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Type 1 Diabetes in Adults

Type 1 Diabetes in Adults. Andrej Janež, MD PhD Dept. of Endocrinology Diabetes and Metabolic Diseases University Medical Center Ljubljana. Prevalence of Diabetes in the United States. US Population: 275 Million in 2000. Undiagnosed diabetes 5.2 million . Diagnosed type 2 diabetes

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Type 1 Diabetes in Adults

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  1. Type 1 Diabetes in Adults Andrej Janež, MD PhD Dept. of Endocrinology Diabetes and Metabolic Diseases University Medical Center Ljubljana

  2. Prevalence of Diabetesin the United States US Population: 275 Million in 2000 Undiagnosed diabetes 5.2 million Diagnosed type 2 diabetes 12 million Diagnosed type 1 diabetes ~1.0 million Type 1 diabetes misdiagnosed as type 2 diabetes ~1.0 million Centers for Disease Control. Available at: http://www.cdc.gov/diabetes/pubs/estimates.htm;EURODIAB ACE Study Group. Lancet. 2000;355:873-876; Harris MI. In: NationalDiabetes Data Group. Diabetes in America. 2nd ed. Bethesda, Md: NIDDK;1995:15-36; U.S. Census Bureau Statistical Abstract of the U.S.; 2001

  3. Incidence of Type 1 Diabetes • Incidence increasing by 3.4% per year • 50% of patients diagnosed before age 20 years • 50% of patients diagnosed after age 20 years • Often mistaken for type 2 diabetes—may make up 10% to 30% of individuals diagnosed with type 2 diabetes • Oral agents ineffective; insulin therapy required • Autoimmune process slower and possibly different • Can usually be confirmed by beta cell antibodies • Loss of c-peptide EURODIAB ACE Study Group. Lancet. 2000;355:873-876; Naik RG, Palmer JP. Curr Opin Endocrinol Diabetes. 1997;4:308-315

  4. Making the Diagnosis of Type 1 Diabetes Symptoms of diabetes Polyuria, polydipsia, polyphagia, diabetic plus ketoacidosis (DKA) Random plasma glucose200 mg/dL* Fasting plasma glucose (FPG)126 mg/dL* Oral glucose tolerance test (OGTT) with 2-hour value200 mg/dL* Loss of c-peptidec-peptide<0.8 ng/dL Presence of islet autoantibodiesGADA, ICA, IA-2A, IAA *Requires confirmation by repeat testing American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S5-S10

  5. Natural History of “Pre”–Type 1 Diabetes Putative trigger -Cell mass 100% Cellular autoimmunity Circulating autoantibodies (ICA, GAD65, ICA512A, IAA) Loss of first-phase insulin response (IVGTT) Abnormal glucosetolerance (OGTT) Clinical onset Genetic predisposition Insulitis-Cell injury -Cell insufficiency Diabetes Time Eisenbarth GS. N Engl J Med. 1986;314:1360-1368

  6. Rationale for Intensive Therapyof Type 1 DiabetesGlucose Control Is Critical

  7. Risk of Progression ofMicrovascular Complications vs A1C DCCT Relative risk 20 Retinopathy Neuropathy 15 Microalbuminuria 10 5 0 1 5 6 7 8 9 10 11 12 A1C (%) A1C=hemoglobin A1c Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254

  8. Intensive Therapy for Diabetes:Reduction in Incidence of Complications T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus. *Not statistically significant due to small number of events. †Showed statistical significance in subsequent epidemiologic analysis. DCCT Research Group. N Engl J Med. 1993;329:977-986; Ohkubo Y, et al. Diabetes Res Clin Pract. 1995;28:103-117; UKPDS 33: Lancet. 1998;352: 837-853; Stratton IM, et al. Brit Med J. 2000;321:405-412.

  9. Long-term Microvascular Risk Reduction in Type 1 DiabetesCombined DCCT-EDIC Intensive Conventional Retinopathy progression (incidence) 12% A1C 10% 8% 6% P<0.001 P<0.001 P=0.61 DCCTEnd of randomized treatment EDICYear 1 EDICYear 7 No. Evaluated Conventional 169 203 220 581 158 192 200 Intensive 191 222 197 596 170 218 180 DCCT/EDIC Research Group. JAMA. 2002;287:2563-2569

  10. Cost-Effectiveness of IntensiveTherapy in Type 1 Diabetes DCCT Modeling Study DCCT Research Group. JAMA. 1996;276:1409-1415

  11. Principles of Intensive Therapy ofType 1 DiabetesTargets

  12. Current Targets for Glycemic Control *Peak American Diabetes Association. Diabetes Care. 2004,27:S15-S35. The American Association of Clinical Endocrinologists. Endocr Pract. 2002; 8(suppl. 1):40-82. Chacra AR, et al. Diabetes Obes Metab. 2005;7:148-160. IDF (Europe) European Diabetes Policy Group. Diabet Med. 1999;16:716-730.

  13. Principles of Intensive Therapy ofType 1 DiabetesInsulin Options

  14. Action Profiles of Insulins 2 3 4 5 6 7 8 9 12 13 14 15 16 17 18 19 20 21 22 23 24 0 1 10 11 Aspart, glulisine, lispro 4–5 hours Regular 6–8 hours Plasma insulin levels NPH 12–16 hours Detemir ~14 hours Ultralente 18–20 hours Glargine ~24 hours Hours Burge MR, Schade DS. Endocrinol Metab Clin North Am. 1997;26:575-598; Barlocco D. Curr Opin Invest Drugs. 2003;4:1240-1244; Danne T et al. Diabetes Care. 2003;26:3087-3092

  15. Normal Daily Plasma Insulin ProfileNondiabetic Obese Individuals U/mL 100 B L D 80 60 40 20 1200 2400 1800 0800 0600 0600 Time of day B=breakfast; L=lunch; D=dinner Polonsky KS et al. N Engl J Med. 1988;318:1231-1239

  16. Basal/Bolus Treatment Program with Rapid-acting and Basal Analogs Breakfast Lunch Dinner Rapid Rapid Rapid Plasma insulin Basal 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Time

  17. Physiologic Multiple Injection RegimensThe Basal-Bolus Insulin Concept • Basal insulin • Controls glucose production between meals and overnight • Near-constant levels • Usually ~50% of daily needs • Bolus insulin (mealtime or prandial) • Limits hyperglycemia after meals • Immediate rise and sharp peak at 1 hour postmeal • 10% to 20% of total daily insulin requirement at each meal • For ideal insulin replacement therapy, each component should come from a different insulin with a specific profile or via an insulin pump (with one insulin)

  18. Basal-bolus Therapy: • More frequent decision making, testing, and insulin dosing • Allows for variable food consumption based on hunger level • Ability to skip meal or snack if desired (bedtime) • Reduced variability of insulin absorption • Easy to adapt to acute changes in schedule (exercise, sleeping in on weekends)

  19. Insulin pens Faster and easier than syringes Improve patient attitude and adherence Have accurate dosing mechanisms, but inadequate resuspension of NPH may be a problem Insulin Injection Devices

  20. Mealtime Insulin and Severe HypoglycemiaAspart vs Regular Insulin Favors RegularInsulin Favors Aspart P Values NS 0.076 <0.050 <0.005 All severe hypoglycemia Nocturnal event Nocturnal, glucagon required 4–6 hours postmeal 0.1 1 10 Relative risk Home PD et al. Diabet Med. 2000;17:762-770

  21. Variable Basal Rate Continuous Subcutaneous Insulin Infusion (CSII) 75 Breakfast Lunch Dinner 50 Bolus Plasma Insulin µU/ml) Bolus Bolus 25 Basal Infusion 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Time

  22. Insulin PumpsContinuous Subcutaneous Insulin Infusion (CSII) • For motivated patients • Expensive • External, programmable pump connected to an indwelling subcutaneous catheter • Only rapid-acting insulin • Programmable basal rates • Bolus dose without extra injection • New pumps with dose calculator function • Bolus history • Requires support system of qualified providers

  23. CSII vs Multiple Injections of InsulinMeta-analyses Pickup et al. 12 RCTs Weissberg-Benchell et al. 11 RCTs InjectionTherapyBetter PumpTherapyBetter Blood glucose concentration Glycated hemoglobin A1C Insulin dose -2 -1 0 1 2 Mean difference RCT=randomized controlled trial Pickup J et al. BMJ. 2002;324:1-6; Weissberg-Benchell J et al. Diabetes Care. 2003;26:1079-1087

  24. Balancing Risk of Severe Hypoglycemia Against the Risk of ComplicationsDCCT Retinopathy Progression Severe Hypoglycemia 100 patient-years 120 100 patient-years 16 14 100 12 80 10 60 8 6 40 4 20 2 0 0 8.0 10.5 5.0 5.5 6.0 6.5 7.0 7.5 8.5 9.0 9.5 10.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 5.0 A1C (%) A1C (%) DCCT Research Group. N Engl J Med. 1993;329:977-986

  25. HypoglycemiaRisk Factors • Behavioral Factors • Dietary inconsistency • Prolonged fasting • Missed meal or snack • Strenuous exercise • Patient Factors • Hypoglycemia unawareness • History of previous hypoglycemia • Defective glucose counterregulation • Long duration of diabetes • Erratic insulin absorption • Age less than 5 to 7 years • Medical Factors • Drug side effects (-blockers) • Dosing errors • Unpredictable insulin kinetics • Inappropriate insulin distribution

  26. Weight Gain • Insulin therapy reverses catabolic effects of diabetes • Glycosuria reduced • Normal fuel-storage mechanisms restored • Risk of hypoglycemia often causes patients to increase caloric intake and avoid exercise • Risk of weight gain decreases with more physiologic insulin administration • Flexible insulin dosing to meet dietary and exercise needs

  27. Future Glucose Monitors Guardian™ CGMS External Closed-Loop • Minimally invasive continuous glucose monitors • Implanted glucose sensors • Implanted insulin pumps • “Closed-loop” systems Freestyle Navigator™ Implanted Closed-Loop

  28. Can Type 1 Diabetes Be “Cured?”Islet Cell Transplantation 7 Type 1 Patients, Aged 29 to 54 Years, With History of Severe Hypoglycemia and Metabolic Instability MeanC-peptide(ng/mL) Mean A1C (%) * 5.7 8.4% * * 2.5 5.7% 0.48 Baseline 6 monthsafter transplant Baseline 90 min postmeal Fasting 6 monthsafter transplant *P<0.001 vs baseline Shapiro AMJ et al. N Engl J Med. 2000;343:230-238

  29. Opportunities for Intervention inType 1 Diabetes TrialNet Multiple antibody positive Genetically at risk Loss of first-phase insulin response -Cell mass Newly diagnosed diabetes Genetic predisposition Insulitis-Cell injury -Cell insufficiency Diabetes Time

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