Glucocorticoids suppress GLP-1 secretion: possible contribution to their diabetogenic effects

Evidence indicates that subtle abnormalities in glucocorticoid (GC) 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 glucagon-like peptide-1 (GLP-1). However, while defective GLP-1 secretion has been correlated to 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 if GCs could exert direct effects on GLP-1-producing L-cells in terms of GLP-1 secretion and cell viability. We demonstrate here that the glucocorticoid receptor (GR) is expressed in GLP-1-producing cells, where GR activation in response to dexamethasone induces serum- and glucocorticoid-inducible kinase 1 (SGK1) expression but did not influence preproglucagon expression or cell viability. Further, dexamethasone treatment of enteroendocrine GLUTag cells reduced GLP-1 secretion induced by glucose, 2-deoxy-D-glucose, fructose and potassium, while 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-produci...
Source: Clinical Science - Category: Biomedical Science Authors: Source Type: research