This Article Full Text Full Text (PDF) All Versions of this Article: 147/11/5110    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Attali, V. Articles by Leibowitz, G. Search for Related Content PubMed PubMed Citation Articles by Attali, V. Articles by Leibowitz, G. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB GLUCOSE MALIC ACID SUCCINIC ACID

Regulation of Insulin Secretion and Proinsulin Biosynthesis by Succinate

Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel

Address all correspondence and requests for reprints to: Gil Leibowitz, M.D., Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, P.O. Box 12000, Jerusalem 91120, Israel. E-mail: gleib{at}hadassah.org.il.

Succinate stimulates insulin secretion and proinsulin biosynthesis. We studied the effects of reduced nicotinamide adenine dinucleotide phosphate (NADPH)-modulating pathways on glucose- and succinate-stimulated insulin secretion and proinsulin biosynthesis in the rat and the insulin-resistant Psammomys obesus. Disruption of the anaplerotic pyruvate/malate shuttle by phenylacetic acid inhibited glucose- and succinate-stimulated insulin secretion and succinate-stimulated proinsulin biosynthesis in both species. In contrast, phenylacetic acid failed to inhibit glucose-stimulated proinsulin biosynthesis in P. obesus islets. Inhibition of the NADPH-consuming enzyme neuronal nitric oxide synthase (nNOS) with L-N^G-nitro-L-arginine methyl ester or with N^G-monomethyl-L-arginine^G doubled succinate-stimulated insulin secretion in rat islets, suggesting that succinate- and nNOS-derived signals interact to regulate insulin secretion. In contrast, nNOS inhibition had no effect on succinate-stimulated proinsulin biosynthesis in both species. In P. obesus islets, insulin secretion was not stimulated by succinate in the absence of glucose, whereas proinsulin biosynthesis was increased 5-fold. Conversely, under stimulating glucose levels, succinate doubled insulin secretion, indicating glucose-dependence. Pyruvate ester and inhibition of nNOS partially mimicked the permissive effect of glucose on succinate-stimulated insulin secretion, suggesting that anaplerosis-derived signals render the ß-cells responsive to succinate. We conclude that ß-cell anaplerosis via pyruvate carboxylase is important for glucose- and succinate-stimulated insulin secretion and for succinate-stimulated proinsulin biosynthesis. In P. obesus, pyruvate/malate shuttle dependent and independent pathways that regulate proinsulin biosynthesis coexist; the latter can maintain fuel stimulated biosynthetic activity when the succinate-dependent pathway is inhibited. nNOS signaling is a negative regulator of insulin secretion, but not of proinsulin biosynthesis.

This article has been cited by other articles:

				M. Fraenkel, M. Ketzinel-Gilad, Y. Ariav, O. Pappo, M. Karaca, J. Castel, M.-F. Berthault, C. Magnan, E. Cerasi, N. Kaiser, et al. mTOR Inhibition by Rapamycin Prevents {beta}-Cell Adaptation to Hyperglycemia and Exacerbates the Metabolic State in Type 2 Diabetes Diabetes, April 1, 2008; 57(4): 945 - 957. [Abstract] [Full Text] [PDF]

				S. Weksler-Zangen, I. Raz, S. Lenzen, A. Jorns, S. Ehrenfeld, G. Amir, A. Oprescu, Y. Yagil, C. Yagil, D. H. Zangen, et al. Impaired Glucose-Stimulated Insulin Secretion Is Coupled With Exocrine Pancreatic Lesions in the Cohen Diabetic Rat Diabetes, February 1, 2008; 57(2): 279 - 287. [Abstract] [Full Text] [PDF]