title: Inorganic nitrite improves components of the metabolic syndrome independent of weight change in a murine model of obesity and insulin resistance.
abstract: Nitrite acts as an endocrine source of bioactive nitric oxide, impacting vascular reactivity, angiogenesis and cytoprotection. Nitrite has recently been shown to have a metabolic role although its effects and mechanisms of action in the obese insulin-resistant state are unknown. We examined glucose tolerance and insulin secretion using the frequently sampled intravenous glucose tolerance test and insulin sensitivity using the hyperinsulinaemic euglycaemic clamp in obese male ob(lep) mice administered nitrite (100 mg kg(-1) day(-1) ) or saline (control) for 7 days and compared responses to the known insulin-sensitizing effects of rosiglitazone (6 mg kg(-1) day(-1) ). Under weight-matched conditions, nitrite lowered blood pressure relative to saline and rosiglitazone, whereas only rosiglitazone was effective at reducing hepatic glucose output and basal blood glucose. Both nitrite and rosiglitazone produced improvements, relative to saline, in glucose tolerance (12,524 ± 602, 12,811 ± 692 vs.14,428 ± 335 mg (dl min)(-1) , respectively; P < 0.05) and insulin sensitivity (8.6 ± 0.7, 7.9 ± 0.3 vs. 6.6 ± 0.5 mg kg(-1) min(-1) , respectively; P < 0.001), but there was no effect on insulin secretion. Nitrite exhibited an uncoupling of mitochondrial respiration and a decrease in ATP generation in muscle that was independent of mitochondrial biogenesis or activation of uncoupling proteins. There was no insulin-stimulated phosphorylation of Akt, but nitrite increased the phosphorylation of AMP-activated protein kinase. We conclude that nitrite improves two key components of the metabolic syndrome, blood pressure and insulin sensitivity, independent of weight and with effectiveness comparable to rosiglitazone.
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, 3459 Fifth Avenue 628 NW, Pittsburgh, PA, 15213, USA.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Singamsetty
authors.affiliation: First Department of Internal Medicine, Showa University, School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8666, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, 3459 Fifth Avenue 628 NW, Pittsburgh, PA, 15213, USA.
authors.forename: Lanping
authors.initials: L
authors.lastname: Guo
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, 3459 Fifth Avenue 628 NW, Pittsburgh, PA, 15213, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Corey
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, 3459 Fifth Avenue 628 NW, Pittsburgh, PA, 15213, USA.
authors.forename: Yinna
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, 3459 Fifth Avenue 628 NW, Pittsburgh, PA, 15213, USA.
authors.forename: Jesus
authors.initials: J
authors.lastname: Tejero
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, 3459 Fifth Avenue 628 NW, Pittsburgh, PA, 15213, USA.
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: McVerry
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, 3459 Fifth Avenue 628 NW, Pittsburgh, PA, 15213, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, 3459 Fifth Avenue 628 NW, Pittsburgh, PA, 15213, USA.
authors.forename: Sruti
authors.initials: S
authors.lastname: Shiva
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh, 3459 Fifth Avenue 628 NW, Pittsburgh, PA, 15213, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: O'Donnell
mesh_terms: D000818:Animals; D001794:Blood Pressure; D001835:Body Weight; D019069:Cell Respiration; D007333:Insulin Resistance; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy*; D051379:Mice; D008820:Mice, Obese; D009573:Nitrites / Q000627:therapeutic use*; D009765:Obesity / Q000188:drug therapy*
chemical_list: D009573:Nitrites