Forårsmøde, Dansk Selskab for Intern Medicin 07.03.08
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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

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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

University of Copenhagen

Research Director

Department for Translational Diabetology

Steno Diabetes Center


Etio pathogenesis of type 2 diabetes

Etio-pathogenesis of Type 2 Diabetes

Genetic susceptibility

Obesity

Inflammation

b-cell dysfunction/apoptosis

Insulin resistance

+

Type 2 diabetes


Thomas mandrup poulsen md dmsc professor in medical research methodology

Adipokine expression and secretion by adipose tissue in lean subjects

Bastard J-P Eur Cytokine Netw 2006; 17: 4-12


Thomas mandrup poulsen md dmsc professor in medical research methodology

Adipokine expression and secretion by adipose tissue in insulin-resistant, obese subjects

Bastard J-P Eur Cytokine Netw 2006; 17: 4-12


Thomas mandrup poulsen md dmsc professor in medical research methodology

Model of integration of inflammatory and metabolic pathways that interfere with insulin action

Hotamisligil GS Diabetes 2005; Suppl.2: S73-78


Thomas mandrup poulsen md dmsc professor in medical research methodology

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


Intervention studies on surrogate end points

Intervention studies on surrogate end-points

DrugAcronym SurrogateRef

PravastatinPRINCECRPindep. of LDL1

PravastatinCARECRP”2

GlitazonesCRP, leptin, PAI-1, TNFa3

AspirinBG3, 4

NSAIDBG5

Anti TNF, short termInsulin sensitivity, no effect6-9

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


Etio pathogenesis of type 2 diabetes1

Etio-pathogenesis of Type 2 Diabetes

Inflammation

b-cell dysfunction/apoptosis


Islet inflammation and il 1 in type 2 diabetes

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)


Thomas mandrup poulsen md dmsc professor in medical research methodology

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


Thomas mandrup poulsen md dmsc professor in medical research methodology

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


Thomas mandrup poulsen md dmsc professor in medical research methodology

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


Conclusions

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


Thomas mandrup poulsen md dmsc professor in medical research methodology

Investigators

The Steno TeamThe Zürich Team

Modelling and biostatistics


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