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

The mechanisms underlying the glucose dependence of arginine vasopressin (AVP)-stimulated insulin secretion were examined in a hamster insulin-secreting cell line (HIT cells). At 1.67 mm glucose, 100 nm AVP stimulated biphasic changes in free cytosolic Ca2+ ([Ca2+]i) and insulin secretion. The initial spike of [Ca2+]i came from an intracellular pool and was accompanied by parallel changes in the levels of inositol 1,4,5-trisphosphate. The following sustained increase in [Ca2+]i was associated with membrane depolarization and Ca2+ influx through voltage-dependent Ca2+ channels. The rapid phase of insulin secretion and the [Ca2+]i spike were resistant to the Ca2+ channel blocker nimodipine, whereas 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 secretion. However, the increase in inositol 1,4,5-trisphosphate was similar to that seen at 1.67 mm glucose. Both the AVP-induced [Ca2+]i spike and sustained [Ca2+]i increase were augmented by glucose. We concluded 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 triggered by AVP are glucose dependent and explain the sensitivity of AVP-stimulated insulin release to this metabolite.