DEXAMETHASONE INDUCES POSTTRANSLATIONAL DEGRADATION OF GLUT2 AND INHIBITION OF INSULIN-SECRETION IN ISOLATED PANCREATIC BETA-CELLS - COMPARISON WITH THE EFFECTS OF FATTY-ACIDS

GLUT2 expression is strongly decreased in glucose-unresponsive pancrea tic beta cells of diabetic rodents. This decreased expression is due t o circulating factors distinct from insulin or glucose, Here we evalua ted the effect of palmitic acid and the synthetic glucocorticoid desam ethasone on GLUT2 expression by in vitro cultured rat pancreatic islet s. Palmitic acid induced a 40% decrease in GLUT2 mRNA levels with, how ever, no consistent effect on protein expression, Dexamethasone, in co ntrast, had no effect on GLUT2 mRNA, but decreased GLUT2 protein by ab out 65%. The effect of dexamethasone was more pronounced at high gluco se concentrations and was inhibited by the glucocorticoid antagonist R U-486. Biosynthetic labeling experiments revealed that GLUTS translati on rate was only minimally affected by dexamethasone, but that its hal f-life was decreased by 50%, indicating that glucocorticoids activated a posttranslational degradation mechanism. This degradation mechanism was not affecting all membrane proteins, since the alpha subunit of t he Na+/K+-ATPase was unaffected, Glucose-induced insulin secretion was strongly decreased by treatment with palmitic acid and/or dexamethaso ne. The insulin content was decreased (similar to 55 percent) in the p resence of palmitic acid, but increased (similar to 180%) in the prese nce of dexamethasone. We conclude that a combination of elevated fatty acids and glucocorticoids can induce two common features observed in diabetic beta cells, decreased GLUT2 expression, and loss of glucose-i nduced insulin secretion.