Signal transduction mechanisms in nutrient-induced insulin secretion

Abstract

The knowledge of the mechanism whereby glucose and other fuel stimuli promote the release of insulin by the pancreatic beta cell remains fragmentary. The closure of metabolically sensitive K+ channels and a rise in cytosolic free Ca2+ are key features of beta-cell metabolic signal transduction. However, these two signalling events do not account for the dose dependence of glucose-induced insulin secretion. In fact, recent evidence indicates that there are KATP channel and Ca2+ independent 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 support of two new concepts: 1) oscillations in the glycolytic pathway and beta-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 signalling. Finally, we propose that the altered expression of genes encoding enzymes in the pathway of malonyl-CoA formation and fatty acid oxidation contributes to the beta-cell insensitivity to glucose in some patients with non-insulin-dependent diabetes mellitus.

Fat storage in pancreas and in insulin-sensitive tissues in pathogenesis of type 2 diabetes

“…Among these mechanisms, increase in malonyl-CoA derived from glucose metabolism inhibits CPT-1, the rate-limiting step in fatty acid oxidation. 9 LC-CoA then accumulate in the cytosol where they may also be used as a precursor for diacylglycerol or phosphatidic acid synthesis. Various combinations of the three signalling molecules may then activate specific protein kinase C (PKC) isoforms.…”

The malonyl-CoA–long-chain acyl-CoA axis in the maintenance of mammalian cell function

“…The provision of acyl-CoA, or a complex lipid synthesized therefrom, appears to be essential for the insulin secretory mechanism [115][116][117][118]. Fatty acids acutely stimulate insulin secretion and the effect is mimicked by fatty acid analogues that generate non-metabolizable acyl-CoA esters within the cells [119].…”

Control of Insulin Secretion by Cytochrome c and Calcium Signaling in Islets with Impaired Metabolism

“…Insulin secretion rate (ISR) 3 is determined both by K ATP -dependent pathways involving increased calcium (Ca 2ϩ ) influx, as well as by K ATP -independent pathways involving the generation of metabolic factors (1)(2)(3)(4)(5). Increased Ca 2ϩ in the absence of elevated metabolic rate does not elicit second-phase insulin secretion (6,7).…”