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1 United States; Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia, Missouri, United States
2 Internal Medicine, Division of Nephrology, University of Missouri-Columbia School of Medicine, Columbia, Missouri, United States
3 Internal Medicine, University of Missouri Columbia, Columbia, Missouri, United States
4 Internal Medicine, University of Missouri Columbia, Columbia, Missouri, United States; Internal Medicine, University of Missouri, Columbia, Missouri, United States
5 Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia, Missouri, United States
6 Dept. of Family and Community Medicine, University of Missouri School of Medicine Columbia, Missouri, Camdenton, United States; , United States
7 Internal Medicine, University of Missouri School of Medicine, Columbia, Missouri, United States
8 Hypertension Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
9 Medicine,Physiology and Pharmacology, Director of Diabetes and Cardiovascular Center, Columbia, Missouri, United States
* To whom correspondence should be addressed. E-mail: sowersj{at}health.missouri.edu.
Renin-angiotensin-aldosterone system (RAAS) activation mediates increases in reactive oxygen species (ROS) and impaired insulin signaling. The transgenic Ren2 rat manifests increased tissue renin-angiotensin system activity, elevated serum aldosterone, hypertension, and insulin resistance. To explore the role of aldosterone in the pathogenesis of insulin resistance we investigated the impact of in vivo treatment of with a mineralocorticoid receptor (MR) antagonist on insulin sensitivity in Ren2 and aged-matched Sprague Dawley (SD) control rats. Both groups (age 6-8 wks) were implanted with subcutaneous time-release pellets containing spironolactone (0.24 mg/day) or placebo over 21 days. Systolic blood pressure (SBP) and intraperitoneal glucose tolerance test were determined. Soleus muscle IRS-1, tyrosine phosphorylated IRS-1, protein kinase B (Akt) phosphorylation, GLUT4 levels and insulin stimulated 2-deoxyglucose uptake were evaluated in relation to NADPH subunit expression/oxidase activity and ROS production (chemiluminescence and 4-HNE immunostaining). Along with increased soleus muscle NADPH oxidase activity and ROS, there was systemic insulin resistance, and reduced muscle IRS-1 tyrosine phosphoryation, Akt phosphorylation/activation, and GLUT4 expression in the Ren2 group (each p<0.05). Despite not decreasing blood pressure, low dose spironolactone treatment improved soleus muscle insulin signaling parameters and systemic insulin sensitivity in concert with reductions in NADPH oxidase subunit expression/activity and ROS production (each p<0.05). Our findings suggest that aldosterone contributes to insulin resistance in the transgenic Ren2, in part, by increasing NADPH oxidase activity in skeletal muscle tissue.
This article has been cited by other articles:
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  J. R. Sowers, A. Whaley-Connell, and M. Epstein Narrative Review: The Emerging Clinical Implications of the Role of Aldosterone in the Metabolic Syndrome and Resistant Hypertension Ann Intern Med, June 2, 2009; 150(11): 776 - 783. [Abstract] [Full Text] [PDF]
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 A. Whaley-Connell, J. Habibi, Y. Wei, A. Gutweiler, J. Jellison, C. E. Wiedmeyer, C. M. Ferrario, and J. R. Sowers Mineralocorticoid receptor antagonism attenuates glomerular filtration barrier remodeling in the transgenic Ren2 rat Am J Physiol Renal Physiol, May 1, 2009; 296(5): F1013 - F1022. [Abstract] [Full Text] [PDF]
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