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J. Biol. Chem., Vol. 282, Issue 9, 6043-6052, March 2, 2007

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Synergistic Potent Insulin Release by Combinations of Weak Secretagogues in Pancreatic Islets and INS-1 Cells^*

From the Childrens Diabetes Center, University of Wisconsin Medical School, Madison, Wisconsin 53706

Insulin secretion by the beta cell depends on anaplerosis in which insulin secretagogues are metabolized by mitochondria into molecules that are most likely exported to the extramitochondrial space where they have signaling roles. However, very little is known about the products of anaplerosis. We discovered an experimental paradigm that has begun to provide new information about these products. When various intracellular metabolites were applied in combination to overnight-cultured rat or human pancreatic islets or to INS-1 832/13 cells, they interacted synergistically to strongly stimulate insulin release. When these same metabolites were applied individually to these cells, insulin stimulation was poor. Discerning the contributions of the individual compounds to metabolism has begun to allow us to dissect some of the pathways involved in insulin secretion, which was not possible from studying individual secretagogues. Monomethyl succinate (MMS) combined with a barely stimulatory concentration of -ketoisocaproate (KIC) (2 mM) stimulated insulin release in cultured rat islets 18-fold (versus 21-fold for 16.7 mM glucose). MMS plus low glucose (2 mM) or pyruvate (5 mM) gave 11- and 9-fold stimulations. These agents also potentiated MMS-induced insulin release in fresh islets, and KIC plus MMS gave synergistic insulin release in cultured human islets. In INS-1 cells, neither MMS nor KIC (10 mM) was an insulin secretagogue, but when added together KIC (2 mM) and MMS stimulated insulin release 7-fold (versus 12-fold for glucose). In islets and INS-1 cells, conditions that stimulated insulin release caused large relative increases in acetoacetate, which is a precursor of pathways to short chain acyl-CoAs. Liquid chromatography-tandem mass spectrometry measurements of acetyl-CoA, acetoacetyl-CoA, succinyl-CoA, hydroxymethylglutaryl-CoA, and malonyl-CoA confirmed that they were increased by insulin secretagogues. The results suggest a new mechanism of insulin secretion in which anaplerosis increases short chain acyl-CoAs that have roles in insulin exocytosis.

Received for publication, July 13, 2006 , and in revised form, January 5, 2007.

^* This work was supported by National Institutes of Health Grant DK28348 and by a gift from the Oscar C. Rennebohm Foundation. 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 To whom correspondence may be addressed: 3459 Medical Science Center, 1300 University Ave., Madison, WI 53706. E-mail: mjmacdon{at}wisc.edu.

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