Diabetes Mellitus

2. Diabetes Mellitus

3. Estimated prevalence of diabetes worldwide in 2025 Number of persons <5,000 5,000 – 74,000 75,000 – 349,000 350,000 – 1,500,000 >1,500,000 No data available A projected 300 million people with diabetes worldwide by 2025 WHO. The World Health Report 1998; 91; King H, et al.Diabetes Care 1998; 21:1414–1431.

5. Pathophysiology- Type 2 DM • 1. Progressive beta cell dysfunction: -Reduced Insulin secretion in response to serum glucose • 2. Insulin resistance: genetic -increases with age and weight. - glucotoxicity - lipotoxicity

6. Pathophyisiology-T2DM • 3. Impaired insulin processing: proinsulin ratio increase to 40% in T2DM from a nl ratio of 10-15%

7. Pathophysiology -Type 1DM • Epidemiology: - bimodal: a. one peak at 4-6 years of age b. second in early puberty (10-14 years) • M=F.

8. Genetic susceptibility -T1DM  •  • No family history: 0.4 % •  • affected mother: 2 - 4 % •  • affected father: 5 to 8 % •  • both parents affected: 30 % •  • Non-twin sibling of affected patient: 5 % •  • Dizygotic twin: 8 % •  • Monozygotic twin: 50 % lifetime risk

9. Environmental factors-T1DM    • Viral infections •  • Immunizations •  • Diet: cow's milk at an early age •  • Vitamin D deficiency •  • Perinatalfactors:maternal age, h/o pre-eclampsia, and neonatal jaundice • Low birth weight decreases the risk of developing type 1 diabetes

10. Type 1 versus type 2 diabetes  1 • Body habitus : T2DM: overweight T1DM: not overweight and often have a recent history of weight loss. 2 • Age : T2DM :after the onset of puberty. T1DM bimodal: 4 -6 yrs, and10 -14 yrs

11. 3• Insulin resistance : acanthosisnigricans,HTN, dyslipidemia, and PCOS 4• FH: type 2 > type 1 5• Autoimmune Abs: T1DM: +:GAD, tyrosine phosphatase (IA2), and/or insulin Abs T2DM: 30 % have + Abs

12. Insulin resistance and -cell dysfunction Increased lipolysis and release of free fatty acids Elevated circulating FFA lipotoxicity High insulin demand -Cell dysfunction Insulin resistance glucotoxicity Decreased glucose uptake into glucose output Hyperglycemia muscle and adipose tissue and raised hepatic Type 2 diabetes

15. Beta-cell function progressively declines 100 Diabetes diagnosis 80 60 Beta-cell function (%, HOMA) 40 20 Extrapolation of beta-cell function prior to diagnosis 0 –12 –10 –8 –6 –4 –2 0 2 4 6 8 Years from diagnosis HOMA: homeostasis model assessmentLebovitz. Diabetes Reviews1999;7:139–53 (data are from the UKPDS population: UKPDS 16. Diabetes 1995;44:1249–58)

16. Genetic susceptibilty- T2DM - T2DM is 2-6x (blacks> whites) • 39% have at least one parent with the disease • monozygotic twin: 90 % • The lifetime risk for a first-degree relative of a pt with T2DM is 5-10 x higher than age- & wt-matched

17. ROLE OF DIET, OBESITY, AND INFLAMMATION • Increasing weight and less exercise • Obesity epidemic • Increasing T2DM in children and adolescents

19. MAJOR RISK FACTORS ( Type2DM) - FH of DM - Overweight (BMI > 25 kg/m2) -physical inactivity -Race/ethnicity (African-Americans, Hispanic-Americans) - h/o IFG or IGT -History of GDM or delivery of a baby weighing >9 lbs -Signs of insulin resistance or conditions associated with insulin resistance : *Hypertension ( 140/90 mmHg in adults) *HDL cholesterol 35 mg/dl (0.90 mmol/l) and/or a triglyceride level 250 mg/dl (2.82 mmol/l) *Polycystic ovary syndrome *acanthosisnigricans

20. Symptoms • Polyuria, increased frequency of urination, nocturia. • Increased thirst, and dry mouth • Weight loss • Blurred vision • Numbness in fingers and toes • Fatigue • Impotence (in some men)

21. Signs • Weight loss: muscle weakness • Decreases sensation • Loss of tendon reflexes • Foot Inter-digital fungal infections • Retinal changes by fundoscopy

22. Criteria for the diagnosis of diabetes 1. A1C ≥6.5 %. * • 2. FPG ≥126 mg/dL. Fasting is defined as no caloric intake for at least 8 h.* • 3. Two-hour plasma glucose ≥200 mg/dLduring an OGTT. 75 g anhydrous glucose dissolved in water.* • 4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dL . * In the absence of unequivocal hyperglycemia, criteria 1-3 should be confirmed by repeat testing.

25. Diabetes Prevention-DPP trial 3234 obese (average BMI 34 kg/m2) age 25-85 yrs at high risk for DM (Obese+ IFG/IGT) were randomized to: • 1. Intensive lifestyle changes: 7 % wt loss ( low-fat diet and exercise for 150 min/ wk) • 2. metformin (850 mg BID) + information on diet and exercise • 3. Placebo plus information on diet and exercise

26. DPP • The intensive lifestyle and metformin interventions reduced the cumulative incidence of diabetes by 58 and 31 %, respectively compared to placebo.

27. DPP • The diet and exercise group lost an average of 6.8 kg (7%) of wt / 1st yr. • At 3 years, fewer patients in this group developed diabetes (14 versus 22 and 29 % in the metformin and placebo groups) • Lifestyle intervention was effective in men and women in all age groups and in all ethnic groups.

28. DPP • 16 % reduction in DM risk for every kg lost • Improvements in insulin sensitivity and insulin secretion, correlated directly with decreased risk of diabetes

29. Management of Type2DM • 1. Lifestyle modifications: • - Medical nutrition therapy • - increased physical activity • - wt reduction • 2. Oral Drug Therapy/Noninsulin sc therapy • 3. Insulin therapy

30. Key challenges of type 2 diabetes: outcome Ford et al (NHANES). Diabetes Care 2008;31:102–4 43% of patients do notachieve glycaemic targets (HbA1c<7%)

31. Current available Therapy • 1. Biguanides: Metformin • -decrease hepatic glucose output • -increases glucose utilization in peripheral tissues (such as muscle and liver) • -antilipolytic effect • -increases intestinal glucose utilization • Efficacy : HbA1c reduction by 1-1.5%

32. Side Effects: GI upset initially, Lactic acidosis ( 9 cases per 100,000 person-years of exposure)e ) • C/I : renal impairment S.Cr > 1.5 mg/dl males, and S.Cr > 1.4 Females, liver failure, advanced heart failure, sepsis, hypotension.

33. Drug therapy-2 • 2. Sufonylureas and Meglitinides: Glibenclamide, Repagnilide • - Mechanism: activate SU receptor, stimulate insulin secretion • - Efficacy : HbA1c reduction 1-2 % ( SU), <1% Glinides • - S/E: Hypoglycemia, wt gain • - C/I: pregnancy,

34. Drug therapy-3 • 3. Alpha- glucosidase inhibitors: Acarbose • - inhibits GI glucose absorption • - prominent GI S/E • - modest HbA1c reductions 0.6%

35. 4. Thiazolidinediones: Pioglitazones,Rosiglitazones • - PPAR Gamma agonists • -insulin sensitizer on adipose tissue, liver, skeletal muscles. • -S/E: fluid retention-edema,CHF, Hepatotoxicity, bone fractures, macular edema • -Efficacy: HbA1c reduction 1-1.5 %

36. Drug therapy-3 • 5. Incretin based therapy: • a. DPP4 Inhibitors: • - inhibit Dipeptidylpeptidase 4 enzyme which inactivates native GLP-1 • - given orally • - Efficacy:HbA1c reduction 0.6 -0.8 %, up to 1% if higher baseline HbA1c (>9%) • -S/E: ? Pancreatitis, hepatotoxicity, Skin reactions

37. b. GLP1 agonists: • Exenetide: synthetic exendin4, from saliva of Gila monster, 53% homology with natural GLP1. • - augments insulin release (glucose- dependent ). • - slows gastric emptying, • -suppresses inappropriately elevated glucagon levels, and leads to weight loss • - HbA1c reduction 1.1% • -S/E : GI (nausea), acute pancreatitis,acute renal failure.

38. Drug therapy 4 Liraglutide :GLP-1 analog, binds to serum albumin resulting in slower degradation, • -Once daily injection • - HbA1c reduction of 1.5% • -significant weight reduction • - S/E: GI, pancreatitis, ? Thyroid C-cell hyperplasia/malignancy in animal studies.

39. 6. Amylinanalogues:AMYLIN is a 37-amino acid peptide that is stored in pancreatic beta cells and is co-secreted with insulin . Amylin is deficient in type 1 diabetes and relatively deficient in insulin-requiring type 2 diabetes • -slowed gastric emptying, • -regulation of postprandial glucagon • - reduction of food intake

40. Drug therapy 5 • PRAMLINTIDE : amylin analog • -approved for both type 1 and insulin-treated type 2 diabetes. • -effects are glucose-dependent and are overridden as serum glucose levels fall. It does not cause hypoglycemia • -HbA1c reduction < 1% • S/E : nausea, increase hypoglycemia risk if insulin dose not reduced.

41. Insulins 1. Ultra-short acting : Aspart-Lispro-Glulisine • 2. Short acting: Regular • 3. Intermediate acting : NPH • 4. intermediate—long : Insulin Detimir • 5. Long acting : Insulin Glargine

42. Most therapies result in weight gain over time UKPDS: up to 8 kg in 12 years ADOPT: up to 4.8 kg in 5 years 100 8 Insulin (n=409) 7 6 96 5 Glibenclamide (n=277) Change in weight (kg) 4 Weight (kg) 92 3 2 88 1 Metformin (n=342) 0 0 3 6 9 12 0 0 1 2 3 4 5 Years from randomisation Years Conventional treatment (n=411); diet initially then sulphonylureas, insulin and/or metformin if FPG >15 mmol/L Rosiglitazone Metformin Glibenclamide UKPDS 34. Lancet 1998:352:854–65. n=at baseline; Kahn et al (ADOPT). NEJM 2006;355(23):2427–43

43. Over time, glycaemic control deteriorates Conventional* Rosiglitazone UKPDS ADOPT Glibenclamide Metformin Metformin Glibenclamide 9 Insulin 8.5 8 8 7.5 7.5 Median HbA1c (%) 7 Recommended treatment target <7.0%† 7 6.5 6.5 6 6.2% – upper limit of normal range 0 1 2 3 4 5 0 2 4 6 8 10 6 Time (years) Years from randomisation *Diet initially then sulphonylureas, insulin and/or metformin if FPG>15 mmol/L; †ADA clinical practice recommendations. UKPDS 34, n=1704 UKPDS 34. Lancet 1998:352:854–65; Kahn et al (ADOPT). NEJM 2006;355(23):2427–43

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