title: 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 K(v)1.5. In INS-1 cells, dexamethasone stimulates the transcription of K(v)1.5, increases the repolarizing outward current, reduces peak values of [Ca(2+)](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 K(v)1.5 channel inhibitor MSD-D. Dexamethasone also increases expression of K(v)1.5 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 Ca(2+) entry through voltage-gated Ca(2+) channels and insulin release.
authors.affiliation: Department for Physiology, University of Tübingen, Tübingen, Germany. susanne.ullrich@uni-tuebingen.de <susanne.ullrich@uni-tuebingen.de>
authors.forename: Susanne
authors.initials: S
authors.lastname: Ullrich
authors.forename: Susanne
authors.initials: S
authors.lastname: Berchtold
authors.forename: Felicia
authors.initials: F
authors.lastname: Ranta
authors.forename: Guiscard
authors.initials: G
authors.lastname: Seebohm
authors.forename: Guido
authors.initials: G
authors.lastname: Henke
authors.forename: Adrian
authors.initials: A
authors.lastname: Lupescu
authors.forename: Andreas F
authors.initials: AF
authors.lastname: Mack
authors.forename: Cho-Ming
authors.initials: CM
authors.lastname: Chao
authors.forename: Jiping
authors.initials: J
authors.lastname: Su
authors.forename: Roland
authors.initials: R
authors.lastname: Nitschke
authors.forename: Dorothea
authors.initials: D
authors.lastname: Alexander
authors.forename: Björn
authors.initials: B
authors.lastname: Friedrich
authors.forename: Peer
authors.initials: P
authors.lastname: Wulff
authors.forename: Dietmar
authors.initials: D
authors.lastname: Kuhl
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000494:pharmacology*; D017874:Immediate-Early Proteins; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015735:Mifepristone / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009865:Oocytes; D015221:Potassium Channels / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation; D014982:Xenopus laevis; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D003907:Dexamethasone; D005938:Glucocorticoids; D017874:Immediate-Early Proteins; D007328:Insulin; D015735:Mifepristone; D009687:Nuclear Proteins; D015221:Potassium Channels; D017346:Protein Serine-Threonine Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases