The Succinate Mechanism of Insulin Release

Abstract

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-3-methylglutaryl-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 2؉ . 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.

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

“…Short Chain Acyl-CoAs-Third, the results support the hypothesis that short chain acyl-CoAs are important for insulin secretion (2,14). In general, acetoacetate and ␣-ketoglutarate were increased by conditions that stimulated insulin release in both islets (Table 6) and INS-1 832/13 cells (Table 8).…”

“…In an effort to explain part of the requirement for the high rate of anaplerosis in insulin secretion, we proposed the "succinate mechanism" of insulin release (2,14). This hypothesis used our own data and data from the literature to suggest why methyl esters of succinic acid have consistently been found to be the only insulinotropic esters of any esters of a citric acid cycle intermediate tested, or the most insulinotropic, depending on the individual study.…”

13C NMR Isotopomer Analysis of Anaplerotic Pathways in INS-1 Cells

“…Although INS-1 832/13 cells differ in several aspects of glucose metabolism compared with ␤-cells (7-10), many of the mechanisms that couple insulin secretion to glucose metabolism, such as glucose transport, mitochondrial oxidation, and anaplerosis are similar (1)(2)(3)(4)(5)(6)11). Hence, these results are likely to extrapolate to glucose-stimulated insulin secretion in islets.…”

“…Although, it is well established that glucose-stimulated insulin secretion requires mitochondrial carbohydrate oxidation to drive ATP production (1), a number of studies have suggested that intermediates (e.g. malonyl-CoA (2, 3), succinate (4), and glutamate (5)) generated, directly or indirectly, from anaplerosis may act as second messengers linking glucose oxidation with insulin secretion.…”

Enhanced mitochondrial metabolism may account for the adaptation to insulin resistance in islets from C57BL/6J mice fed a high-fat diet

“…Furthermore, 10 mmol/l of the monomethyl ester of succinate (methylsuccinate), a secretagogue that may stimulate insulin secretion via flux through the anaplerotic pathway involving malic enzyme or direct activation of complex II (succinate dehydrogenase) in the respiratory chain [20], had no stimulatory effect on insulin secretion in control islets (Fig. 5), confirming previous observations in mouse islets [20]. In contrast, the addition of methylsuccinate to islets from HF mice revealed a dramatic increase in insulin secretion.…”