Glucocorticoids suppress GLP-1 secretion: possible contribution to their diabetogenic effects.
Evidence indicates that subtle abnormalities in GC (glucocorticoid) plasma concentrations and/or in tissue sensitivity to GCs are important in the metabolic syndrome, and it is generally agreed that GCs induce insulin resistance. In addition, it was recently reported that short-term exposure to GCs reduced the insulinotropic effects of the incretin GLP-1 (glucagon-like peptide 1). However, although defective GLP-1 secretion has been correlated with insulin resistance, potential direct effects of GCs on GLP-1-producing L-cell function in terms of GLP-1 secretion and apoptosis have not been studied in any greater detail. In the present study, we sought to determine whether GCs could exert direct effects on GLP-1-producing L-cells in terms of GLP-1 secretion and cell viability. We demonstrate that the GR (glucocorticoid receptor) is expressed in GLP-1-producing cells, where GR activation in response to dexamethasone induces SGK1 (serum- and glucocorticoid-inducible kinase 1) expression, but did not influence preproglucagon expression or cell viability. In addition, dexamethasone treatment of enteroendocrine GLUTag cells reduced GLP-1 secretion induced by glucose, 2-deoxy-D-glucose, fructose and potassium, whereas the secretory response to a phorbol ester was unaltered. Furthermore, in vivo administration of dexamethasone to rats reduced the circulating levels of GLP-1 concurrent with induction of insulin resistance and glucose intolerance. We can conclude that GR activation in GLP-1-producing cells will diminish the secretory responsiveness of these cells to subsequent carbohydrate stimulation. These effects may not only elucidate the pathogenesis of steroid diabetes, but could ultimately contribute to the identification of novel molecular targets for controlling incretin secretion.
['Kappe|Camilla|C|', 'Fransson|Liselotte|L|', 'Wolbert|Petra|P|', 'Ortsäter|Henrik|H|']
D000818:Animals D001786:Blood Glucose D002460:Cell Line D003907:Dexamethasone D003920:Diabetes Mellitus D015536:Down-Regulation D019858:Enteroendocrine Cells D052216:Glucagon-Like Peptide 1 D005938:Glucocorticoids D007328:Insulin D007333:Insulin Resistance D008297:Male D051379:Mice D017208:Rats, Wistar D011965:Receptors, Glucocorticoid D015398:Signal Transduction D013997:Time Factors
glucocorticoids insulin resistance dexamethasone glucagon-like peptide-1