IncreasedO‐glycosylation of insulin signaling proteins results in their impaired activation and enhanced susceptibility to apoptosis in pancreatic β‐cells
- 14 April 2004
- journal article
- fj express-summary
- Published by Wiley in The FASEB Journal
- Vol. 18 (9), 959-961
- https://doi.org/10.1096/fj.03-0725fje
Abstract
Because adverse effects of glucose were attributed to its increased routing through the hexosamine pathway (HBP), we inquired whether HBP activation affects pancreatic beta-cell survival. Exposure of human islets to high glucose resulted in increased apoptosis of beta-cells upon serum deprivation that was reversed by azaserine. Also, glucosamine, a direct precursor of the downstream product of the HBP, increased human beta-cells apoptosis upon serum deprivation, which was reversed by benzyl-2-acetamido-2-deoxy-alpha-d-galactopyranoside (BADGP), an inhibitor of protein O-glycosylation. These results were reproduced in RIN rat beta-cells. Glucosamine treatment resulted in inhibition of tyrosine-phosphorylation of the insulin receptor (IR), IRS-1, and IRS-2, which was associated with increased O-glycosylation. These changes caused impaired activation of the PI 3-kinase/Akt survival signaling that resulted in reduced GSK-3 and FOXO1a inactivation. BADGP reversed the glucosamine-induced reduction in insulin-stimulated phosphorylation of IR, IRS-1, IRS-2, Akt, GSK-3, and FOXO1a. Impaired FOXO1a inactivation sustained expression of the pro-apoptotic protein Bim, without affecting Bad, Bcl-XL, or Bcl-2 expression. These results indicate that hyperglycemia may increase susceptibility to apoptosis of human and rat beta-cell through activation of the HBP. Increased routing of glucose through this metabolic pathway results in impaired activation of the IR/IRSs/PI3-kinase/Akt survival pathway by induction of O-glycosylation of signaling moleculesKeywords
Funding Information
- Ministero dell’Istruzione, dell’Università e della Ricerca
This publication has 45 references indexed in Scilit:
- Chronic hyperglycemia impairs insulin secretion by affecting insulin receptor expression, splicing, and signaling in RIN β‐cell line and human islets of LangerhansThe FASEB Journal, 2003
- PKC ζ Enhances Insulin-like Growth Factor 1-Dependent Mitogenic Activity in the Rat Clonal β Cell Line RIN 1046-38Biochemical and Biophysical Research Communications, 2002
- Apoptosis in the beta cells: cause or consequence of insulin secretion defect in diabetes?Annals of Medicine, 2002
- Transcriptional regulation of human insulin receptor gene by the high‐mobility group protein HMGI(Y)The FASEB Journal, 2001
- The common Arg 972 polymorphism in insulin receptor substrate‐1 causes apoptosis of human pancreatic isletsThe FASEB Journal, 2000
- Molecular and Functional Characterization of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP-38)/Vasoactive Intestinal Polypeptide Receptors in Pancreatic -Cells and Effects of PACAP-38 on Components of the Insulin Secretory SystemEndocrinology, 1999
- The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitusJCI Insight, 1999
- Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase BNature, 1995
- Causes of insulin resistanceNature, 1995
- Prolonged exposure of human pancreatic islets to high glucose concentrations in vitro impairs the beta-cell function.JCI Insight, 1992