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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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

Genetic susceptibility

Obesity

Inflammation

b-cell dysfunction/apoptosis

Insulin resistance

+

Type 2 diabetes


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


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

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 Diabetes

Inflammation

b-cell dysfunction/apoptosis


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)


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 b-cell function

  • The results suggest that long-term inhibition of IL-1 action may preserve b-cell function in Type 2 diabetic patients


Investigators

The Steno TeamThe Zürich Team

Modelling and biostatistics


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