Increased glucocorticoid receptor expression in human skeletal muscle cells may contribute to the pathogenesis of the metabolic syndrome.
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)-alpha and 11beta-hydroxysteroid dehydrogenase type I (11beta-HSD1)-mediated intracellular synthesis of active cortisol from inactive cortisone. We have analyzed GRalpha and 11beta-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 GRalpha under basal conditions and levels of insulin resistance (r(2) = 0.34, P < 0.05), BMI (r(2) = 0.49, P < 0.01), percent body fat (r(2) = 0.34, P < 0.02), and blood pressure (r(2) = 0.86, P < 0.001). Similar associations were evident when myoblasts were incubated with physiological levels of cortisol (P < 0.01 for all). Importantly, GRalpha expression was unaffected by variations in in vivo concentrations of insulin, IGF-1, or glucose concentrations. In common with the GR, 11beta-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 < 0.001), BMI (r(2) = 0.63, P < 0.005), and blood pressure (r(2) = 0.27, P < 0.05). Regulation of GRalpha and 11beta-HSD1 by cortisol was abolished by the GR antagonist RU38486. In summary, our data suggest that raised skeletal muscle cell expression of GRalpha and 11beta -HSD1-mediated regulation of intracellular cortisol may play a fundamental role in mechanisms contributing to the pathogenesis of the metabolic syndrome.
Whorwood
Christopher B
CB
Endocrine and Metabolism Unit, University Department of Medicine, University of Portsmouth, Portsmouth, UK.
Donovan
Stephen J
SJ
Flanagan
Daniel
D
Phillips
David I W
DI
Byrne
Christopher D
CD
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000328:Adult; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D001794:Blood Pressure; D015992:Body Mass Index; D002459:Cell Fusion; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D015342:DNA Probes; D005786:Gene Expression Regulation / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D015309:Glucose Clamp Technique; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics; D006946:Hyperinsulinism; D007150:Immunohistochemistry; D007328:Insulin / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D024821:Metabolic Syndrome / Q000502:physiology*; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology*; D011965:Receptors, Glucocorticoid / Q000235:genetics*
D001786:Blood Glucose; D016895:Culture Media, Serum-Free; D015342:DNA Probes; D007328:Insulin; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; D006913:Hydroxysteroid Dehydrogenases; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human