • DIDMOAD (Wolfram) syndrome • Myotonic dystrophy and other muscular disorders • Lipoatrophic diabetes • Type-1 glycogen storage disease • Cystic fibrosis

  18. Epidemiology and Pathogenesis of Type-1 Diabetes

  19. Type-1 Diabetes • Develops predominantly in children and young adults • Can occur in all age groups • Occurs in all continents • Marked geographical variation • Finland and Sardinia highest, 30-35 cases per 100,000 children aged up to 14 years • oriental populations lowest, <1 per 100,000

  20. Geographical variation • Variability is unexplained: • genetic factors • environmental factors • Incidence in childhood in increasing • ‘outbreaks’ suggest infectious agents • seasonal variation, highest in autumn and winter when viral infections more prevalent

  21. Presentation • Peak age of onset 11-13 years • 10% of diabetic patients over 60 years are insulin dependent • In UK the prevalence of type-1 DM is 1% (20% of total DM patients) • 20% of typical type-2 DM display evidence of autoimmunity

  22. Natural History of Type-1 DM • Commonest cause is autoimmune destruction of B-cells • Interaction between genetic factors and environment • Onset is abrupt, but B-cell antigens may be present for many years • Pre-diabetic state mild abnormalities of insulin secretion and glucose tolerance can be detected

  23. ‘Honeymoon period’ • After starting insulin, some patients need very small amounts • Last 2-12 months • Improvement in B-cell function once ‘glucose toxicity’ removed • True remission rare • Research into preserving B-cell function

  24. Genetic Factors (1) • Account for a third of the susceptibility to type-1 DM • 36% concordance for monozygotic twins • Over 20 regions of the human genome show some linkage with type-1 DM • Strongest linkage is with HLA genes within the MCH region on chrom. 6

  25. Genetic Factors (2) • HLA haplotypes DR3 and DR4 predispose to type-1 DM • linkage disequilibrium with true susceptibility loci • HLA class II antigens on the cell surface present foreign and self antigens to T-lymphocytes and initiate the auto- immune response

  26. Genetic Factors (3) • Strong linkage between HLA-DR and DQ regions • Polymorphisms of the DQB1 gene resulting in amino acid substitution in class II antigens may determine B-cell damage • Region of the insulin gene on chrom. 11 is linked to type-1 DM, insulin or pre-cursors can act as B-cell autoantigens

  27. Environmental Factors • Viruses • Dietary components • Stress • Drugs and toxins

  28. Viruses • Viruses can directly destroy B-cells or indirectly by an autoimmune response • Mumps • Occasionally precedes IDDM • autoimmune B-cell destruction • islet cell antibodies develop • can induce interleukin production and HLA hyperexpression in B-cells

  29. Viruses • Coxsackie B • IgM anti-coxsackie B antibodies in newly diagnosed type-1 DM • Antigen identified in islets post-mortem • Direct cytotoxic action on B-cells • Retroviruses • Rubella • CMV • Epstein-Barr

  30. Nutrients • ? Nitrosamines in diet • Breast feeding • short duration associated with increased risk of adult Type-1 diabetes in some studies • Antibodies to cow’s milk protein found in higher titres in children with recent onset type-1 diabetes

  31. Epidemiology and Pathogenesis of Type-2 Diabetes

  32. Type 1 Type 2 Incidence of type 2 diabetes rapidly increasing 3 million in the UK by 2010 3000 2500 2000 Diabetes prevalence (thousands) 1500 1000 500 0 2010 2000 1995 Amos AF et al. Diabet Med 1997;14(Suppl 5);S1–S85

  33. Geographical variation • Large variation • Highest in some native American tribes (Pima Indians) in Arizona (50%) and South Pacific Islands • Low prevalence in least developed rural communities • Prevalence is closely associated with BMI

  34. Type-2 Diabetes in the UK • Prevalence: • 1-2% for the white population • 11% for Indian • 9% for African-Caribbeans • Compared to white patients Indian patients have younger age of onset of type-2 diabetes and earlier protinuria and renal disease, and excess CHD.

  35. Type-2 Diabetes • Accounts for 85% of the diabetic population • Patients do not require insulin to remain alive, although 20% are treated with insulin to control blood glucose • Peak age of onset is 60 years, younger age of onset seen with MODY

  36. Type-2 Diabetes • Is characterized by variable combinations of insulin resistance and insulin deficiency • Insulin deficiency is less severe than type-1 diabetes and insulin levels remain high enough to prevent excess lipolysis and ketoacidosis • Patients are C-peptide positive

  37. Insulin Resistance Inability of insulin to produce its usual biological effects at circulating concentrations that are effective in normal subjects.

  38. Acquired causes of insulin resistance • 1) Obesity • truncal obesity (visceral fat) is related to insulin resistance • BMI >35 have 40 x risk of developing DM compared with those with BMI < 23 • visceral fat is especially susceptible to lipolysis and hence raised NEFA • truncal obesity is associated with increased proportion of white muscle fibres which are more insulin resistant than red fibres

  39. 2) Reduced physical activity • exercise increases : • insulin sensitive red fibres • fat oxidative enzymes • tissue (white adipose) sensitivity to catecholamines and enhancing lipolysis • hence exercise increases insulin sensitivity & increased utilisation of fat as fuel • 3) Malnutrition in foetal/early infant life • low birth wt. assoc with metabolic syndorme X in later life (obesity,insulin resistance & DM, hypertension, dyslipidaemia, atherosclerosis)

  40. Management of Type II Diabetes • Aims :- • Abolish symptoms and acute complications of hyperglycaemia • Reduce threat of chronic complications • Increase life expectancy • Restore quality of life

  41. Genetics of Type II Diabetes • High rate of concordance (60-100%) for the disease in identical twins • Familial aggregation • Different prevalence in ethnic groups • Polygenic trait with environmental factors • MODY (0.3% type-2) mutations in glucokinase gene • Mutations in mitochondrial DNA (rare)

  42. Complications

  43. Complications of Diabetes • Microvascular: • Nephropathy • Retinopathy • Neuropathy • Macrovascular • Coronary heart disease / Stroke /lipids • Peripheral vascular disease • Blood pressure

  44. Retinopathy • Type-1: • Rare less than 5 years of diabetes • With increasing prevalence the incidence rises to a peak at 15-20 years • Severe proliferative retinopathy also increases with diabetes duration, >20yrs • Type-2: • Can be present at diagnosis • Increased incidence of macular oedema

  45. Retinopathy • Risk Factors: • Poor glycaemic control • Genetic factors • Blood pressure • Smoking

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