Diabetes mellitus is a complex of syndromes characterized metabolically by hyperglycemia and altered glucose metabolism, and associated pathologically with specific microvascular and macrovascular complications. 1
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Terms and Definitions Type 1 (T1DM): Type 2 (T2DM): absolute insulin deficiency, usually from autoimmune mediated destruction of the pancreatic cells (β cells) that make insulin combined effects of insulin resistance coupled with relative insulin deficiency Incidence and Prevalence of Type 1 Diabetes Prevalence in school-age children in US: 1.9 per 1000 Annual incidence: 12 to 15 cases per 100,000 Male: Female ratio: 1:1 Peak ages: 5 to 7 years puberty Mostly Caucasians affected, African-Americans are at 20-30% less risk Seasonal variation: peak in fall and winter 3
Incidence Type 1 Diabetes per 100,000 per year Children <=14 40 35 30 25 20 15 10 5 0 China Karvonnen et al., Diabetes Care, 23:1516, 2000 Venezuela Israel Kuwait Denmark Lazio Canda USA Sardinia Finland 4
Which HLA Loci Are Involved? DP DQ DR B C A + +++ +++?? + Common HLA Haplotypes 6p DQB1 DQA1DRB1 DRA High Risk DR3: DQB1*0201, DQA1*0501, DRB1*0301 DR4: DQA1*0301, DQB1*0302, DRB1*0401 Protective DR2: DQB1*0602, DQA1*0102,, DRB1*1501 BDC 5
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How to make the diagnosis Labs: Antibodies against GAD65, Insulin & IA-2 (more unspecific: Islet cell IgG) If (+) patient has type 1 diabetes Fasting glucose and C-peptide: Absent C-peptide indicates insulin dependent diabetes 7
Hypoglycemia is the most frequent complication of Type 1 diabetes The frequent occurrence is due to the imprecise match between exogenous insulin administered and insulin requirements which are affected by activity, food intake, insulin sensitivity Normal glucose counterregulation requires glucagon and catecholamine responses Both are impaired in Type 1 diabetes and hence, insulin induced falls in glucose are not met by spontaneous counterregulation. Plasma Glucose (mg/dl) Glucose counterregulation after insulin 120 100 80 60 40 20 0 0 10 20 25 30 Time T1DM Normal T2DM 8
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Mechanisms of complications: A unified field theory? Polyol pathway involving aldose reductase Binding of advanced glycation endproducts to the receptor for advanced glycation endproducts (RAGE) and intracellular signaling Organ specific? e.g. TGF-beta, VEGF Activation of Protein kinase C? 11
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EDIC study progression of retinopathy after the DCCT EDIC study Cardiovascular Disease after the DCCT 18
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Diagnosing Diabetes Diagnosis Diabetes Impaired fasting glucose or impaired glucose tolerance Normal Fasting Test 126 mg/dl or higher 110-125 mg/dl 110 mg/dl or lower Casual Test 200 mg/dl or higher (with symptoms 140-199 mg/dl 140mg/dl or lower 20
DPT-1 Parenteral Insulin Trial Time to Diabetes 1.0 Survival Distribution Function 0.9 0.8 0.7 0.6 0.5 0.4 0.3 60% have diabetes at 5-years 0.2 0.1 0.0 Number at Risk 339 275 197 138 79 27 1 0 1 2 3 4 5 6 7 Years Followed 21
Hemoglobin A1c is the gold standard measurement for assessment of diabetes management Hemoglobin A1c specifically refers to the Amadori product Of the N-terminal valine of each beta chain of HbA with glucose Glucose + Hemoglobin A Schiff Base (reversible) Amadori Product It is a reliable index of average blood glucose concentrations over the preceding 6 8 weeks. 22
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PUMP OPTIONS Features 3 options for meal boluses Temporary basal rate Increase or decrease from 30 minutes to 24 hours Patient supplied one pump Remote control feature for bolus rate programming Features One bolus rate option Temporary basal rate Increase for twelve hours and decrease four hours Basal insulin delivery every three minutes Waterproof Patient supplied two pumps 24
Recommendations for follow-up Hemoglobin A1c every 3 months Lipids yearly (goal of LDL< 100 mg/dl) Renal studies (urine for microalbumin) yearly Eye exam yearly Foot exam at each visit Cardiac evaluation (i.e. stress test) beginning at age 35 25
Graft Survival (insulin independence) Islet Transplant Registry Edmonton 85% Months post transplant 26
Intrahepatic Islet Transplantation PERCUTANEOUS TRANSHEPATIC CATHETERIZATION Reversal of lesions of diabetic nephropathy with Pancreas transplantation Fioretto et al, NEJM 1998 27
% 1c HbA 14 12 10 8 6 4 0 Glycated HbA 1c 0 5 10 15 20 25 30 35 Time (months) Pre 8.1% ± 0.5 Current 5.8% ± 0.1 p < 0.001, ANOVA 1.0 Survival Distribution Function 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 P- Value< 0.001 (Log Rank Test) Number at Risk 2697 42172 1828 39575 1416 32593 1068 24565 755 19377 517 14737 357 10678 173 5563 ICA + ICA - 0 1 2 3 4 5 6 7 DPT-1 Time to Diabetes ICA+ vs ICAn = 44,869 Years Followed STRATA: ICA + ICA - 8 28
DPT-1 Time to Diabetes By Number of Antibodies 1.0 Survival Distribution Function 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 P- Value< 0.001 (Log Rank Test) Number at Risk 24151 22297 1718 1401 405 297 378 255 147 95 17049 1045 229 192 61 11807 743 163 130 40 9052 557 118 78 30 7439 457 91 49 22 6198 371 66 31 16 3524 199 35 14 8 0 1 2 3 4 0 1 2 3 4 5 6 7 n = 26799 Years Followed 8 STRATA: 0 1 2 3 4 29
DPT-1 Parenteral Insulin Trial Time to Diabetes By Treatment 1.0 0.9 Survival Distribution Function 0.8 0.7 0.6 0.5 0.4 0.3 0.2 P- Value= 0.796 (Log Rank Test) Control Treated 0.1 0.0 Number at Risk 169 144 170 131 96 101 69 69 39 40 13 14 1 Intervention Observation 0 1 2 3 4 5 6 7 STRATA: New Engl J Med 2002; 346:1685-91 Years Followed Intervention Observation AUC of C-peptide response to MMTT at study entry and after 12 months Drug treated Control 320 320 AUC (pmol/ml/240 min) 240 160 80 AUC (pmol/ml/240 min) 240 160 80 0 0 12 Time (months) 0 0 12 Time (months) 30
Challenges An intervention that can arrest the ongoing immune response and induce tolerance Beta cell replacement with tolerance to the graft mechanical or even more physiological replacement? A supply of beta cells to accomplish the above Is hypoglycemia preventable? Markers for individuals at risk for complications and interventions that will block the effects of hyperglycemia directly or the associated abnormalities. 31