RESUMO
BACKGROUND: High doses of anti-inflammatory drugs, such as aspirin and salicylates, improve glucose metabolism in insulin resistant and type 2 diabetic patients. It has also been shown that the glucose lowering effect is related to the unspecific ability of these drugs to inhibit inhibitor kinaseß (IKKß). In this study we have investigated the effect of a selective IKKß-inhibitor on beta cell survival and the prevention of diet induced type 2 diabetes in the gerbil Psammomys obesus (P. obesus). METHODOLOGY/PRINCIPAL FINDINGS: P. obesus were fed a diabetes inducing high energy diet for one month in the absence or presence of the IKKß-inhibitor. Body mass, blood glucose, HbA(1C), insulin production and pancreatic insulin stores were measured. The effects on beta cell survival were also studied in INS-1 cells and primary islets. The cells were exposed to IL-1ß and subsequently reactive oxygen species, insulin release and cell death were measured in the absence or presence of the IKKß-inhibitor. In primary islets and beta cells, IL-1ß induced the production of reactive oxygen species, reduced insulin production and increased beta cell death, which were all reversed by pre-treatment with the IKKß-inhibitor. In P. obesus the IKKß-inhibitor prevented the development of hyperglycaemia and hyperinsulinaemia, and maintained pancreatic insulin stores with no effect on body weight. CONCLUSIONS/SIGNIFICANCE: Inhibition of IKKß activity prevents diet-induced diabetes in P. obesus and inhibits IL-1ß induced reactive oxygen species, loss of insulin production and beta cell death in vitro.
