TY - JOUR
T1 - Kinome analysis reveals nongenomic glucocorticoid receptor-dependent inhibition of insulin signaling
AU - Löwenberg, Mark
AU - Tuynman, Jurriaan
AU - Scheffer, Meike
AU - Verhaar, Auke
AU - Vermeulen, Louis
AU - van Deventer, Sander
AU - Hommes, Daniel
AU - Peppelenbosch, Maikel
PY - 2006
Y1 - 2006
N2 - 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 1,176 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
AB - 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 1,176 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
U2 - https://doi.org/10.1210/en.2005-1602
DO - https://doi.org/10.1210/en.2005-1602
M3 - Article
C2 - 16574792
SN - 0013-7227
VL - 147
SP - 3555
EP - 3562
JO - Endocrinology
JF - Endocrinology
IS - 7
ER -