Thomas Mandrup-Poulsen, MD, DMSc Professor in Medical Research Methodology
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Dias 1 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 Forårsmøde, Dansk Selskab for Intern Medicin 07.03.08 Frontiers of Internal Medicine Type 2 diabetes- en inflammatorisk sygdom?
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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 - PowerPoint PPT Presentation
Transcript of Thomas Mandrup-Poulsen, MD, DMSc Professor in Medical Research Methodology
Dias 1
Thomas Mandrup-Poulsen, MD, DMSc
Professor in Medical Research MethodologyCore Unit for Medical Research MethodologyInstitute for Biomedical SciencesUniversity of Copenhagen
Research DirectorDepartment for Translational DiabetologySteno Diabetes Center
Forårsmøde, Dansk Selskab for Intern Medicin 07.03.08Frontiers of Internal Medicine
Type 2 diabetes- en inflammatorisk sygdom?
Etio-pathogenesis of Type 2 Diabetes
Insulin resistance -cell dysfunction/apoptosis
Type 2 diabetes
Genetic susceptibility
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Obesity
Inflammation
Adipokine expression and secretion by adipose tissue in lean subjects
Bastard J-P Eur Cytokine Netw 2006; 17: 4-12
Adipokine expression and secretion by adipose tissue in insulin-resistant, obese subjects
Bastard J-P Eur Cytokine Netw 2006; 17: 4-12
Model of integration of inflammatory and metabolic pathways that interfere with insulin action
Hotamisligil GS Diabetes 2005; Suppl.2: S73-78
Kolb H, Mandrup-Poulsen T. Diabetologia 2005; 48: 1038-50
Low-grade elevated systemic levels of CRP and IL-6 in Type 2 diabetes
CRP IL-6
Intervention studies on surrogate end-points
Pravastatin PRINCE CRP indep. of LDL 1Pravastatin CARE CRP ” 2
Glitazones CRP, leptin, PAI-1, TNF3
Aspirin BG 3, 4NSAID BG 5
Anti TNF, short term Insulin sensitivity, no effect 6-9
Drug Acronym Surrogate Ref
1 Albert MA et al JAMA 2001; 286: 64-702 Ridker PM et al Circulation 1999; 100: 230-53 Dandona P et al JCEM 2003; 88: 2422-94 Ebstein W. Berlin Klin Wochenschrift 1876; 13: 3375 Robertson RP Diabetes 1983; 32: 231-4
6 Ofei F et al Diabetes 1996; 45: 881-57 Paquot N et al JCEM 2000; 85: 1316-198 Di Rocco P et al Obes Res 2004; 12: 734-99 Dominguez H et al J Vasc Res 2005; 42: 517-25
Etio-pathogenesis of Type 2 Diabetes
-cell dysfunction/apoptosis
Inflammation
Islet inflammation and IL-1 in Type 2 diabetes
• IL-1 causes functional inhibition and apoptosis of -cells1
• Macrophage infiltration in islets of Type 2 diabetic animals and patients2
• Glucose-induced human -cell apoptosis prevented by IL-1Ra3
• -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: 2356-703 Maedler K et al J Clin Invest 2002,110;851-604 Boni-Schnetzler M et al ADA 2007 Diabetes 2007 (suppl. 1)
Larsen CM et al N Engl J Med 2007; 356; 1517-26
Larsen CM et al N Engl J Med 2007; 356; 1517-26
Larsen CM et al N Engl J Med 2007; 356; 1517-26
Conclusions • This study provides proof-of-principle that IL-
1 is an important mediator of impaired glycemia in Type 2 diabetes by affecting -cell function
• The results suggest that long-term inhibition of IL-1 action may preserve -cell function in Type 2 diabetic patients
The Steno Team The Zürich Team
Modelling and biostatistics
Investigators
