Direct glucocorticoid inhibition of insulin secretion. An in vitro study of dexamethasone effects in mouse islets.
The direct effects of glucocorticoids on pancreatic beta cell function were studied with normal mouse islets. Dexamethasone inhibited insulin secretion from cultured islets in a concentration-dependent manner: maximum of approximately 75% at 250 nM and IC50 at approximately 20 nM dexamethasone. This inhibition was of slow onset (0, 20, and 40% after 1, 2, and 3 h) and only slowly reversible. It was prevented by a blocker of nuclear glucocorticoid receptors, by pertussis toxin, by a phorbol ester, and by dibutyryl cAMP, but was unaffected by an increase in the fuel content of the culture medium. Dexamethasone treatment did not affect islet cAMP levels but slightly reduced inositol phosphate formation. After 18 h of culture with or without 1 microM dexamethasone, the islets were perifused and stimulated by a rise in the glucose concentration from 3 to 15 mM. Both phases of insulin secretion were similarly decreased in dexamethasone-treated islets as compared with control islets. This inhibition could not be ascribed to a lowering of insulin stores (higher in dexamethasone-treated islets), to an alteration of glucose metabolism (glucose oxidation and NAD(P)H changes were unaffected), or to a lesser rise of cytoplasmic Ca2+ in beta cells (only the frequency of the oscillations was modified). Dexamethasone also inhibited insulin secretion induced by arginine, tolbutamide, or high K+. In this case also the inhibition was observed despite a normal rise of cytoplasmic Ca2+. In conclusion, dexamethasone inhibits insulin secretion through a genomic action in beta cells that leads to a decrease in the efficacy of cytoplasmic Ca2+ on the exocytotic process.
Lambillotte
C
C
Unité d'Endocrinologie et Métabolisme, University of Louvain Faculty of Medicine, Brussels, Belgium.
Gilon
P
P
Henquin
J C
JC
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001402:B-Lymphocytes / Q000378:metabolism; D003994:Bucladesine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D037342:Pertussis Toxin; D010703:Phorbol Esters / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D014044:Tolbutamide / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D005938:Glucocorticoids; D007295:Inositol Phosphates; D007328:Insulin; D010703:Phorbol Esters; D011965:Receptors, Glucocorticoid; D010566:Virulence Factors, Bordetella; D009249:NADP; D003994:Bucladesine; D003907:Dexamethasone; D001120:Arginine; D014044:Tolbutamide; D000242:Cyclic AMP; D037342:Pertussis Toxin; D005947:Glucose; D011188:Potassium; D002118:Calcium