Low-dose spironolactone reduces reactive oxygen species generation and improves insulin-stimulated glucose transport in skeletal muscle in the TG(mRen2)27 rat

Abstract

JR. Low-dose spironolactone reduces reactive oxygen species generation and improves insulin-stimulated glucose transport in skeletal muscle in the TG(mRen2)27 rat. Am J Physiol Endocrinol Metab 295: E110 -E116, 2008. First published April 29, 2008 doi:10.1152/ajpendo.00258.2007.-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 with a mineralocorticoid receptor (MR) antagonist on insulin sensitivity in Ren2 and aged-matched Sprague-Dawley (SD) control rats. Both groups (age 6 -8 wk) 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 insulin receptor substrate-1 (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-hydroxy-2-nonenal immunostaining). Along with increased soleus muscle NADPH oxidase activity and ROS, there was systemic insulin resistance and reduced muscle IRS-1 tyrosine phosphorylation, Akt phosphorylation/activation, and GLUT4 expression in the Ren2 group (each P Ͻ 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 Ͻ 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. Ren2 rat; mineralocorticoid receptor blockade THE ROLES OF INSULIN RESISTANCE in the pathophysiology of type 2 diabetes mellitus (T2DM) and the metabolic syndrome are well established (33,38), and exploration of the mechanisms leading to diminished insulin sensitivity is a field of active research.

Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance

“…For example, an aldosterone excess in patients with primary aldosteronism is related to impaired glucose homeostasis (52) as well as insulin resistance (28). Several recent publications (99,194), as well as recent data from our laboratory (102), have suggested that these detrimental effects on insulin signaling are mediated by inflammatory/ oxidative stress effects of mineralocorticoids. Indeed, in the TG(mRen2)22 rat, which manifests insulin resistance (18), in vivo MR antagonism with subpressor doses of spironolactone substantially improve ex vivo insulin stimulated increases in glucose uptake in skeletal muscle, a phenomenon that is linked to reductions in NADPH oxidase activity and attenuation of ROS in soleus muscle tissue (102).…”

“…Insulin and IGF-1 also regulate developmental and physiological growth and remodeling of the heart (41, 78,94,102,142,163,223,234) (Fig. 2).…”

“…2). The peptides accomplish these effects by signaling through the PI3K/Akt pathway (78,102,223). Downstream from Akt, activation of the mammalian target of rapamycin promotes cardiac growth, whereas suppression of glycogen synthase kinase-3␤, as well as FOXO phosphorylation, also modulates cardiomyocyte growth (78,223).…”

Role of aldosterone and angiotensin II in insulin resistance: an update

“…From an experimental standpoint, it has been demonstrated that in vivo MR antagonism results in decreased NADPH oxidase activity and oxidative stress, in concert with improved insulin-stimulated glucose uptake as well as attenuated whole-body insulin resistance in skeletal muscle in a transgenic rodent model of inappropriately active tissue RAAS. 37 Nonetheless, clinical studies have not always confirmed previous experimental and clinical observations suggesting improved insulin sensitivity through aldosterone reduction and/or MR blockade. In the EPHESUS trial, MR blockade significantly reduced hypoglycaemia by approximately 43%, which could indicate impaired glycaemic control.…”

Aldosterone and the mineralocorticoid receptor in insulin resistance and diabetes

“…Likewise, when MCR were blocked in the Ren2 rat (a model of secondary hyperaldosteronism and insulin resistance) insulin sensitivity and insulin receptor signaling improved markedly, while NADPH oxidase activity and ROS production declined 35 . (5) release of the chaperone HSP90, traslocation of the aldo-MCR complex to the nucleus, and (6) transactivation of target genes.…”