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J. Biol. Chem., Vol. 281, Issue 23, 15884-15892, June 9, 2006

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Specific Regulation of IRS-2 Expression by Glucose in Rat Primary Pancreatic Islet -Cells^*

Melissa K. Lingohr¹², Isabelle Briaud¹, Lorna M. Dickson, Jill F. McCuaig, Cristina Alárcon, Barton L. Wicksteed, and Christopher J. Rhodes³

From the The Pacific Northwest Research Institute and Department of Pharmacology, University of Washington, Seattle, Washington 98122

Insulin receptor substrate 2 (IRS-2) plays a critical role in pancreatic -cells. Increased IRS-2 expression promotes -cell growth and survival, whereas decreased IRS-2 levels lead to apoptosis. It was found that IRS-2 turnover in rat islet -cells was rapid, with mRNA and protein half-lives of 90 min and 2 h, respectively. However, this was countered by specific glucose-regulated IRS-2 expression mediated at the transcriptional level. Glucose (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 12 mM glucose (p 0.01). Glucose (15 mM) regulation of islet -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 -cells followed that of IRS-2 mRNA. Glucose metabolism was necessary for increased IRS-2 expression in -cells. Moreover, inhibition of a glucose-induced rise in islet -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 -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 -cells, these data further the idea that controlled IRS-2 expression in -cells could be a therapeutic means to promote -cell survival and delay the onset of the disease.

Received for publication, January 13, 2006 , and in revised form, March 22, 2006.

^* This work was supported by National Institutes of Health Grants DK 55269 and DK 60266 (fellowship to M. K. L.) and the Juvenile Diabetes Research Foundation (fellowship to I. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ These authors contributed equally to this study.

² Current address: Dept. of Pathology, Wayne State University School of Medicine, 550 E. Canfield, Detroit, MI 48201.

³ To whom correspondence should be addressed: Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122. Tel.: 206-860-6777; Fax: 206-726-1217; E-mail: cjr{at}pnri.org.

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