Atorvastatin induces insulin sensitization in Zucker lean and fatty rats

Background: The 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors ('statins') have been implicated in preventing new onset type 2 diabetes, whereas the mechanism of this effect is not known. We investigated the effects of an HMG-CoA reductase inhibitor, atorvastatin, on insulin sensitization in Zucker lean and fatty rats. Methods and results: In vivo studies of insulin sensitization were performed in chow fed Zucker lean and fatty rats treated with atorvastatin 50 mg/kg/day (ATORVA_50) and results were compared to Zucker lean and fatty rats treated with drug vehicle only (CONT). Additional Zucker lean rats were treated with an intermediate dose of atorvastatin 25 mg/kg/day (ATORVA_25). Treatment with atorvastatin resulted in a dose-dependent improvement in whole body insulin sensitivity in both lean and fatty rats, with an approximately two-fold increase in glucose infusion rate and glucose disposal (Rd) in ATORVA_50 versus CONT (p < 0.01). Atorvastatin 50 mg/kg/day resulted in an increase in 2-deoxyglucose (2-DOG) uptake by skeletal muscles (approximately two-fold increase in 2-DOG uptake in quadriceps (p = 0.06) and gastrocnemius (p < 0.01)) in lean Zucker rats. Insulin-stimulated phosphorylation of Akt/PKB was significantly increased in skeletal muscle of ATORVA_50 versus CONT in both lean and fatty rats. Conclusion: Atorvastatin induces insulin sensitization in Zucker lean and fatty rats. This may be a clinically important pleiotropic effect if confirmed in insulin resistant humans.