Metabolic control of beta-cell function

Abstract

Glucose-induced insulin secretion is pulsatile. Glucose metabolism generates oscillations in the ATP/ADP ratio which lead to opening and closing of ATP-sensitive K(+)-channels producing subsequent oscillations in membrane potential, cytoplasmic calcium and insulin release. Metabolic signals derived from glucose can also stimulate insulin release independent of their effects on ATP-sensitive K(+)-channels. The ATP/ADP ratio may mediate both ATP-sensitive K(+)-channel-dependent and -independent pathways of secretion. Glucose metabolism also results in an increase in long-chain acyl-CoA, which is proposed to act as an effector molecule in the beta -cell. Long-chain acyl-CoA has a variety of effects in the beta -cell that may effect insulin secretion including opening ATP-sensitive K(+)-channels, activating endoplasmic reticulum Ca(2+)-ATPases and stimulating classical protein kinase C activity. In addition to stimulating insulin release, nutrients also effect gene expression, protein synthesis and beta -cell proliferation. Gene expression is effected by nutrient induction of a variety of immediate early response genes. Glucose stimulates proinsulin biosynthesis both at the translational and transcriptional level. beta -cell proliferation, as a result of insulin-like growth factor and growth hormone mitogenic pathways, is also glucose dependent. Thus, many beta -cell functions in addition to secretion are controlled by nutrient metabolism.