Horm Metab Res 2009; 41(12): 899-904
DOI: 10.1055/s-0029-1234071
Humans, Clinical

© Georg Thieme Verlag KG Stuttgart · New York

Effect of RU486 on Hepatic and Adipocyte Gene Expression Improves Diabetes Control in Obesity-type 2 Diabetes

A. I. Taylor1 , N. Frizzell1 , A. M. McKillop1 , P. R. Flatt1 , V. A. Gault1
  • 1The SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, UK
Further Information

Publication History

received 09.04.2009

accepted 07.07.2009

Publication Date:
10 August 2009 (online)

Abstract

Cortisol has wide-ranging actions, namely in gluconeogenesis and glycogenesis and exerts its effects through the glucocorticoid receptor. In the present study, we examined effects of glucocorticoid receptor blockade on type 2 diabetes control using the antagonist, RU486. Obese diabetic mice received daily injections of vehicle or RU486 over 28 days. Food intake, body weight, and plasma glucose were measured frequently. At 28 days, glucose tolerance, insulin sensitivity, and plasma triglycerides were assessed. Epididymal white adipose tissue and liver were excised for measurement of gene expression. Daily administration of RU486 had no effect on body weight or food intake, but plasma glucose concentrations were significantly lowered (1.4–1.6-fold; p<0.05 to p<0.001). Glucose concentrations were also significantly reduced (2.2-fold; p<0.001) following a glucose challenge. Similarly, exogenous insulin evoked a significantly greater reduction in plasma glucose (3.6-fold; p<0.01). Gene expression analysis revealed a significant reduction in hepatic mRNA of key enzymes, namely PEPCK-C (25%; p<0.01) and G6 Pase (32%; p<0.01) and also 11β-HSD1 (18%; p<0.05). Investigation of adipose tissue gene expression also demonstrated reduced expression in 11β-HSD1 (47%; p<0.05) and LPL (47%; p<0.001). These data demonstrate wide-ranging effects of glucocorticoid receptor antagonism on gene expression and metabolism, illustrating the therapeutic potential of specific glucocorticoid receptor antagonists in obesity-related diabetes.

References

Correspondence

V. A. Gault

The SAAD Centre for Pharmacy and Diabetes

School of Biomedical Sciences

University of Ulster

Coleraine BT52 1SA

Northern Ireland

UK

Phone: +28/7032 33 22

Fax: +28/7032 49 65

Email: [email protected]