SIGNAL-TRANSDUCTION MECHANISMS IN NUTRIENT-INDUCED INSULIN-SECRETION

The knowledge of the mechanism whereby glucose and other fuel stimuli promote the release of insulin by the pancreatic beta cell remains fra gmentary. The closure of metabolically sensitive Kf channels and a ris e in cytosolic free Ca2+ are key features of beta-cell metabolic signa l transduction. However, these two signalling events do not account fo r the dose dependence of glucose-induced insulin secretion. In fact, r ecent evidence indicates that there are K-ATP channel and Ca2+ indepen dent pathway(s) of beta-cell activation which remain to be defined. In this review, we have limited our attention to the recent developments in our understanding of the mode of action of nutrient secretagogues. A particular emphasis is placed in summarising the evidence in suppor t of two new concepts: 1) oscillations in the glycolytic pathway and b eta-cell metabolism contribute to the oscillatory nature of beta-cell ionic events and insulin secretion; 2) malonyl-CoA and long chain acyl -CoA esters may act as metabolic coupling factors in beta-cell signall ing, Finally we propose that the altered expression of genes encoding enzymes in the pathway of malonyl-CoA formation and fatty acid oxidati on contributes to the beta-cell insensitivity to glucose in some patie nts with non-insulin-dependent diabetes mellitus.