Nutrient-secretion coupling in the pancreatic islet beta-cell: recent advances

Abstract

Insulin secretion from pancreatic islet beta-cells is a tightly regulated process, under the close control of blood glucose concentrations, and several hormones and neurotransmitters. Defects in glucose-triggered insulin secretion are ultimately responsible for the development of type II diabetes, a condition in which the total beta-cell mass is essentially unaltered, but beta-cells become progressively "glucose blind" and unable to meet the enhanced demand for insulin resulting for peripheral insulin resistance. At present, the mechanisms by which glucose (and other nutrients including certain amino acids) trigger insulin secretion in healthy individuals are understood only in part. It is clear, however, that the metabolism of nutrients, and the generation of intracellular signalling molecules including the products of mitochondrial metabolism, probably play a central role. Closure of ATP-sensitive K+(K(ATP)) channels in the plasma membrane, cell depolarisation, and influx of intracellular Ca2+, then prompt the "first phase" on insulin release. However, recent data indicate that glucose also enhances insulin secretion through mechanisms which do not involve a change in K(ATP) channel activity, and seem likely to underlie the second, sustained phase of glucose-stimulated insulin secretion. In this review, I will discuss recent advances in our understanding of each of these signalling processes.