1. Dr. Sarbast Fakhradin MBChB, MSc Diabetes Care & Management

2. Diabetes mellitus It is a clinical syndrome characterised by hyperglycaemia caused by absolute or relative deficiency of insulin and this affects the metabolism of carbohydrate, protein and fat, and can cause significant disturbance of water and electrolyte homeostasis. Complications: 1. Acute metabolic decompensation. 2. Chronic complications affecting the eye, the kidney and the nervous system.

3. Epidemiology Worldwide prevalence is 366 million patients & its rising, mainly type 2. UK is around 4%, but is much higher in the Middle and Far East (11-30%).

4. 350 A.D. : "water tasters" diagnosed diabetes by tasting the urine. 1675 : the word "mellitus," meaning honey, was added to the name "diabetes," meaning siphon. 1800s: chemical tests to detect the presence of sugar in the urine. The first diabetes treatment involved prescribed exercise (horseback riding) 1700s and 1800s: dietary changes could help manage diabetes In 1889 researchers in France, showed that the removal of a dog's pancreas could induce diabetes. In 1900s a German scientist, found that injecting pancreatic extract into patients could help control diabetes. In 1920 Frederick Banting, a physician from Canada, first had the idea to use insulin to treat diabetes in lab, 1922 in human, then awarded the Nobel prize.

5. Classification of DM: Primary: Type 1 (A or B) & Type 2 Other specific types: Genetic defects of β-cell function/insulin action Pancreatic disease (pancreatitis, pancreatectomy, neoplastic disease, cystic fibrosis, haemochromatosis) Excess endogenous production of hormonal antagonists to insulin (growth hormone; glucocorticoids; glucagon; catecholamines; thyroid hormones) Drug-induced (corticosteroids, thiazide, phenytoin) Viral infections (congenital rubella, mumps, Coxsackie virus B) Associated with genetic syndromes (Down's syndrome; Klinefelter's syndrome; Turner's syndrome; DIDMOAD (Wolfram's syndrome)-diabetes insipidus, diabetes mellitus, optic atrophy, nerve deafness; Friedreich's ataxia; myotonic dystrophy) Gestational diabetes LADA & MODY

6. Metabolic actions of insulin Increase (anabolic effects)Decrease (anticatabolic effects) Carbohydrate metabolism Glucose transport (muscle, adipose tissue) Gluconeogenesis Glycogenolysis Glucose phosphorylation Glycogenesis Glycolysis Pyruvate dehydrogenase activity Pentose phosphate shunt Lipid metabolism Triglyceride synthesisLipolysis Fatty acid synthesis (liver)Lipoprotein lipase (muscle) Lipoprotein lipase activity (adipose tissue) Ketogenesis Fatty acid oxidation (liver) Protein metabolism Amino acid transportProtein degradation Protein synthesis

7. Pancreatic structure and endocrine function:

9. Cont.

10. Aetiology & pathogenesis of diabetes Type 1 DM: Pathology: T cell-mediated autoimmune destruction of the β cells in pancreas. Insulitis: recurrent infiltration of islets with mononuclear cells Patchiness of the lesion. β-cell specificity of the destructive process, with the glucagon and other hormone-secreting cells in the islet remaining intact. Islet cell antibodies (glutamic acid decarboxylase (GAD)) can be detected. Associated with other autoimmune disorders, including thyroid disease, coeliac disease, Addison's disease, pernicious anaemia, & vitiligo.

11. Honeymoon period: its occur after initial clinical presentation of type 1 DM during which time glycemic control is achieved with modest doses of insulin or rarely insulin isnt needed Genetic Predisposition: It is account for about one-third of the susceptibility to type 1 diabetes. Short arm of chromosome 6 (Polygenetic inheritance). HLA haplotypes DR3 and/or DR4. Concordance rate between monozygotic twins is less than 40%.

12. Environmental Factors: 1. Infection: A. Hygiene hypothesis : reduced exposure to microorganisms in early childhoods limits maturation of immune system and increases susceptibility to autoimmune disease. B. viral infection: mumps, Coxsackie B4, retroviruses, rubella (in utero), cytomegalovirus and Epstein-Barr virus. 2. Stress 3. Dietary factors: Various nitrosamines (found in smoked and cured meats), coffee, & cow’s milk have been proposed as potentially diabetogenic. 4. Immunological factors: Hyperglycaemia accompanied by the classical symptoms of diabetes occurs only when 70-90% of β cells have been destroyed.

13. Type 2 DM: Pathology: Insulin resistance & β-cell failure It is a complex condition there is a combination of insulin resistance in liver and muscle together with impaired pancreatic β-cell function leading to 'relative' insulin deficiency. Intra-abdominal 'central' adipose tissue is metabolically active, and releases large quantities of FFAs, cytokines, & adipokines which act on specific receptors to influence sensitivity to insulin. Sedentary lifestyle leads to obesity & more insulin-resistant. There might be fatty infiltration of the liver (non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). At the time of diagnosis, around 50% of β-cell function has been lost.

14. Some pathological changes are typical such as is deposition of amyloid. Heavy deposition of islets with amyloid is rare without diabetes, but small quantities are very common in elderly non diabetic patients. Hyperglycemia & elevated FFA are toxic to β-cell However, while β-cell numbers are reduced, α-cell mass is unchanged and glucagon secretion is increased, which may contribute to the hyperglycaemia. Genetic predisposition: Its not HLA linked & autoimmunity or viral infections are less significant Concordance rates for type 2 diabetes might reach 100% A mutation of the glucokinase gene is associated with some cases of the uncommon syndrome of maturity onset diabetes in the young (MODY), constitute less than 5% of all cases of type 2 diabetes

15. Environmental factors: Diet & obesity: Type 2 diabetes is associated with overeating, especially when combined with obesity and underactivity. The risk of developing type 2 diabetes increases tenfold in people with a body mass index (BMI) > 30 kg/m 2. Obesity probably acts as a diabetogenic factor (through increasing resistance to the action of insulin) only in those who are genetically predisposed both to insulin resistance and to β-cell failure. Sweet foods rich in refined carbohydrate consumed frequently may increase the demand for insulin secretion, while high-fat foods may increase FFAs and exacerbate insulin resistance.

16. Environmental factors: Cont. Age: Type 2 diabetes is more common in the middle-aged and elderly. Pregnancy: During normal pregnancy, insulin sensitivity is reduced through the action of placental hormones and this affects glucose tolerance. The insulin- secreting cells of the pancreatic islets may be unable to meet this increased demand in women genetically predisposed to develop diabetes. The term 'gestational diabetes' refers to hyperglycaemia occurring for the first time during pregnancy. Repeated pregnancy increases the likelihood of developing irreversible diabetes, particularly in obese women; 80% of women with gestational diabetes ultimately develop permanent diabetes.

17. α -Cells (glucagon) Normal T2DM β-Cells (insulin) Disorganised and misshapen Marked reduction in β-cell number Amyloid plaques Amyloid plaque Changes in Pancreatic Islet Morphology Represent Underlying Functional Defects

18. Therefore the main etiologies of type 2 DM are: 1. Relative insulin deficiency 2. Increase hepatic production of glucose. 3. Insulin resistance which usually accompanies obesity this includes: Abnormal insulin molecule An excessive amount of circulating antagonists. Target tissue defect(common cause)

19. Natural History of type 2 DM:

20. 1. 2-6 fold increased risk of heart disease, stroke and peripheral vascular disease. 2. 60% will die of cardiovascular problems. 3. 60-80% are hypertensive. 4. 60-70% have some kind of peripheral neuropathy.

21. 5. Up to 50% of all amputations occur in diabetic patients. 6. Is the single commonest (13.8%) cause of blindness in those of working age. 7. Nephropathy occurs in about 25% 8. Accounts for 8-10% of healthcare budget.

22. Xanthelasma

23. Arcus Senilis

24. Diabetic Retinopathy

25. Acanthosis nigricans

27. Thank you Questions?