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:
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.
1. Progressive beta cell dysfunction: -Reduced Insulin secretion in response to serum glucose 2. Insulin resistance: genetic -increases with age and weight. - glucotoxicity - lipotoxicity
3. Impaired insulin processing: proinsulin ratio increase to 40% in T2DM from a nl ratio of 10-15%
Epidemiology: - bimodal: a. one peak at 4-6 years of age b. second in early puberty (10-14 years) M=F.
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
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
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
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
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
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)
- 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
Increasing weight and less exercise Obesity epidemic Increasing T2DM in children and adolescents
- 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
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)
Weight loss: muscle weakness Decreases sensation Loss of tendon reflexes Foot Inter-digital fungal infections Retinal changes by fundoscopy
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.
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
The intensive lifestyle and metformin interventions reduced the cumulative incidence of diabetes by 58 and 31 %, respectively compared to placebo. metformin
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.
16 % reduction in DM risk for every kg lost Improvements in insulin sensitivity and insulin secretion, correlated directly with decreased risk of diabetes
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
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.
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.
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
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.
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
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