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

Serum- and Glucocorticoid-Inducible Kinase 1 (SGK1) Mediates Glucocorticoid-Induced Inhibition of Insulin Secretion Susanne Ullrich 1 , Susanne Berchtold 1 , Felicia Ranta 1 , Guiscard Seebohm 1 , Guido Henke 1 , Adrian Lupescu 1 , Andreas F. Mack 2 , Cho-Ming Chao 3 , Jiping Su 3 , Roland Nitschke 4 , Dorothea Alexander 5 , Björn Friedrich 6 , Peer Wulff 7 , Dietmar Kuhl 8 and Florian Lang 1 1 Department for Physiology, University of Tübingen, Tübingen, Germany 2 Deparment of Anatomy, University of Tübingen, Tübingen, Germany 3 Department for Neurophysiology, University of Cologne, Cologne, Germany 4 Institut für Biologie I, Life Imaging Facility, Freiburg, Germany 5 Department of Orthopedics, University of Tübingen, Tübingen, Germany 6 Department of Internal Medicine, University of Tübingen, Tübingen, Germany 7 Department of Clinical Neurobiology, University Hospital of Neurology, Heidelberg, Germany 8 Department of Biology, Chemistry, and Pharmacy, Free University Berlin, Berlin, Germany Address correspondence and reprint requests to Dr. Susanne Ullrich, Institut für Physiologie Gmelinstrasse, 5 D-72076 Tübingen, Germany. E-mail: susanne.ullrich{at}uni-tuebingen.de 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 a