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Activation of the Hexosamine Pathway Leads to Phosphorylation of Insulin Receptor Substrate-1 on Ser³⁰⁷ and Ser⁶¹² and Impairs the Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin Insulin Biosynthetic Pathway in RIN Pancreatic ß-Cells

Department of Experimental and Clinical Medicine (F.A., E.L., F.P., G.S.), University of Catanzaro-Magna Græcia, 88100 Catanzaro, Italy; Laboratory of Molecular Medicine (C.D., M.F., R.L.), Department of Internal Medicine, University of Rome-Tor Vergata, 00133 Rome, Italy; and Department of Endocrinology and Metabolism (S.D.G., S.D.P., P.M.), Metabolic Unit, University of Pisa, 56100 Pisa, Italy

Address all correspondence and requests for reprints to: Giorgio Sesti, M.D., Dipartimento di Medicina Sperimentale e Clinica, Università di Catanzaro-Magna Græcia, Via Tommaso Campanella, 115, 88100 Catanzaro, Italy. E-mail: sesti{at}unicz.it.

Many adverse effects of glucose were attributed to its increased routing through the hexosamine pathway (HBP). There is evidence for an autocrine role of the insulin signaling in ß-cell function. We tested the hypothesis that activation of the HBP induces defects in insulin biosynthesis by affecting the insulin-mediated protein translation signaling. Exposure of human pancreatic islets and RIN ß-cells to glucosamine resulted in reduction in glucose- and insulin-stimulated insulin biosynthesis, which in RIN ß-cells was associated with impairment in insulin-stimulated insulin receptor substrate-1 (IRS-1) phosphorylation at Tyr⁶⁰⁸ and Tyr⁶²⁸, which are essential for engaging phosphatidylinositol 3-kinase (PI 3-kinase). These changes were accompanied by impaired activation of PI 3-kinase, and activation of Akt/mammalian target of rapamycin/phosphorylated heat- and acid-stable protein-1/p70S6 kinase pathway. RIN ß-cells exposed to high glucose exhibited increased c-Jun N-terminal kinase (JNK) and ERK1/2 activity, which was associated with increased IRS-1 phosphorylation at serine (Ser)³⁰⁷ and Ser⁶¹², respectively, that inhibits coupling of IRS-1 to the insulin receptor and is upstream of the inhibition of IRS-1 tyrosine phosphorylation. Azaserine reverted the stimulatory effects of high glucose on JNK and ERK1/2 activity and IRS-1 phosphorylation at Ser³⁰⁷ and Ser⁶¹². Glucosamine mimicked the stimulatory effects of high glucose on JNK and ERK1/2 activity and IRS-1 phosphorylation at Ser³⁰⁷ and Ser⁶¹². Inhibition of JNK and MAPK kinase-1 activity reverted the negative effects of glucosamine on insulin-mediated protein synthesis. These results suggest that activation of the HBP accounts, in part, for glucose-induced phosphorylation at Ser³⁰⁷ and Ser⁶¹² of IRS-1 mediated by JNK and ERK1/2, respectively. These changes result in impaired coupling of IRS-1 and PI 3-kinase, and activation of the Akt/mammalian target of rapamycin/phosphorylated heat- and acid-stable protein-1/p70S6 kinase pathway.

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