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J. Biol. Chem., Vol. 280, Issue 39, 33487-33496, September 30, 2005

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Glucose-regulated Glucagon Secretion Requires Insulin Receptor Expression in Pancreatic -Cells^*

Jingyu Diao1, Zeenat Asghar, Catherine B. Chan, and Michael B. Wheeler2

From the Departments of Physiology and Medicine, University of Toronto, Ontario M5S 1A8, Canada and the Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Prince Edward Island C1A 4P3, Canada

The insulin receptor (IR) and its signaling appear to be essential for insulin secretion from pancreatic -cells. However, much less is known about the role of the IR in -cells. To assess the role of the IR in glucagon and insulin secretion, we engineered adeno-viruses for high efficiency small interference RNA (siRNA)-IR expression in isolated mouse pancreatic islets and lentiviruses for siRNA-IR expression in pancreatic - and -cell lines (-TC6 and MIN6) with specific, long term stable IR knockdown. Western blot analysis showed that these strategies resulted in 60-80% reduction of IR protein in islets and - and -cell lines. Cell growth was reduced by 35-50% in -TC and MIN6 cells stably expressing siRNA-IR, respectively. Importantly, glucagon secretion, in response to glucose (25 to 2.8 mM), was completely abolished in islets expressing siRNA-IR, whereas secretion increased 1.7-fold in islets expressing control siRNA. In contrast, there was no difference in glucose-stimulated insulin secretion when comparing siRNA-IR and siRNA control, with both groups showing a 1.7-fold increase. Islet glucagon and insulin content were also unaffected by IR knockdown. To further explore the role of the IR, siRNA-IR was stably expressed in pancreatic cell lines, which dramatically suppressed glucose-regulated glucagon secretion in -TC6 cells (3.4-fold) but did not affect GSIS in MIN6 cells. Defects in siRNA-IR-expressing -cells were associated with an alteration in the activity of Akt and p70^S6K where insulin-induced phosphorylation of protein kinase B/AKt was greatly reduced while p70^S6K activation was enhanced, suggesting that the related pathways play important roles in cell function. This study provides direct evidence that appropriate expression of the IR in -cells is required for glucose-dependent glucagon secretion.

Received for publication, June 8, 2005 , and in revised form, July 11, 2005.

^* This work was supported in part by the Canadian Institutes of Heath Research (CIHR) (Grant MOP 12898 to M. B. W. and C. B. C.) and from the Canadian Diabetes Association (CDA) (to M. B. W.). 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.

¹ Supported by a Fellowship Award from the CDA.

² Supported by an Investigator Award from CIHR. To whom correspondence should be addressed: Dept. of Physiology, 1 King's College Circle, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Tel.: 416-978-6737; Fax: 416-978-4940; E-mail: michael.wheeler{at}utoronto.ca.

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