AUGMENTATION OF INSULIN RELEASE BY GLUCOSE IN THE ABSENCE OF EXTRACELLULAR CA2- NEW INSIGHTS INTO STIMULUS-SECRETION COUPLING( )

Glucose stimulates insulin secretion in the pancreatic beta-cell by me ans of a synergistic interaction between at least two signaling pathwa ys. One, the K-ATP channel-dependent pathway, increases the entry of C a2+ through voltage-gated channels by closure of the K-ATP channels an d depolarization of the beta-cell membrane. The resulting increase in [Ca2+](i) stimulates insulin exocytosis. The other, a K-ATP channel-in dependent pathway requires that [Ca2+](i) be elevated and augments the Ca2+-stimulated release. These mechanisms are in accord with the beli ef that glucose-stimulated insulin secretion has an essential requirem ent for extracellular Ca2+ and increased [Ca2+](i). However, when prot ein kinases A and C are activated simultaneously, a large effect of gl ucose to augment insulin release can be seen in the absence of extrace llular Ca2+, under conditions in which [Ca2+](i) is not increased, and even when [Ca2+](i) is decreased to low levels by intracellular chela tion with BAPTA. In the presence or absence of Ca2+, there are similar ities in the characteristics of augmentation of insulin release that s uggest that only one augmentation mechanism may be involved. These sim ilarities include time course, glucose dose-responses, augmentation by nutrients other than glucose such as alpha-ketoisocaproate (alpha-KIC ), and augmentation by the fatty acids palmitate and myristate. Howeve r, augmentation in the presence and absence of Ca2+ is distinctly diff erent in GTP dependency. Therefore, exocytosis under these two conditi ons appears to be triggered differently-one by Ca2+ and the other by G TP or a GTP-dependent mechanism. The augmentation pathways are likely responsible for time-dependent potentiation of secretion and for the s econd phase of glucose-stimulated insulin release.