title: Increased basal level of Akt-dependent insulin signaling may be responsible for the development of insulin resistance.
abstract: 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.
authors.affiliation: Division of Translational Biology, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Hui-Yu
authors.initials: HY
authors.lastname: Liu
authors.forename: Tao
authors.initials: T
authors.lastname: Hong
authors.forename: Ge-Bo
authors.initials: GB
authors.lastname: Wen
authors.forename: Jianmin
authors.initials: J
authors.lastname: Han
authors.forename: Degen
authors.initials: D
authors.lastname: Zuo
authors.forename: Zhenqi
authors.initials: Z
authors.lastname: Liu
authors.forename: Wenhong
authors.initials: W
authors.lastname: Cao
mesh_terms: D000818:Animals; D004272:DNA, Mitochondrial / Q000032:analysis / Q000096:biosynthesis; D004041:Dietary Fats / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D015151:Immunoblotting; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance / Q000502:physiology*; D050356:Lipid Metabolism / Q000502:physiology; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D012313:RNA / Q000096:biosynthesis / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000096:biosynthesis; D014157:Transcription Factors; D014158:Transcription, Genetic
chemical_list: D004272:DNA, Mitochondrial; D004041:Dietary Fats; D007328:Insulin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000081082:Phosphoinositide-3 Kinase Inhibitors; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D012313:RNA; D051058:Oncogene Protein v-akt; D005978:Glutathione