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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
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 that interfere with insulin actionin 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 that interfere with insulin action

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


Etio pathogenesis of type 2 diabetes1
Etio-pathogenesis of Type 2 Diabetes that interfere with insulin action

Inflammation

b-cell dysfunction/apoptosis


Islet inflammation and il 1 in type 2 diabetes
Islet inflammation and IL-1 in Type 2 diabetes that interfere with insulin action

  • 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 that interfere with insulin action


Larsen CM et al N Engl J Med 2007; 356; 1517-26 that interfere with insulin action


Larsen CM et al N Engl J Med 2007; 356; 1517-26 that interfere with insulin action


Conclusions
Conclusions that interfere with insulin action

  • 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 that interfere with insulin action

The Steno Team The Zürich Team

Modelling and biostatistics


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