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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.

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Presentation on theme: "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."— Presentation transcript:

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3 Number of persons <5,000 5,000 – 74,000 75,000 – 349, ,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.

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

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

8  No family history: 0.4 %  affected mother: %  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 Viral infections  Immunizations  Diet: cow's milk at an early age  Vitamin D deficiency  Perinatal factors:maternal age, h/o pre- eclampsia, and neonatal jaundice  Low birth weight decreases the risk of developing type 1 diabetes

10 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, and yrs

11 3 Insulin resistance : acanthosis nigricans,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 High insulin demand glucotoxicity lipotoxicity Increased lipolysis and release of free fatty acids Elevated circulating FFA Decreased glucose uptake into glucose output Hyperglycemia Type 2 diabetes  -Cell dysfunction muscle and adipose tissue and raised hepatic

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15 Beta-cell function progressively declines Extrapolation of beta-cell function prior to diagnosis –4–46–10–8–8–6–6–2– –128 Diabetes diagnosis Years from diagnosis Beta-cell function (%, HOMA) HOMA: homeostasis model assessment Lebovitz. Diabetes Reviews 1999;7:139–53 (data are from the UKPDS population: UKPDS 16. Diabetes 1995;44:1249–58)

16 - 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  Increasing weight and less exercise  Obesity epidemic  Increasing T2DM in children and adolescents

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19 - 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 *acanthosis nigricans

20  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  Weight loss: muscle weakness  Decreases sensation  Loss of tendon reflexes  Foot Inter-digital fungal infections  Retinal changes by fundoscopy

22 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/dL during 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.

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25 3234 obese (average BMI 34 kg/m2) age 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  The intensive lifestyle and metformin interventions reduced the cumulative incidence of diabetes by 58 and 31 %, respectively compared to placebo. metformin

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

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

29  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 43% of patients do not achieve glycaemic targets (HbA 1c <7%) Ford et al (NHANES). Diabetes Care 2008;31:102–4

31  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  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  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 %

36  5. Incretin based therapy:  a. DPP4 Inhibitors:  - inhibit Dipeptidylpeptidase 4 enzyme which inactivates native GLP-1  - given orally  - Efficacy:HbA1c reduction %, 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 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. Amylin analogues: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  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 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 Glibenclamide (n=277) Years from randomisation Insulin (n=409) Metformin (n=342) Conventional treatment (n=411); diet initially then sulphonylureas, insulin and/or metformin if FPG >15 mmol/L UKPDS: up to 8 kg in 12 yearsADOPT: up to 4.8 kg in 5 years Weight (kg) Rosiglitazone Metformin Glibenclamide Change in weight (kg) Years UKPDS 34. Lancet 1998:352:854–65. n=at baseline; Kahn et al (ADOPT). NEJM 2006;355(23):2427–43

43 6.2% – upper limit of normal range Median HbA 1c (%) Conventional* Glibenclamide Metformin Insulin UKPDS Years from randomisation Recommended treatment target <7.0% † Time (years) ADOPT Metformin Glibenclamide Rosiglitazone Over time, glycaemic control deteriorates *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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