The antiinflammatory cytokine interleukin-1 receptor antagonist protects from high-fat diet-induced hyperglycemia.
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.
Sauter
Nadine S
NS
Larry L. Hillblom Islet Research Center, University of California Los Angeles, Los Angeles, California 90095-7345, USA.
Schulthess
Fabienne T
FT
Galasso
Ryan
R
Castellani
Lawrence W
LW
Maedler
Kathrin
K
D054392:Adipokines / Q000097:blood; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy / Q000517:prevention & control; D004036:Diet, Atherogenic; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D004435:Eating / Q000187:drug effects; D018149:Glucose Intolerance / Q000188:drug therapy; D006943:Hyperglycemia / Q000209:etiology / Q000517:prevention & control*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D015430:Weight Gain / Q000187:drug effects
D054392:Adipokines; D000893:Anti-Inflammatory Agents; D053590:Interleukin 1 Receptor Antagonist Protein