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

Susanne U. Trost, Darrell D. Belke, Wolfgang F. Bluhm, Markus Meyer, Eric Swanson, Wolfgang H. Dillmann

Research output: Contribution to journalArticlepeer-review

136 Scopus citations

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)-α and 11β-hydroxysteroid dehydrogenase type I (11β-HSD1)-mediated intracellular synthesis of active cortisol from inactive cortisone. We have analyzed GRα and 11β-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. Positive associations were evident between myoblast expression of GRα under basal conditions and levels of insulin resistance (r2 = 0.34, P < 0.05), BMI (r2 = 0.49, P < 0.01), percent body fat (r2 = 0.34, P < 0.02), and blood pressure (r2 = 0.86, P < 0.001). Similar associations were evident when myoblasts were incubated with physiological levels of cortisol (P < 0.01 for all). Importantly, GRα expression was unaffected by variations in in vivo concentrations of insulin, IGF-1, or glucose concentrations. In common with the GR, 11β-HSD1 expression in myoblasts incubated with physiological concentrations of cortisol in vitro was positively associated with levels of insulin resistance (r2 = 0.68, P < 0.001), BMI (r2 = 0.63, P < 0.005), and blood pressure (r2 = 0.27, P < 0.05). Regulation of GRα and 11β-HSD1 by cortisol was abolished by the GR antagonist RU38486. In summary, our data suggest that raised skeletal muscle cell expression of GRα and 11β-HSD1-mediated regulation of intracellular cortisol may play a fundamental role in mechanisms contributing to the pathogenesis of the metabolic syndrome.

Original languageEnglish (US)
Pages (from-to)1066-1075
Number of pages10
JournalDiabetes
Volume51
Issue number4
DOIs
StatePublished - 2002
Externally publishedYes

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