THE MECHANISMS UNDERLYING THE GLUCOSE DEPENDENCE OF ARGININE VASOPRESSIN-INDUCED INSULIN-SECRETION IN BETA-CELLS

The mechanisms underlying the glucose dependence of arginine vasopress in (AVP)-stimulated insulin secretion were examined in a hamster insul in-secreting cell line (HIT cells). At 1.67 mm glucose, 100 nm AVP sti mulated biphasic changes in free cytosolic Ca2+ ([Ca2+]i) and insulin secretion. The initial spike of [Ca2+]i came from an intracellular poo l and was accompanied by parallel changes in the levels of inositol 1, 4,5-trisphosphate. The following sustained increase in [Ca2+]i was ass ociated with membrane depolarization and Ca2+ influx through voltage-d ependent Ca2+ channels. The rapid phase of insulin secretion and the [ Ca2+]i spike were resistant to the Ca2+ channel blocker nimodipine, wh ereas the sustained insulin secretion and the protracted increase in [ Ca2+]i were inhibited by nimodipine. Thus, biphasic increases in [Ca2]i mediated the biphasic insulin secretory pattern. In the absence of glucose, 100 nm AVP triggered a transient smaller spike in (Ca2+]i but did not stimulate membrane depolarization, Ca2+ influx, or insulin se cretion. However, the increase in inositol 1,4,5-trisphosphate was sim ilar to that seen at 1.67 mm glucose. Both the AVP-induced [Ca2+]i spi ke and sustained [Ca2+]i increase were augmented by glucose. We conclu ded that the initial AVP receptor-mediated activation of phospholipase -C is not altered by glucose, but both intracellular Ca2+ release and extracellular Ca2+ influx through voltage-dependent Ca2+ channels trig gered by AVP are glucose dependent and explain the sensitivity of AVP- stimulated insulin release to this metabolite.