A Role for the Malonyl-CoA/Long-Chain Acyl-CoA Pathway of Lipid Signaling in the Regulation of Insulin Secretion in Response to Both Fuel and Nonfuel Stimuli

Abstract

The malonyl-CoA/long-chain acyl-CoA (LC-CoA) model of glucose-induced insulin secretion (GIIS) predicts that malonyl-CoA derived from glucose metabolism inhibits fatty acid oxidation, thereby increasing the availability of LC-CoA for lipid signaling to cellular processes involved in exocytosis. For directly testing the model, INSr3 cell clones overexpressing malonylCoA decarboxylase in the cytosol (MCDc) in a tetracycline regulatable manner were generated, and INS(832/ 13) and rat islets were infected with MCDc-expressing adenoviruses. MCD activity was increased more than fivefold, and the malonyl-CoA content was markedly diminished. This was associated with enhanced fat oxidation at high glucose, a suppression of the glucoseinduced increase in cellular free fatty acid (FFA) content, and reduced partitioning at elevated glucose of exogenous palmitate into lipid esterification products. MCDc overexpression, in the presence of exogenous FFAs but not in their absence, reduced GIIS in all ␤-cell lines and in rat islets. It also markedly curtailed the stimulation of insulin secretion by other fuel and nonfuel secretagogues. In the absence of MCDc overexpression, the secretory responses to all types of secretagogues were amplified by the provision of exogenous fatty acids. In the presence of exogenous FFAs, the fatty acyl-CoA synthetase inhibitor triacsin C reduced secretion in response to glucose and nonfuel stimuli. The data show the existence of important links between the metabolic coupling factor malonyl-CoA, the partitioning of fatty acids, and the stimulation of insulin secretion to both fuel and nonfuel stimuli. Diabetes 53:

Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling

“…This finding is in keeping with the previous observation that NEFA augment insulin secretion in response not only to glucose but also to all fuel and nonfuel secretagogues, including GLP-1 [13]. The present findings reinforce the concept that NEFA are not only essential for insulin secretion [23] but are also involved in enhancement of secretion in response to a wide variety of Fig.…”

“…We propose a model (Fig. 7) in which glucose promotes activity in a beta cell TG-FA cycle by (1) the malonyl-CoA/LC-CoA switch of fatty metabolism from oxidation to esterification [3,13]; (2) providing glycerol-3-phosphate (Gly-3-P) for synthesis of complex glycerolipids; and (3) activation of lipolysis, as demonstrated in this study. NEFA also contribute to activation of the cycle by providing the other substrate (LC-CoA) for condensation with Gly-3-P.…”

“…3c). Interestingly, elevated glucose resulted in higher levels of non-esterified palmitate (an index of cellular LCCoA [13]) in ZF compared with ZL islets (66 and 98% higher than ZL at 8 and 16 mmol/l glucose, respectively) (Fig. 3f).…”

“…As anaplerosis is the pathway by which glucose increases malonyl-CoA levels, these results led us to hypothesise that enhanced glucose-induced increases in malonyl-CoA/long chain acyl-CoA (LC-CoA) signalling may also be involved in ZF islet compensation. This is based on the malonyl-CoA/LC-CoA model of lipid signalling for insulin secretion that we have described previously [12,13]. Central to the model is that an increase in glucose, via increasing malonyl-CoA, which inhibits carnitine palmitoyltransferase-1 (CPT1), as was first described by McGarry and Brown [14], switches the partitioning of NEFA in the beta cell away from oxidation towards the accumulation of LC-CoA and fatty acid acylation and esterification products (e.g.…”

“…Central to the model is that an increase in glucose, via increasing malonyl-CoA, which inhibits carnitine palmitoyltransferase-1 (CPT1), as was first described by McGarry and Brown [14], switches the partitioning of NEFA in the beta cell away from oxidation towards the accumulation of LC-CoA and fatty acid acylation and esterification products (e.g. diacylglycerol [3,[13][14][15]), which are proposed to have direct regulatory effects on insulin secretion [3,12,13].…”