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Specific regulation of IRS-2 expression by glucose in rat primary pancreatic islet beta-cells.

Lingohr M.K., Briaud I., Dickson L.M., McCuaig J.F., Alarcon C., Wicksteed B.L., Rhodes C.J.

Insulin receptor substrate 2 (IRS-2) plays a critical role in pancreatic beta-cells. Increased IRS-2 expression promotes beta-cell growth and survival, whereas decreased IRS-2 levels lead to apoptosis. It was found that IRS-2 turnover in rat islet beta-cells was rapid, with mRNA and protein half-lives of approximately 90 min and approximately 2 h, respectively. However, this was countered by specific glucose-regulated IRS-2 expression mediated at the transcriptional level. Glucose (> or = 6 mM) increased IRS-2 mRNA and protein levels in a dose-dependent manner, reaching a maximum 4-fold increase in IRS-2 mRNA and a 5-6-fold increase in IRS-2 protein levels at > or = 12 mM glucose (p < or = 0.01). Glucose (15 mM) regulation of islet beta-cell IRS-2 gene expression was rapid, with a significant increase in IRS-2 mRNA levels within 2 h that reached a maximum 4-fold increase by 4 h. IRS-2 protein expression in beta-cells followed that of IRS-2 mRNA. Glucose metabolism was necessary for increased IRS-2 expression in beta-cells. Moreover, inhibition of a glucose-induced rise in islet beta-cell cytosolic [Ca2+]i prevented an increase in IRS-2 expression, indicating this was Ca2+-dependent. The glucose-induced rise in IRS-2 levels correlated with increased IRS-2 tyrosine phosphorylation and downstream activation of protein kinase B. These data indicate that fluctuations of glucose in the normal physiological range (5-15 mM) promote beta-cell survival via regulation of IRS-2 expression and a subsequent parallel protein kinase B activation. Given that the onset of type-2 diabetes is marked by loss of beta-cells, these data further the idea that controlled IRS-2 expression in beta-cells could be a therapeutic means to promote beta-cell survival and delay the onset of the disease.

J. Biol. Chem. 281:15884-15892(2006) [PubMed] [Europe PMC]