title: Regulation of insulin secretion and proinsulin biosynthesis by succinate.
abstract: 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 beta-cells responsive to succinate. We conclude that beta-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.
authors.affiliation: Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, P.O. Box 12000, Jerusalem 91120, Israel.
authors.forename: Veronique
authors.initials: V
authors.lastname: Attali
authors.forename: Marcela
authors.initials: M
authors.lastname: Parnes
authors.forename: Yafa
authors.initials: Y
authors.lastname: Ariav
authors.forename: Erol
authors.initials: E
authors.lastname: Cerasi
authors.forename: Nurit
authors.initials: N
authors.lastname: Kaiser
authors.forename: Gil
authors.initials: G
authors.lastname: Leibowitz
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D002952:Citric Acid Cycle; D000242:Cyclic AMP / Q000502:physiology; D005849:Gerbillinae; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008293:Malates / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors; D011384:Proinsulin / Q000096:biosynthesis*; D019289:Pyruvic Acid / Q000378:metabolism; D051381:Rats; D019802:Succinic Acid / Q000494:pharmacology*
chemical_list: D007328:Insulin; D008293:Malates; D009249:NADP; C030298:malic acid; D019289:Pyruvic Acid; D011384:Proinsulin; D019802:Succinic Acid; D000242:Cyclic AMP; D052248:Nitric Oxide Synthase Type I; D005947:Glucose; D015056:1-Methyl-3-isobutylxanthine; D019331:NG-Nitroarginine Methyl Ester