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Kinome Analysis Reveals Nongenomic Glucocorticoid Receptor-Dependent Inhibition of Insulin Signaling

Laboratory of Experimental Internal Medicine (M.L., J.T., M.S., A.V., L.V.S, S.v.D.) and Department of Gastroenterology and Hepatology (M.L., D.H.), Academic Medical Center, NL-1105 AZ Amsterdam, The Netherlands; and Department of Cell Biology (M.P.), University of Groningen, NL-9713 AV Groningen, The Netherlands

Address all correspondence and requests for reprints to: Mark Löwenberg, Laboratory of Experimental Internal Medicine, Academic Medical Center, Meibergdreef 9, NL-1105 AZ Amsterdam, The Netherlands. E-mail: m.lowenberg{at}amc.uva.nl.

Glucocorticoids (GCs) are powerful immunosuppressive agents that control genomic effects through GC receptor (GR)-dependent transcriptional changes. A common complication of GC therapy is insulin resistance, but the underlying molecular mechanism remains obscure. Evidence is increasing for rapid genomic-independent GC action on cellular physiology. Here, we generate a comprehensive description of nongenomic GC effects on insulin signaling using peptide arrays containing 1176 different kinase consensus substrates. Reduced kinase activities of the insulin receptor (INSR) and several downstream INSR signaling intermediates (i.e. p70S6k, AMP-activated protein kinase, glycogen synthase kinase-3, and Fyn) were detected in adipocytes and T lymphocytes due to short-term treatment with dexamethasone (DEX), a synthetic fluorinated GC. Western blot analysis confirmed suppressed phosphorylation of the INSR and a series of downstream INSR targets (i.e. INSR substrate-1, p70S6k, protein kinase B, phosphoinositide-dependent protein kinase, Fyn, and glycogen synthase kinase-3) after DEX treatment. DEX inhibited insulin signaling through a GR-dependent (RU486 sensitive) and transcription-independent (actinomycin D insensitive) mechanism. Overall, we postulate here a molecular mechanism for GC-induced insulin resistance based on nongenomic GR-dependent inhibition of insulin signaling.

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