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Thomas Mandrup-Poulsen, MD, DMSc Professor in Medical Research Methodology

Forårsmøde, Dansk Selskab for Intern Medicin 07.03.08 Frontiers of Internal Medicine. Type 2 diabetes- en inflammatorisk sygdom?. Thomas Mandrup-Poulsen, MD, DMSc Professor in Medical Research Methodology Core Unit for Medical Research Methodology Institute for Biomedical Sciences

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Thomas Mandrup-Poulsen, MD, DMSc Professor in Medical Research Methodology

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  1. Forårsmøde, Dansk Selskab for Intern Medicin 07.03.08 Frontiers of Internal Medicine Type 2 diabetes- en inflammatorisk sygdom? Thomas Mandrup-Poulsen, MD, DMSc Professor in Medical Research Methodology Core Unit for Medical Research Methodology Institute for Biomedical Sciences University of Copenhagen Research Director Department for Translational Diabetology Steno Diabetes Center

  2. Etio-pathogenesis of Type 2 Diabetes Genetic susceptibility Obesity Inflammation b-cell dysfunction/apoptosis Insulin resistance + Type 2 diabetes

  3. Adipokine expression and secretion by adipose tissue in lean subjects Bastard J-P Eur Cytokine Netw 2006; 17: 4-12

  4. Adipokine expression and secretion by adipose tissue in insulin-resistant, obese subjects Bastard J-P Eur Cytokine Netw 2006; 17: 4-12

  5. Model of integration of inflammatory and metabolic pathways that interfere with insulin action Hotamisligil GS Diabetes 2005; Suppl.2: S73-78

  6. Low-grade elevated systemic levels of CRP and IL-6 in Type 2 diabetes CRP IL-6 Kolb H, Mandrup-Poulsen T. Diabetologia 2005; 48: 1038-50

  7. Intervention studies on surrogate end-points Drug Acronym Surrogate Ref Pravastatin PRINCE CRP indep. of LDL 1 Pravastatin CARE CRP ” 2 Glitazones CRP, leptin, PAI-1, TNFa 3 Aspirin BG 3, 4 NSAID BG 5 Anti TNF, short term Insulin sensitivity, no effect 6-9 1 Albert MA et al JAMA 2001; 286: 64-70 2 Ridker PM et al Circulation 1999; 100: 230-5 3 Dandona P et al JCEM 2003; 88: 2422-9 4 Ebstein W. Berlin Klin Wochenschrift 1876; 13: 337 5 Robertson RP Diabetes 1983; 32: 231-4 6 Ofei F et al Diabetes 1996; 45: 881-5 7 Paquot N et al JCEM 2000; 85: 1316-19 8 Di Rocco P et al Obes Res 2004; 12: 734-9 9 Dominguez H et al J Vasc Res 2005; 42: 517-25

  8. Etio-pathogenesis of Type 2 Diabetes Inflammation b-cell dysfunction/apoptosis

  9. Islet inflammation and IL-1 in Type 2 diabetes • IL-1 causes functional inhibition and apoptosis of b-cells1 • Macrophage infiltration in islets of Type 2 diabetic animals and patients2 • Glucose-induced human b-cell apoptosis prevented by IL-1Ra3 • b-cells express IL-1 mRNA in Type 2 diabetic patients4 1 Mandrup-Poulsen T et al Diabetologia 1986; 29: 63‑67 2 Ehses J et al Diabetes 2007; 56: 2356-70 3 Maedler K et al J Clin Invest 2002,110;851-60 4 Boni-Schnetzler M et al ADA 2007 Diabetes 2007 (suppl. 1)

  10. Larsen CM et al N Engl J Med 2007; 356; 1517-26

  11. Larsen CM et al N Engl J Med 2007; 356; 1517-26

  12. Larsen CM et al N Engl J Med 2007; 356; 1517-26

  13. Conclusions • This study provides proof-of-principle that IL-1 is an important mediator of impaired glycemia in Type 2 diabetes by affecting b-cell function • The results suggest that long-term inhibition of IL-1 action may preserve b-cell function in Type 2 diabetic patients

  14. Investigators The Steno Team The Zürich Team Modelling and biostatistics

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