Cyclosporin-induced inhibition of insulin release. Possible role of voltage-dependent calcium transport channels.
The exposure of normal pancreatic islets to cyclosporin-A (1 microgram/ml) for 24 hr resulted in significant inhibition of glucose-induced (16.7 mM) insulin release from 197 +/- 14 microU/10 islets/15 min (control) to 103 +/- 14 microU/10 islets/15 min (Cy-A-treated islets; P less than 0.001). Cy-A did not alter insulin release in the presence of non-stimulatory (1.7 mM) or submaximally effective glucose concentrations (9.2 mM). In parallel experiments, Cy-A reduced glucose-stimulated increases in cytosolic free calcium concentrations, [Ca2+]i (217 +/- 15 nM without and 137 +/- 3 nM with Cy-A in the presence of 16.7 mM glucose, P less than 0.01). To better define the site of Cy-A action, we studied its effect on insulin release and increases in [Ca2+]i induced by either K+ (50 mM), which promotes Ca2+ influx via voltage-dependent Ca2+ channels, or by forskolin (20 microM), dibutyryl cyclic AMP (1 mM) or arachidonic acid (49 microM), all of which stimulate mobilization of intracellular Ca2+ stores. Cy-A significantly inhibited K+-induced changes (203 +/- 13 nM without and 77 +/- 6 nM with Cy-A, respectively, P less than 0.001), but not those induced by forskolin, dibutyryl cyclic AMP or arachidonic acid. These observations suggest that Cy-A inhibits insulin release by interfering with Ca2+ influx via voltage-dependent calcium channels.
Draznin
B
B
Medical Research Service, Denver Veterans Administration Medical Center, CO 80220.
Metz
S A
SA
Sussman
K E
KE
Leitner
J W
JW
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D003524:Cyclosporins / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D001095:Arachidonic Acids; D015220:Calcium Channels; D003524:Cyclosporins; D007328:Insulin; D016718:Arachidonic Acid; D005947:Glucose; D002118:Calcium