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Preservation of Beta-Cells in Type 2 Diabetes: Is it Possible?

Preservation of Beta-Cells in Type 2 Diabetes: Is it Possible?. Faramarz Ismail-Beigi, MD, PhD Departments of Medicine and Biochemistry Case Western Reserve University Cleveland, Ohio October 10, 2012, Isfahan. OUTLINE.

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Preservation of Beta-Cells in Type 2 Diabetes: Is it Possible?

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  1. Preservation of Beta-Cells in Type 2 Diabetes: Is it Possible? Faramarz Ismail-Beigi, MD, PhD Departments of Medicine and Biochemistry Case Western Reserve University Cleveland, Ohio October 10, 2012, Isfahan

  2. OUTLINE • Role of insulin resistance and beta cell function in type 2 diabetes; derangements in diabetes • How is beta cell function measured? • Can beta cell function be enhanced and preserved? insulin metformin and sulfonyureas thiazolodinediones GLP-1 agonists and DPP-4 inhibitors

  3. 100 75 50 IGT Postprandial Hyperglycemia Type 2 Diabetes Phase I Type 2 Diabetes Phase III 25 Type 2 Diabetes Phase II 0 -12 -10 -6 -2 0 2 6 10 14 Years from diagnosis Decline of -Cell Function in the UKPDS Illustrates Progressive Nature of Diabetes Beta cell function (%)

  4. Relative Beta-Cell Volume in NGT, IFG, and T2DM SD Relative β-cell Volume (%) (Mean +/- SE) Butler AE, et al. Diabetes 2003;52:102-110.

  5. Insulin Secretion vs. Insulin Sensitivity Glucose stimulated Ist Phase Insulin Secretion Disposition Index

  6. Relationship Between Insulin Secretion and Insulin Sensitivity; Disposition Index 6 5 10 4 3 9 8 2 1 7 Acute Insulin Secretion (relative units) D C E A B 0 0 5 10 Insulin Sensitivity Index (relative units)

  7. Beta-Cell Function and Insulin Sensitivity in Subjects With Varying Degrees of Dysglycemia Whole body Sensitivity to Insulin Beta-cell Sensitivity to Glucose Ferrannini et al. J Clin Endocrinol Metab 90:493-500, 2005

  8. Beta-Cell Dysfunction Gastaldelli A, et al. Diabetologia. 47:31-39, 2004

  9. Cumulative Incidence of Diabetes as a Function of Acute Insulin Release and Sensitivity to Insulin Pratley, R.E., Weyer, C. Diabetologia 44: 929-945, 2001

  10. Genetics of Type 2 Diabetes ~30% incidence with one parent affected ~70% incidence with both parent affected Virtually all of the susceptibility genes identified thus far have to do with insulin secretion

  11. OUTLINE • Role of insulin resistance and beta cell function in type 2 diabetes • How is beta cell function measured? • Can beta cell function be enhanced and preserved? insulin metformin and sulfonyureas thiazolodinediones GLP-1 agonists and DPP-4 inhibitors

  12. Methods For Measurement Of Beta-Cell Function • Static tests • HOMA-B (using fasting glucose and insulin) • Plasma pro-insulin/insulin ratio • Dynamic tests • 3. Insulin and c-peptide response to glucagon • 4. First phase insulin release to IV glucose • 5. First and second phase insulin release to IV glucose • Insulinogenic Index • Insulin and c-peptide response to oral glucose • at 30 minutes (change in insulin/change in glucose) • 7. Hyperglycemia plus arginine (maximal capacity) • 8. Clamp methodology

  13. Early Insulin Secretion (first-phase) 17 normal men Glucose infused rapidly and then clamped at 14 mM Pratley and Weyer. Diabetologia 44:929-945, 2001

  14. Early Insulin Secretion (first-phase)Acute Insulin Release 17 normal men Glucose infused rapidly and then clamped at 14 mM Pratley and Weyer. Diabetologia 44: 929-945, 2001

  15. Loss of First-Phase Insulin Response Type 2 (n=9) -30 0 30 60 90 120 TIME (min) 20 G glucose i.v. 120 Normal (n=9) 100 80 PLASMA INSULIN (µU/ml) 60 40 20 0 -30 0 30 60 90 120 TIME (min) Pfeifer et al. Am J Med. 70:579-588, 1981.

  16. Acute Insulin Release versus Fasting Glucose Pratley, R.E., Weyer, C. Diabetologia 44: 929-945, 2001

  17. Acute Insulin Release in the Progression of Normal to Pre-diabetes to Diabetes Pratley, R.E., Weyer, C. Diabetologia 44: 929-945, 2001

  18. OUTLINE • Role of insulin resistance and beta cell function in type 2 diabetes • How is beta cell function measured? • Can beta cell function be enhanced and preserved? insulin metformin and sulfonyureas thiazolodinediones GLP-1 agonists and DPP-4 inhibitors

  19. Beta-Cell Function in Type 2 Diabetes: Can It Be Improved?? β-cell function in T2DM Beta-cell Function (% Normal) (Years Pre-diagnosis) (Years Post-diagnosis) U.K. Prospective Diabetes Study Group, Diabetes 44:1249-1258, 1995

  20. Effect of Early Insulin Rx on Glycemic Control in Newly-Diagnosed Type 2 Diabetics (Design) • 44 patients with newly diagnosed type 2 • Fasting glucoses > 300 mg/dL • 10-14 days of insulin Rx to preprandial glucose of 90-130 mg/dL • OGGT at 2 weeks • Then, randomized to NPH insulin or metformin ± glicazide MR • OGGT at 6 months • Then, Rx all patients with oral agents • Fasting glucose and insulin at 12 months Chen et al. Diabetes Care 31:1927-1932, 2008

  21. Effect of Early Insulin Rx on Glycemic Control in Newly-Diagnosed Type 2 Diabetics (OGTT) #Results of OGTT performed in patients with A1c < 7.0% at 12 months. *P<0.05 Chen et al. Diabetes Care 31:1927-1932, 2008

  22. Effect of Early Insulin Rx on Beta-cell Function in Newly-Diagnosed Type 2 Diabetes (Design) 382 patients; fasting glucose of 7.0-16.7 mM Random assignment to two weeks of treatment with: • Continuous insulin infusion • Multiple daily doses of insulin, or • Oral hypoglycemic agents (metformin ± glidazide) Then all Rx stopped. Rx: diet + exercise. Patients followed for 12 months. Beta-cell function measured by HOMA-B and acute insulin response to 25 gram IV glucose at baseline, at ~3 weeks, and 1 year. Relapse defined at fasting glucose > 7.0 mM Weng et al. Lancet 371:1753-1760, 2008

  23. Effect of Early Insulin Rx on Beta-cell Function in Newly-Diagnosed Type 2 Diabetes **Before and after 3 weeks of Rx. @ P <0.05 compared to insulin infusion. Weng et al. Lancet 371:1753-1760, 2008

  24. Effect of Early Insulin Rx on Beta-cell Function in Newly-Diagnosed Type 2 Diabetes Weng et al. Lancet 371:1753-1760, 2008

  25. OUTLINE • Role of insulin resistance and beta cell function in type 2 diabetes • How is beta cell function measured? • Can beta cell function be enhanced and preserved? insulin metformin and sulfonyureas thiazolodinediones GLP-1 agonists and DPP-4 inhibitors

  26. Effect of Rosiglitazone on Development of Type 2 Diabetes in Persons with Pre-Diabetes (The Dream Trial) 5269 adults (aged 54.7) with IFG (739), IGT (3028), or both (1502) Randomized and treated with Rosiglitazone (8 mg) or placebo Primary outcome: composite of incident diabetes or death Median follow-up of 3 years The Dream Trial Lancet 363:1096-1105, 2005

  27. Effect of Rosiglitazone on Development of Type 2 Diabetes in Persons with Pre-Diabetes (The Dream Trial) The Dream Trial Lancet 363:1096-1105, 2005

  28. Effect of Thiazolidinediones on Beta-Cell Function in Type 2 Diabetes (Design) Normal and Type 2 diabetic patients Diabetic patients were randomized to pioglitazone or placebo for 4 months Then treated with pioglitazone or rosiglitazone for another 4 months 2-h OGTT preformed several different times Two-step englycemic insulin clamps (40 and 160 mU/m2 per min) Data on normal and drug-naive diabetic group receiving pioglitazone Insulin secretion corrected for changes in insulin resistance Gastaldelli et al. Am J Physiol. 292:E871-E883, 2007

  29. Effect of Pioglitazone on Beta-Cell Function Parameter of Beta-Cell Function * p <0.05 Gastaldelli et al. Am J Physiol. 292:E871-E883, 2007

  30. ADOPT Study • Recently-diagnosed type 2 diabetes (1-3 years) • 4,360 patients, randomized double-blind study • Testing the efficacy of rosiglitazone vs metformin vs glyburide for 4 years • Primary Outcome: time to monotherapy failure • Secondary Outcomes: FBS, HbA1c, beta-cell function Kahn S, et al. N Engl J Med. 355:2427-2443, 2006

  31. ADOPT Study Kahn S, et al. N Engl J Med. 355:2427-2443, 2006

  32. ADOPT Study Kahn S, et al. N Engl J Med. 355:2427-2443, 2006

  33. OUTLINE • Role of insulin resistance and beta cell function in type 2 diabetes • How is beta cell function measured? • Can beta cell function be enhanced and preserved? insulin metformin and sulfonyureas thiazolodinediones GLP-1 agonists and DPP-4 inhibitors

  34. Effect of GLP-1 on Islet Function and Insulin Sensitivity in Type 2 Diabetes Six well controlled patients with type 2 diabetes Insulin sensitivity measured by euglycemic hyperinsulinemic clamp GLP-1 infusion vs saline (acute experiment) Islet function measured by arginine stimulation of acute insulin response at three glucose levels: basal, 14 mM, and 28 mM Ahren et al. J Clin Endocrinol Metab. 82:473-477, 1997

  35. Effect of GLP-1 on Islet Function and Insulin Sensitivity in Type 2 Diabetes Ahren et al. J Clin Endocrinol Metab. 82:473-477, 1997

  36. Time (min) Effect of GLP-1 on Islet Function and Insulin Sensitivity in Type 2 Diabetes Saline = open circles GLP-1 = filled circles Glucose levels are: Fasting at 0 min 14 mM at 30 min 28 mM at 220 min Ahren et al. J Clin Endocrinol Metab. 82:473-477, 1997

  37. Beta-Cell Function in Type 2 Diabetes: Can It Be Improved?? β-cell function in T2DM Beta-cell Function (% Normal) (Years Pre-diagnosis) (Years Post-diagnosis) U.K. Prospective Diabetes Study Group, Diabetes 44:1249-1258, 1995

  38. GRADE Study The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study

  39. GRADE TrialA Comparative Effectiveness Study In patients with recent onset of Type 2 diabetes, what is the most effective agent to be added to metformin? Metformin plus a GLP-1 agonist Metformin plus a DPP-4 inhibitor Metformin plus a sulfonylurea Metformin plus insulin

  40. GRADE Study: Primary Outcome • Primary outcome is Rx failure defined as a hemoglobin A1c (HbA1c) >7%, subsequently confirmed (intention-to-treat).

  41. GRADE Study: Secondary Outcomes • Metabolic • Cardiovascular • Microvascular • Adverse effects • Side-effects • Adherence, tolerability • Health economics • Other

  42. GRADE Study: Secondary Outcomes Metabolic • HbA1c • Fasting plasma glucose (FPG) values • Hypoglycemia episodes • Body weight, waist and hip circumferences, body mass index (BMI) • Measurements derived from MTT to assess insulin resistance, beta-cell function, and other metabolic parameters

  43. Thank You

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