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 P-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 beta-cells to glucosamine resulted in reduction in glucose- and insulin-stimulated insulin biosynthesis, which in RIN beta-cells was associated with impairment in insulin-stimulated insulin receptor substrate-1 (IRS-1) phosphorylation at Tyr(608) and Tyr(628) which are essential for engaging phosphatidylinositol 3-kinase (PI 3kinase). 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 beta-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 Ser(612), 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 Ser(307) and Ser(612). Glucosamine mimicked the stimulatory effects of high glucose on JNK and ERK1/2 activity and IRS-1 phosphorylation at Ser(307) and Ser(612). 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 Ser(307) and Ser(612) 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.

Andreozzi, F., D'Alessandris, C., Federici, M., Laratta, E., Del Guerra, S., Del Prato, S., et al. (2004). Activation of the hexosamine pathway leads to phosphorylation of insulin receptor substrate-1 on Ser(307) and Ser(612) and impairs the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin insulin biosynthetic pathway in RIN pancreatic beta-cells. ENDOCRINOLOGY, 145(6), 2845-2857 [10.1210/en.2003-0939].

Activation of the hexosamine pathway leads to phosphorylation of insulin receptor substrate-1 on Ser(307) and Ser(612) and impairs the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin insulin biosynthetic pathway in RIN pancreatic beta-cells

FEDERICI, MASSIMO;LAURO, RENATO;SESTI, GIORGIO
2004-01-01

Abstract

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 P-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 beta-cells to glucosamine resulted in reduction in glucose- and insulin-stimulated insulin biosynthesis, which in RIN beta-cells was associated with impairment in insulin-stimulated insulin receptor substrate-1 (IRS-1) phosphorylation at Tyr(608) and Tyr(628) which are essential for engaging phosphatidylinositol 3-kinase (PI 3kinase). 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 beta-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 Ser(612), 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 Ser(307) and Ser(612). Glucosamine mimicked the stimulatory effects of high glucose on JNK and ERK1/2 activity and IRS-1 phosphorylation at Ser(307) and Ser(612). 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 Ser(307) and Ser(612) 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.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore M-EDF/01 - Metodi e Didattiche delle Attivita' Motorie
Settore MED/09 - Medicina Interna
English
Con Impact Factor ISI
azaserine; glucosamine; glucose; hexosamine; insulin; insulin receptor; insulin receptor substrate 1; mitogen activated protein kinase 1; phosphatidylinositol 3 kinase; protein kinase B; S6 kinase; serine; stress activated protein kinase; synapsin I; target of rapamycin kinase; article; controlled study; enzyme activation; enzyme activity; enzyme inhibition; human; human cell; insulin synthesis; pancreas islet beta cell; priority journal; protein phosphorylation; protein synthesis; signal transduction; translation initiation; 1-Phosphatidylinositol 3-Kinase; Adaptor Proteins, Signal Transducing; Animals; Carrier Proteins; Cells, Cultured; Dose-Response Relationship, Drug; Glucosamine; Glucose; Hexosamines; Humans; Insulin; Intracellular Signaling Peptides and Proteins; Islets of Langerhans; Phosphoproteins; Phosphorylation; Protein Biosynthesis; Protein Kinases; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Rats; Ribosomal Protein S6 Kinases, 70-kDa; Serine; Tyrosine
Andreozzi, F., D'Alessandris, C., Federici, M., Laratta, E., Del Guerra, S., Del Prato, S., et al. (2004). Activation of the hexosamine pathway leads to phosphorylation of insulin receptor substrate-1 on Ser(307) and Ser(612) and impairs the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin insulin biosynthetic pathway in RIN pancreatic beta-cells. ENDOCRINOLOGY, 145(6), 2845-2857 [10.1210/en.2003-0939].
Andreozzi, F; D'Alessandris, C; Federici, M; Laratta, E; Del Guerra, S; Del Prato, S; Marchetti, P; Lauro, R; Perticone, F; Sesti, G
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/34887
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