Serum- and Glucocorticoid-Inducible Kinase 1 (SGK1) Mediates Glucocorticoid-Induced Inhibition of Insulin Secretion

Abstract

Glucocorticoid excess predisposes to the development of diabetes, at least in part through impairment of insulin secretion. The underlying mechanism has remained elusive. We show here that dexamethasone upregulates transcription and expression of the serum- and glucocorticoid-inducible kinase 1 (SGK1) in insulin-secreting cells, an effect reversed by mifepristone (RU486), an antagonist of the nuclear glucocorticoid receptor. When coexpressed in Xenopus oocytes, SGK1 increases the activity of voltage-gated K+ channel Kv1.5. In INS-1 cells, dexamethasone stimulates the transcription of Kv1.5, increases the repolarizing outward current, reduces peak values of [Ca2+]i oscillations, and decreases glucose-induced insulin release. The latter effect is reversed by K+ channel blockers 4-aminopyridine and tetraethylammonium and by a more selective Kv1.5 channel inhibitor MSD-D. Dexamethasone also increases expression of Kv1.5 in mouse islets and reduces glucose-induced insulin secretion, an effect reversed by MSD-D. In islets isolated from wild-type but not SGK1 knockout mice, dexamethasone significantly blunted glucose-, forskolin-, and phorbol myristic acid-induced insulin release. In conclusion, dexamethasone stimulates the transcription of SGK1, which in turn upregulates the activity of voltage-gated K+ channels. Increased K+ channel activity reduces Ca2+ entry through voltage-gated Ca2+ channels and insulin release.