We recently found that chromium picolinate (CrPic), a nutritional supplement thought to improve insulin sensitivity in individuals with impaired glucose tolerance, enhances insulin action by lowering plasma membrane (PM) cholesterol. Recent in vivo studies suggest that cholesterol-lowering statin drugs benefit insulin sensitivity in insulin-resistant patients, yet a mechanism is unknown. We report here that atorvastatin (ATV) diminished PM cholesterol by 22% (P < 0.05) in 3T3-L1 adipocytes. As documented for CrPic, this small reduction in PM cholesterol enhanced insulin action. Replenishment of cholesterol mitigated the positive effects of ATV on insulin sensitivity. Co-treatment with CrPic and ATV did not amplify the extent of PM cholesterol loss, or insulin sensitivity gain. In addition, analyses of insulin signal transduction suggest a non-signaling basis of both therapies. Our data reveal an unappreciated beneficial non-hepatic effect of statin action and highlight a novel mechanistic similarity between two recently recognized therapies of impaired glucose tolerance. (C) 2008 Elsevier Inc. All rights reserved.