title: Dexamethasone suppresses phospholipase C activation and insulin secretion from isolated rat islets.
abstract: Dexamethasone inhibits insulin secretion from isolated islets. In the present experiments, possible underlying biochemical mechanisms responsible for defective secretion were explored. Dexamethasone (1 micromol/L) had no immediate deleterious effect on 15 mmol/L glucose-induced insulin release from perifused rat islets. However, a 3-hour preincubation period with 1 micromol/L dexamethasone resulted in parallel reductions in both the first (64%) and second phases (74%) of 15 mmol/L glucose-induced insulin secretion monitored during a dynamic perifusion. When measured after the perifusion, there were no differences in insulin content or in the capacity of control or dexamethasone-treated islets to use glucose. Dexamethasone (1 micromol/L) preexposure also reduced phorbol ester- and potassium-induced secretion. In additional experiments, islets were labeled for 3 hours with 3H-inositol in the presence or absence of 1 micromol/L dexamethasone. The steroid did not affect total 3H-inositol incorporation during the labeling period. However, the capacity of 15 mmol/L glucose, 30 mmol/L KCl, and 100 micromol/L carbachol to activate phospholipase C (PLC), monitored by the accumulation of labeled inositol phosphates, was significantly reduced in dexamethasone-pretreated islets. Inclusion of the nuclear glucocorticoid receptor antagonist RU486 (mifepristone, 10 micromol/L) abolished the adverse effects of dexamethasone on both glucose-induced inositol phosphate accumulation and insulin secretion. Quantitative Western blot analyses revealed that the islet contents of PLCdelta1, PLCbeta1, beta2, beta3, and protein kinase C alpha were unaffected by dexamethasone pretreatment. These findings demonstrate that dexamethasone pretreatment impairs insulin secretion via a genomic action and that impaired activation of the PLC/protein kinase C signaling system is involved in the evolution of its inhibitory effect on secretion.
authors.affiliation: Yale University School of Nursing, New Haven, CT 06536-0740, USA. walter.zawalich@yale.edu
authors.forename: Walter S
authors.initials: WS
authors.lastname: Zawalich
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Tesz
authors.forename: Hanae
authors.initials: H
authors.lastname: Yamazaki
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Zawalich
authors.forename: William
authors.initials: W
authors.lastname: Philbrick
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003864:Depression, Chemical; D003907:Dexamethasone / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D006727:Hormone Antagonists; D007295:Inositol Phosphates; D007328:Insulin; D007527:Isoenzymes; D015735:Mifepristone; D003907:Dexamethasone; D011493:Protein Kinase C; D010738:Type C Phospholipases; D005947:Glucose; D013755:Tetradecanoylphorbol Acetate; D011188:Potassium