Perspectives in Diabetes The Succinate Mechanism of Insulin Release

Nutrient secretagogues can increase the production of succinyl-CoA in rat pancreatic islets. When succinate esters are the secretagogue, succinyl-CoA can be generated via the succinate thiokinase reaction. Other secretagogues can increase production of succinyl-CoA secondary to increasing -ketoglutarate production by glutamate dehydrogenase or mitochondrial aspartate aminotransferase followed by the -ketoglutarate dehydrogenase reaction. Although secretagogues can increase the production of succinyl-CoA, they do not increase the level of this metabolite until after they decrease the level of 3-hydroxy-3methylglutaryl-CoA (HMG-CoA). This suggests that the generated succinyl-CoA initially reacts with acetoacetate to yield acetoacetyl-CoA plus succinate in the succinyl-CoA-acetoacetate transferase reaction. This would be followed by acetoacetyl-CoA reacting with acetyl-CoA to generate HMG-CoA in the HMG-CoA synthetase reaction. HMG-CoA will then be reduced by NADPH to mevalonate in the HMG-CoA reductase reaction and/or cleaved to acetoacetate plus acetyl-CoA by HMG cleavage enzyme. Succinate derived from either exogenous succinate esters or generated by succinylCoA-acetoacetate transferase is metabolized to malate followed by the malic enzyme reaction. Increased production of NADPH by the latter reaction then increases reduction of HMG-CoA and accounts for the decrease in the level of HMG-CoA produced by secretagogues. Pyruvate carboxylation catalyzed by pyruvate carboxylase will supply oxaloacetate to mitochondrial aspartate aminotransferase. This would enable this aminotransferase to supply -ketoglutarate to the -ketoglutarate dehydrogenase complex and would, in part, account for secretagogues increasing the islet level of succinyl-CoA after they decrease the level of HMG-CoA. Mevalonate could be a trigger of insulin release as a result of its ability to alter membrane proteins and/or cytosolic Ca . This is consistent with the fact that insulin secretagogues decrease the level of the mevalonate precursor HMG-CoA. In addition, inhibitors of HMG-CoA reductase interfere with insulin release and this inhibition can be reversed by mevalonate. Diabetes 51:2669–2676, 2002 We (1–4) found that 10 mmol/l levels of exogenous methylesters of succinate (which are converted into succinate in the cell) are almost as potent in promoting insulin release as the most potent insulin secretagogue glucose. This effect was specific in that 10 mmol/l levels of malate and -ketoglutarate and esters of fumarate or citrate did not promote insulin release (3,4). We believe that succinate has unique insulinotropic properties because, as shown in Scheme 1 (Fig.1), it is the only nutrient secretagogue that can react with one enzyme, succinate dehydrogenase (reaction 6 of Scheme 1), which is a direct source of metabolic energy, a second enzyme, succinate thiokinase, which can generate succinyl-CoA (reaction 1 of Scheme 1), and a third enzyme, succinyl-CoA-acetoacetate transferase (SAT) (reaction 2 of Scheme 1), which can react with succinyl-CoA to increase the production of acetoacetyl-CoA (AcAc-CoA). AcAc-CoA, can in turn be utilized via the combined 3-hydroxy-3 methylglutaryl CoA (HMGCoA) synthetase and HMG-CoA reductase reactions to produce mevalonate (reactions 3 and 4 of Scheme 1). We propose that mevalonate or one of its metabolites is a signal of insulin release. In islets, the succinate thiokinase reaction with succinate can consume either GTP or ATP (5). However, this cost in metabolic energy would be more than compensated for when succinate esters are the secretagogues, because a high cellular level of succinate would also increase flux through succinate dehydrogenase. In this reaction, two molecules of ATP are generated per molecule of succinate oxidized. In the sequence of reactions described above, pyruvate via the pyruvate dehydrogenase reaction (reaction 10 of Scheme 1) plus the oxidation of fatty acids and some amino acids could be sources of acetyl-CoA (Ac-CoA) for HMG-CoA synthetase (6). The acetoacetate (AcAc) required for the SAT reaction would be provided for by both HMG-CoA cleavage enzyme (reaction 5 of Scheme 1) and 3-hydroxybutyrate dehydrogenase (reaction 14 of Scheme 1). The AcAc-CoA utilized by HMG-CoA synthetase could be produced by both SAT and ketothiolase (reaction 11 of Scheme 1). The metabolism of succinate itself can produce Ac-CoA and AcAc-CoA (7,8). In rat islet mitochondria, fumarate produced by oxidation of succinate by succinate dehydrogenase is converted into malate by fumarase (reaction 7 of Scheme 1). Malate then enters the cytosol, where it is converted into pyruvate by malic enzyme (reaction 8 of Scheme 1), followed by pyruvate From the Department of Pharmacology, University of Wisconsin Medical School, Madison, Wisconsin; and the Childrens Diabetes Center, University of Wisconsin Medical School, Madison, Wisconsin. Address correspondence and reprint requests to Leonard A. Fahien, University of Wisconsin Medical School, Department of Pharmacology, 301 SMI, 1300 University Ave., Madison, WI 53706. E-mail: [email protected]. Received for publication 7 August 2001 and accepted in revised form 27 February 2002. AcAc, acetoacetate; Ac-CoA, acetyl-CoA; AcAc-CoA, acetoacetyl-CoA; BCH, aminobicyclo (2.2.1) heptane carboxylic acid; GABA, -aminobutyric acid; HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA; SAT, succinyl-CoA-acetoacetate transferase.