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Originally published In Press as doi:10.1074/jbc.M303509200 on August 18, 2003

J. Biol. Chem., Vol. 278, Issue 43, 42080-42090, October 24, 2003
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Glucose-induced Translational Control of Proinsulin Biosynthesis Is Proportional to Preproinsulin mRNA Levels in Islet {beta}-Cells but Not Regulated via a Positive Feedback of Secreted Insulin*

Barton Wicksteed, Cristina Alarcon, Isabelle Briaud, Melissa K. Lingohr, and Christopher J. Rhodes{ddagger}

From the Pacific Northwest Research Institute and Department of Pharmacology, University of Washington, Seattle, Washington 98122-4302

Proinsulin biosynthesis is regulated in response to nutrients, most notably glucose. In the short term (<=2h) this is due to increases in the translation of pre-existing mRNA. However, prolonging glucose stimulation (24 h) also increases preproinsulin mRNA levels. It has been proposed that secreted insulin from the pancreatic {beta}-cell regulates its own synthesis through a positive autocrine feedback mechanism. Here the comparative contributions of translation and mRNA levels on the levels of proinsulin biosynthesis were examined in isolated pancreatic islets. Also, the autocrine role of insulin upon four {beta}-cell functions (insulin secretion, proinsulin translation, preproinsulin mRNA levels, and total protein synthesis) was investigated in parallel. The results showed that proinsulin biosynthesis is regulated, in the short term (1 h), solely at the level of translation, through an ~6-fold increase in response to glucose (2.8 mM versus 16.7 mM glucose). In the longer term, when preproinsulin mRNA levels have increased ~2-fold, a corresponding increase was observed in the fold response of proinsulin translation to a stimulatory glucose concentration (>=10-fold). Importantly, neither exogenously added nor secreted insulin were found to play any role in regulating insulin secretion, proinsulin translation, preproinsulin mRNA levels, or total protein synthesis. The results presented here indicate that long term nutritional state sets the preproinsulin mRNA level in the {beta}-cell at which translation control regulates short term changes in rates of proinsulin biosynthesis in response to glucose, but this is not mediated by any autocrine effect of insulin.

Received for publication, April 4, 2003 , and in revised form, August 7, 2003.

* This work was supported by National Institutes of Health Grants DK47919, DK55269, and DK50610. 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.

{ddagger} To whom correspondence should be addressed: Pacific Northwest Research Inst., 720 Broadway, Seattle, WA 98122-4302. Tel.: 206-860-6777; Fax: 206-726-1202; E-mail: cjr{at}pnri.org.


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