Increased basal level of Akt-dependent insulin signaling may be responsible for the development of insulin resistance

1 Translational Biology, The Hamner Institutes for Health Sciences, Research Triangle Park; 4 Department of Internal Medicine (Endocrinology), Duke University Health System, Durham, North Carolina; 2 The First Affiliated Hospital of the University of South China, Hengyang, Hunan, People's Republic of China; and 3 Department of Medicine (Endocrinology), University of Virginia, Charlottesville, Virginia Submitted 10 June 2009 ; accepted in final form 20 July 2009 A majority of subjects with insulin resistance and hyperinsulinemia can maintain their blood glucose levels normal for the whole life presumably through protein kinase B (Akt)-dependent insulin signaling. In this study, we found that the basal Akt phosphorylation level was increased in liver and gastrocnemius of mice under the high-fat diet (HFD). Levels of mitochondrial DNA and expression of some mitochondrion-associated genes were decreased by the HFD primarily in liver. Triglyceride content was increased in both liver and gastrocnemius by the HFD. Oxidative stress was induced by the HFD in both liver and gastrocnemius. Insulin sensitivity was decreased by the HFD. All of these changes were largely or completely reversed by treatment of animals with the phosphatidylinositol 3-kinase inhibitor LY-294002 during the time when animals usually do not eat. Consequently, the overall insulin sensitivity was increased by treatment with LY-294002. Together, our results indicate that increased basal Akt-dependent insulin signaling suppresses mitochondrial production, increases ectopic fat accumulation, induces oxidative stress, and desensitizes insulin signaling in subjects with insulin resistance and hyperinsulinemia. protein kinase B Address for reprint requests and other correspondence: W. Cao, Division of Translational Biology, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709 (e-mail: wcao{at}thehamner.org ).