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Increased glucocorticoid receptor expression in human skeletal muscle cells may contribute to the pathogenesis of the metabolic syndrome

By Christopher B. Whorwood, Stephen J. Donovan, Daniel Flanagan, David I.W. Phillips and Christopher D. Byrne

Abstract

Altered glucocorticoid hormone action may contribute to the etiology of the metabolic syndrome, but the molecular mechanisms are poorly defined. Tissue sensitivity to glucocorticoid is regulated by expression of the glucocorticoid receptor (GR)-? and 11ß-hydroxysteroid dehydrogenase type I (11ß-HSD1)-mediated intracellular synthesis of active cortisol from inactive cortisone. We have analyzed GR? and 11ß-HSD1 expression in skeletal myoblasts from men (n = 14) with contrasting levels of insulin sensitivity (euglycemic clamp measurements of insulin-dependent glucose disposal rate), blood pressure, and adiposity. <br/>Positive associations were evident between myoblast expression of GR? under basal conditions and levels of insulin resistance (r^2 = 0.34, P &lt; 0.05), BMI (r^2 = 0.49, P &lt; 0.01), percent body fat (r^2 = 0.34, P &lt; 0.02), and blood pressure (r2 = 0.86, P &lt; 0.001). Similar associations were evident when myoblasts were incubated with physiological levels of cortisol (P &lt; 0.01 for all). Importantly, GR? expression was unaffected by variations in in vivo concentrations of insulin, IGF-1, or glucose concentrations. In common with the GR, 11ß-HSD1 expression in myoblasts incubated with physiological concentrations of cortisol in vitro was positively associated with levels of insulin resistance (r^2 = 0.68, P &lt; 0.001), BMI (r^2 = 0.63, P &lt; 0.005), and blood pressure (r^2 = 0.27, P &lt; 0.05). Regulation of GR? and 11ß-HSD1 by cortisol was abolished by the GR antagonist RU38486. In summary, our data suggest that raised skeletal muscle cell expression of GR? and 11ß -HSD1-mediated regulation of intracellular cortisol may play a fundamental role in mechanisms contributing to the pathogenesis of the metabolic syndrome

Topics: RB
Year: 2002
OAI identifier: oai:eprints.soton.ac.uk:26124
Provided by: e-Prints Soton
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