title: Low-dose spironolactone reduces reactive oxygen species generation and improves insulin-stimulated glucose transport in skeletal muscle in the TG(mRen2)27 rat.
abstract: 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 < 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.
authors.affiliation: Department of Internal Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Lastra
authors.forename: Adam
authors.initials: A
authors.lastname: Whaley-Connell
authors.forename: Camila
authors.initials: C
authors.lastname: Manrique
authors.forename: Javad
authors.initials: J
authors.lastname: Habibi
authors.forename: Alex A
authors.initials: AA
authors.lastname: Gutweiler
authors.forename: Lama
authors.initials: L
authors.lastname: Appesh
authors.forename: Melvin R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Yongzhong
authors.initials: Y
authors.lastname: Wei
authors.forename: Carlos
authors.initials: C
authors.lastname: Ferrario
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007150:Immunohistochemistry; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology*; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013148:Spironolactone / Q000494:pharmacology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051275:Glucose Transporter Type 4; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D000451:Mineralocorticoid Receptor Antagonists; D017382:Reactive Oxygen Species; C495694:Slc2a4 protein, rat; D013148:Spironolactone; D019255:NADPH Oxidases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose