EVIDENCE FOR AN ANAPLEROTIC MALONYL-COA PATHWAY IN PANCREATIC BETA-CELL NUTRIENT SIGNALING

A metabolic model of fuel sensing has been proposed in which malonyl-C oA and long-chain acyl-CoA esters may act as coupling factors in nutri ent-induced insulin release (Prentki M, Vischer S, Glennon MC, Regazzi R, Deeney J, Corkey BE: Malonyl-CoA and long chain acyl-CoA esters as metabolic coupling factors in nutrient-induced insulin secretion. J B iol Chem 267:5802-5810, 1992). To gain further insight into the contro l of malonyl-CoA content in islet tissue, we have studied the short- a nd long-term regulation of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) in the beta-cell. These enzymes catalyze the formation of malonyl-CoA and its usage for de novo fatty acid biogenesis. ACC m RNA, protein, and enzymatic activity are present at appreciable levels in rat pancreatic islets and clonal beta-cells (HIT cells). Glucose a ddition to HIT cells results in a marked increase in ACC activity that precedes the initiation of insulin release. Fasting does not modify t he ACC content of islets, whereas it markedly downregulates that of li pogenic tissues. This indicates differential regulation of the ACC gen e in lipogenic tissues and the islets of Langerhans. FAS is very poorl y expressed in islet tissue, yet ACC is abundant. This demonstrates th at the primary function of malonyl-CoA in the beta-cells is to regulat e fatty acid oxidation, not to serve as a substrate for fatty acid bio synthesis. The anaplerotic enzyme pyruvate carboxylase, which allows t he replenishment of citric acid cycle intermediates needed for malonyl -CoA production via citrate, is abundant in islet tissue. Glucose caus es an elevation in beta (HIT)-cell citrate that precedes secretion, an d only those nutrients that can elevate citrate induce effective insul in release. The results provide new evidence in support of the model a nd explain why malonyl-CoA rises markedly and rapidly in islets upon g lucose stimulation: 1) glucose elevates citrate, the precursor of malo nyl-CoA; 2) glucose enhances ACC enzymatic activity; and 3) malonyl-Co A is not diverted to lipids. The data suggest that ACC is a key enzyme in metabolic signal transduction of the beta-cell and provide evidenc e for the concept that an anaplerotic/malonyl-CoA pathway is implicate d in insulin secretion.