REGULATION OF PANCREATIC BETA-CELL ELECTRICAL-ACTIVITY AND INSULIN RELEASE BY PHYSIOLOGICAL AMINO-ACID-CONCENTRATIONS

The mutual enhancement of insulin release by glucose and amino acids i s not clearly understood. In this study, the effects on electrical act ivity and insulin release of a mixture of amino acids and glucose at c oncentrations found in fed (aa(FD)) and fasted (aa(FD)) animals were d etermined using freshly isolated mouse islets. Islets perifused with a a(FD) mixture showed an oscillatory pattern of electrical activity at lower glucose concentrations (5 mmol/l) than in islets perifused with the aa(FT) mixture and with glucose (G) alone (10 mmol/l). The concent ration/response curve for the fraction of time spent by the membrane p otential in the active phase in aa(FD)-stimulated islets was found to be significantly shifted to the left and had a smaller slope than that for glucose-stimulated islets. Insulin release followed the same patt ern. This resulted in a concentration/response curve for glucose that was closer to that recorded ''in vivo''. We have also found that four amino acids (leucine, isoleucine, alanine and arginine) are largely re sponsible for the observed effects and that there is a non-linear enha ncement of insulin release as a consequence of the combined effect of amino acids and glucose. This effect was more pronounced in the second phase of insulin release and was dependent on intracellular Ca2+. The se findings indicate that amino acids account for most of the leftward shift in the concentration/response curve for glucose and that a redu ction in the threshold for the glucose-induced oscillatory electrical activity response and in the generation of Ca2+ spikes accounts for th e triggering of insulin release at lower glucose concentrations. Never theless, the effects on insulin release at high glucose concentrations cannot be explained solely by the increase in glucose-induced electri cal activity.