The antiinflammatory cytokine interleukin-1 receptor antagonist protects from high-fat diet-induced hyperglycemia

Endocrinology. 2008 May;149(5):2208-18. doi: 10.1210/en.2007-1059. Epub 2008 Jan 31.


Subclinical inflammation is a recently discovered phenomenon in type 2 diabetes. Elevated cytokines impair beta-cell function and survival. A recent clinical trial shows that blocking IL-1beta signaling by IL-1 receptor antagonist (IL-1Ra) improves beta-cell secretory function in patients with type 2 diabetes. In the present study, we provide further mechanisms of the protective role of IL-1Ra on the beta-cell. IL-1Ra prevented diabetes in vivo in C57BL/6J mice fed a high-fat/high-sucrose diet (HFD) for 12 wk; it improved glucose tolerance and insulin secretion. High-fat diet treatment increased serum levels of free fatty acids and of the adipokines resistin and leptin, which were reduced by IL-1Ra treatment. In addition, IL-1Ra counteracted adiponectin levels, which were decreased by high-fat feeding. Studies on isolated islets revealed that IL-1Ra specifically acted on the beta-cell. IL-1Ra protected islets from HFD treated animals from beta-cell apoptosis, induced beta-cell proliferation, and improved glucose-stimulated insulin secretion. Insulin mRNA was reduced in islets from mice fed a HFD but normalized in the IL-1Ra group. Our results show that IL-1Ra improves beta-cell survival and function, and support the potential role for IL-1Ra in the treatment of diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipokines / blood
  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use
  • Apoptosis / drug effects
  • Cell Count
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / prevention & control
  • Diet, Atherogenic*
  • Disease Progression
  • Drug Evaluation, Preclinical
  • Eating / drug effects
  • Glucose Intolerance / drug therapy
  • Hyperglycemia / etiology
  • Hyperglycemia / prevention & control*
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / physiology
  • Interleukin 1 Receptor Antagonist Protein / pharmacology*
  • Interleukin 1 Receptor Antagonist Protein / therapeutic use
  • Mice
  • Mice, Inbred C57BL
  • Weight Gain / drug effects


  • Adipokines
  • Anti-Inflammatory Agents
  • Interleukin 1 Receptor Antagonist Protein