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.
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Division of Endocrinology, Diabetes, Metabolism, and Molecular Medicine, New England Medical Center, Boston, Massachusetts.
Soltoff
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SP
Yaney
G C
GC
Boyd
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AE
D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology; D002460:Cell Line; D006224:Cricetinae; D003600:Cytosol / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D009553:Nimodipine / Q000494:pharmacology
D015220:Calcium Channels; D007328:Insulin; D001127:Arginine Vasopressin; D009553:Nimodipine; D015544:Inositol 1,4,5-Trisphosphate; D005947:Glucose; D002118:Calcium