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.