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This Article Full Text Full Text (PDF) Supplemental Tables All Versions of this Article: 297/4/E898    most recent 00374.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Google Scholar Articles by Liu, H.-Y. Articles by Cao, W. PubMed PubMed Citation Articles by Liu, H.-Y. Articles by Cao, W.

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

¹Translational Biology, The Hamner Institutes for Health Sciences, Research Triangle Park; ⁴Department of Internal Medicine (Endocrinology), Duke University Health System, Durham, North Carolina; ²The First Affiliated Hospital of the University of South China, Hengyang, Hunan, People's Republic of China; and ³Department 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