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Pancreatic Glucokinase Is Activated by Insulin-Like Growth Factor-I

Division of Endocrinology and Metabolism (K.Y., K.M., H.I., W.M.C., X.Y., J.L., R.A.M.A., N.K., T.I.), Department of Internal Medicine, Faculty of Medicine, Kagawa University, 761-0793 Kagawa, Japan; Departments of Medicine and Biochemistry and Molecular Biology (N.C.W.W.), Faculty of Medicine, University of Calgary, Health Sciences Center, Calgary, Alberta, Canada T2N 4N1; Departments of Medicine and Physiology and Biophysics (T.G.U.), University of Illinois at Chicago College of Medicine and Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612; and Department of Molecular Physiology and Biophysics (M.A.M.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615

Address all correspondence and requests for reprints to: Koji Murao, M.D., Ph.D., Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa 761-0793, Japan. E-mail: mkoji{at}kms.ac.jp.

Glucokinase (GK) plays a key role in the regulation of glucose use and glucose-stimulated insulin secretion in pancreatic islet cells. Gene targeting of the IGF-I receptor down-regulated pancreatic islet GK activity. That finding prompted us to examine the potential mechanism that may control GK gene activity using an islet cell line, INS-1, known to express IGF-I receptor. Exposure of these cells to IGF-I induced GK protein expression and activity of the enzyme in a dose-dependent manner. In addition, IGF-I induced activity of a reporter construct containing the GK promoter in parallel with the effect on endogenous GK mRNA levels. The stimulatory effect of IGF-I on GK promoter activity was abrogated by wortmannin and LY294002, specific inhibitors of phosphatidylinositol 3-kinase. Exposure of cells to IGF-I elicited a rapid phosphorylation of Akt and FoxO1, a known target of Akt signaling. Constitutively active Akt stimulates the activity of the GK promoter, and a dominant-negative mutant of Akt or mutagenesis of a FoxO1 response element in the GK promoter abolished the ability of IGF-I to stimulate the promoter activity. Furthermore, cell knockdown of FoxO1 with small interfering RNA disrupted the effect of IGF-I on GK expression. These results demonstrate that the phosphatidylinositol 3-kinase/Akt/FoxO1 pathway contributes to the regulation of GK gene expression in response to IGF-I stimulation.