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Increased glucose uptake promotes oxidative stress and PKC- activation in adipocytes of obese, insulin-resistant mice

¹Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978; and ²Department of Clinical Biochemistry, Faculty of Health, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel

Submitted 31 January 2003 ; accepted in final form 20 April 2003

Increased oxidative stress is believed to be one of the mechanisms responsible for hyperglycemia-induced tissue damage and diabetic complications. In these studies, we undertook to characterize glucose uptake and oxidative stress in adipocytes of type 2 diabetic animals and to determine whether these promote the activation of PKC-. The adipocytes used were isolated either from C57Bl/6J mice that were raised on a high-fat diet (HF) and developed obesity and insulin resistance or from control animals. Basal glucose uptake significantly increased (8-fold) in HF adipocytes, and this was accompanied with upregulation of GLUT1 expression levels. Insulin-induced glucose uptake was inhibited in HF adipocytes and GLUT4 content reduced by 20% in these adipocytes. Reactive oxygen species (ROS) increased twofold in HF adipocytes compared with control adipocytes and were largely reduced with decreased glucose concentrations. At zero glucose, ROS levels were reduced to the normal levels seen in control adipocytes. The activity of PKC- increased twofold in HF adipocytes compared with control adipocytes and was further activated by H₂O₂. Moreover, PKC- activity was inhibited in HF adipocytes either by glucose deprivation or by treatment with the antioxidant N-acetyl-L-cysteine. In summary, we propose that increased glucose intake in HF adipocytes increases oxidative stress, which in turn promotes the activation of PKC-. These consequential events may be responsible, at least in part, for development of HF diet-induced insulin resistance in the fat tissue.

oxidative stress; protein kinase C-; insulin resistance; glucose metabolism; C57Bl/6J mice

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