title: Nebivolol improves insulin sensitivity in the TGR(Ren2)27 rat.
abstract: Hypertension is often associated with increased oxidative stress and systemic insulin resistance. Use of β-adrenergic receptor blockers in hypertension is limited because of potential negative influence on insulin sensitivity and glucose homeostasis. We sought to determine the impact of nebivolol, a selective vasodilatory β₁-adrenergic blocker, on whole-body insulin sensitivity, skeletal muscle oxidative stress, insulin signaling, and glucose transport in the transgenic TG(mRen2)27 rat (Ren2). This rodent model manifests increased tissue renin angiotensin expression, excess oxidative stress, and whole-body insulin resistance. Young (age, 6-9 weeks) Ren2 and age-matched Sprague-Dawley control rats were treated with nebivolol 10 mg/(kg d) or placebo for 21 days. Basal measurements were obtained for glucose and insulin to calculate the homeostasis model assessment. In addition, insulin metabolic signaling, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, reactive oxygen species, and ultrastructural changes as evaluated by transmission electron microscopy were examined ex vivo in skeletal muscle tissue. The Ren2 rat demonstrated systemic insulin resistance as examined by the homeostasis model assessment, along with impaired insulin metabolic signaling in skeletal muscle. This was associated with increased oxidative stress and mitochondrial remodeling. Treatment with nebivolol was associated with improvement in insulin resistance and decreased NADPH oxidase activity/levels of reactive oxygen species in skeletal muscle tissue. Nebivolol treatment for 3 weeks reduces NADPH oxidase activity and improves systemic insulin resistance in concert with reduced oxidative stress in skeletal muscle in a young rodent model of hypertension, insulin resistance, and enhanced tissue RAS expression.
authors.affiliation: Diabetes Cardiovascular Center of Excellence, University of Missouri-Columbia School of Medicine, Columbia, MO 65212, USA.
authors.forename: Camila
authors.initials: C
authors.lastname: Manrique
authors.forename: Guido
authors.initials: G
authors.lastname: Lastra
authors.forename: Javad
authors.initials: J
authors.lastname: Habibi
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Pulakat
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schneider
authors.forename: William
authors.initials: W
authors.lastname: Durante
authors.forename: Roger
authors.initials: R
authors.lastname: Tilmon
authors.forename: Jenna
authors.initials: J
authors.lastname: Rehmer
authors.forename: Melvin R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Ferrario
authors.forename: Adam
authors.initials: A
authors.lastname: Whaley-Connell
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D015153:Blotting, Western; D004983:Ethanolamines / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000378:metabolism*; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D046529:Microscopy, Electron, Transmission; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*; D019255:NADPH Oxidases / Q000378:metabolism; D000068577:Nebivolol; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D017382:Reactive Oxygen Species / Q000378:metabolism; D012083:Renin / Q000235:genetics / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D000959:Antihypertensive Agents; D001578:Benzopyrans; D004983:Ethanolamines; D007004:Hypoglycemic Agents; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D017382:Reactive Oxygen Species; C535029:Ren2 protein, rat; D014665:Vasodilator Agents; D000068577:Nebivolol; D019255:NADPH Oxidases; D019869:Phosphatidylinositol 3-Kinases; D012083:Renin; D018631:ras Proteins; D005947:Glucose