Impaired Glucagon Suppression And Reduced Insulin Sensitivity In Subjects With Prediabetes Undergoing Atorvastatin Therapy

Objective: Statin therapy has been linked to an increased risk of type 2 diabetes in high-risk populations; however, the pathophysiology of this association remains to be clarified. We investigated glucagon suppression and its relationship with insulin resistance in prediabetic subjects undergoing atorvastatin therapy; in addition, we studied molecular insulin signaling in pancreatic a-cells exposed to atorvastatin in vitro.Design and methods: Fifty subjects with prediabetes were divided into two groups based on atorvastatin therapy. All subjects underwent an oral glucose tolerance test. Early (0-30 min), late (30-120 min) and overall (0-120 min) glucagon suppression were evaluated. Insulin sensitivity was estimated by the insulin sensitivity index (ISI0-120). Insulin signaling pathway and insulin-mediated glucagon suppression were investigated in pancreatic alpha TC1-6 cells chronically exposed (24 or 48 h) to atorvastatin (100 ng/mL).Results: Individuals on statin therapy (n = 26) showed a significantly reduced early (0-30 min) (P = 0.003) and overall (0-120 min) (P = 0.01) glucagon suppression compared with controls (n = 24). In multivariate regression analysis, early glucagon suppression (0-30 min) exhibited a significant correlation with statin therapy. Regression analysis showed a significant association between ISI0-120 and early(0-30) (r = 0.33, P < 0.05) and overall(0)-(120) (r = 0.38, P < 0.05) glucagon suppression. Moreover, in alpha TC1-6 cells atorvastatin treatment affected insulin-mediated glucagon suppression, insulin receptor phosphorylation and IRS-1-AKT pathway signaling.Conclusions: Prediabetic patients undergoing statin therapy exhibit impaired glucagon suppression associated with lower insulin sensitivity. Our data revealed a new molecular aspect behind the deregulation of insulin sensitivity secondary to statin exposure.