Dexamethasone-induced changes in FAD-glycerophosphate dehydrogenase mRNA, content and activity, and insulin release in human pancreatic islets.
Human pancreatic islets were cultured for 63 hr at 2.8 or 16.7 mM D-glucose in the absence or presence of dexamethasone. In the 1.0 to 10 microM range, dexamethasone caused a concentration-related decrease in the FAD (flavin adenine dinucleotide)-linked mitochondrial glycerophosphate dehydrogenase (mGDH) mRNA content of the islets, and decreased both the mGDH content of the islets and the catalytic activity of the enzyme in islet homogenates, these effects being often more marked in islets cultured at 16.7 mM, rather than 2.8 mM, D-glucose. Even after culture in the presence of no more than 10 nM dexamethasone, namely under conditions in which the mGDH mRNA content and activity were both virtually unaffected, the corticosteroid restored the capacity of the beta-cells to display an increase in insulin output in response to a rise in D-glucose concentration in islets first cultured at 2.8 mM D-glucose but suppressed the insulinotropic action of the hexose in islets first cultured at 16.7 mM D-glucose. Whilst revealing an untoward effect of high concentrations of dexamethasone upon mGDH mRNA, content and activity in human islets, these findings also document a dual effect of a low concentration of the corticosteroid (10 nM) upon the secretory responsiveness of human islets to D-glucose, independently of any significant change in mGDH gene expression. It is proposed that such a dual action may account, in part at least, for both the well known increase in insulin output found in hypercorticism and the more recently discovered unfavourable direct effect of corticosteroid hormones on the secretory activity of islet beta-cells.
Fabregat
M E
ME
Medicine Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clinic, Barcelona, Spain.
Fernandez-Alvarez
J
J
Franco
C
C
Malaisse
W J
WJ
Gomis
R
R
D000328:Adult; D000368:Aged; D015152:Blotting, Northern; D015153:Blotting, Western; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology*; D005993:Glycerolphosphate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology; D012333:RNA, Messenger / Q000378:metabolism*
D005938:Glucocorticoids; D007328:Insulin; D012333:RNA, Messenger; D005182:Flavin-Adenine Dinucleotide; D003907:Dexamethasone; D005993:Glycerolphosphate Dehydrogenase