1. Interleukin-1-Receptor Antagonist in Type 2 Diabetes Mellitus Claus M. Larsen, M.D., Mirjam Faulenbach, M.D., Allan Vaag, M.D., Ph.D., Aage Vølund, M.Sc., Jan A. Ehses, Ph.D., Burkhardt Seifert, Ph.D., Thomas Mandrup-Poulsen, M.D., Ph.D., and Marc Y. Donath, M.D. N Engl J Med 2007:356:1517-26 N Engl J Med 2007:356:1517-26 R2 B.H.Cho

2. Introduction Type 2 DM is a result of failure compensating for insulin resistance due to beta-cell demise through apoptosis. Type 2 DM is a result of failure compensating for insulin resistance due to beta-cell demise through apoptosis. IL-1b promotes the apoptosis of beta cells (produced from beta cells in pancreatic sections of type 2 DM patients). IL-1b promotes the apoptosis of beta cells (produced from beta cells in pancreatic sections of type 2 DM patients). IL-1-receptor antagonist protects human beta cells from glucose-induced functional impairment and apoptosis. IL-1-receptor antagonist protects human beta cells from glucose-induced functional impairment and apoptosis.  balance between IL-1-receptor antagonist & IL-1 might improve beta-cell function and IL-1 might improve beta-cell function and glycemic control in patients with type 2 DM glycemic control in patients with type 2 DM

3. Method Study design Study design placebo-controlled, double-blind, parallel-group study placebo-controlled, double-blind, parallel-group study 70 patients with type 2 diabetes 70 patients with type 2 diabetes IL-1 Rc antagonist (anakinra) VS Placebo IL-1 Rc antagonist (anakinra) VS Placebo continued their baseline antidiabetic therapy continued their baseline antidiabetic therapy No change in dietary habits & other lifestyle habits No change in dietary habits & other lifestyle habits

4. Method Inclusion criteria Inclusion criteria Age>20 Age>20 Type 2 DM>3months Type 2 DM>3months BMI>27 BMI>27 HbA1c>7.5% HbA1c>7.5% No change in medication (types & doses) No change in medication (types & doses)

5. Method Exclusion criteria Exclusion criteria Presence of Ab (GAD 65/islet-cell Ab-2) Presence of Ab (GAD 65/islet-cell Ab-2) HbA1c>12% HbA1c>12% Fasting C-peptide<400pmol/l Fasting C-peptide<400pmol/l Current use of anti-inflammatory drug Current use of anti-inflammatory drug Signs of infection (CRP>30, fever, use of antibiotics) Signs of infection (CRP>30, fever, use of antibiotics) Neutropenia (<2000) or anemia (<11g/dl) Neutropenia (<2000) or anemia (<11g/dl)

6. Method Primary end point Primary end point Level of HbA1c Level of HbA1c Secondary end points Secondary end points Glycemia (fasting glucose level) Glycemia (fasting glucose level) B-cell function (proinsulin/insulin, C-peptide level) B-cell function (proinsulin/insulin, C-peptide level) Insulin sensitivity (HOMA index) Insulin sensitivity (HOMA index) Inflammatory markers (CRP, IL-6) Inflammatory markers (CRP, IL-6) Insulin-regulated gene expression (Bx of muscle) Insulin-regulated gene expression (Bx of muscle) Serum adipokines Serum adipokines

7. Enrollment and Outcomes

8. Baseline characteristics

9. Primary&Secondary end points

10. Secondary end points

11. No difference No difference Insulin resistance Insulin resistance Insulin regulated gene expression Insulin regulated gene expression Serum adipokine levels Serum adipokine levels

12. Adverse events

13. Conclusion There were improved glycemia and beta-cell secretory function and reduced markers of systemic inflammation by the blockade of IL-1 with anakinra. There were improved glycemia and beta-cell secretory function and reduced markers of systemic inflammation by the blockade of IL-1 with anakinra. There were no increase in insulin sensitivity and no significant adverse effects on the use of anakinra. There were no increase in insulin sensitivity and no significant adverse effects on the use of anakinra.