title: Antioxidant treatment normalizes mitochondrial energetics and myocardial insulin sensitivity independently of changes in systemic metabolic homeostasis in a mouse model of the metabolic syndrome.
abstract: Cardiac dysfunction in obesity is associated with mitochondrial dysfunction, oxidative stress and altered insulin sensitivity. Whether oxidative stress directly contributes to myocardial insulin resistance remains to be determined. This study tested the hypothesis that ROS scavenging will improve mitochondrial function and insulin sensitivity in the hearts of rodent models with varying degrees of insulin resistance and hyperglycemia. The catalytic antioxidant MnTBAP was administered to the uncoupling protein-diphtheria toxin A (UCP-DTA) mouse model of insulin resistance (IR) and obesity, at early and late time points in the evolution of IR, and to db/db mice with severe obesity and type-two diabetes. Mitochondrial function was measured in saponin-permeabilized cardiac fibers. Aconitase activity and hydrogen peroxide emission were measured in isolated mitochondria. Insulin-stimulated glucose oxidation, glycolysis and fatty acid oxidation rates were measured in isolated working hearts, and 2-deoxyglucose uptake was measured in isolated cardiomyocytes. Four weeks of MnTBAP attenuated glucose intolerance in 13-week-old UCP-DTA mice but was without effect in 24-week-old UCP-DTA mice and in db/db mice. Despite the absence of improvement in the systemic metabolic milieu, MnTBAP reversed cardiac mitochondrial oxidative stress and improved mitochondrial bioenergetics by increasing ATP generation and reducing mitochondrial uncoupling in all models. MnTBAP also improved myocardial insulin mediated glucose metabolism in 13 and 24-week-old UCP-DTA mice. Pharmacological ROS scavenging improves myocardial energy metabolism and insulin responsiveness in obesity and type 2 diabetes via direct effects that might be independent of changes in systemic metabolism.
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Olesya
authors.initials: O
authors.lastname: Ilkun
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Wilde
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Tuinei
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Karla M P
authors.initials: KM
authors.lastname: Pires
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Heiko
authors.initials: H
authors.lastname: Bugger
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Fraternal Order of Eagles Diabetes Research Center, Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Soto
authors.affiliation: Division of Cardiology, University of Utah School of Medicine, Salt Lake City, UT84112, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wayment
authors.affiliation: Division of Cardiology, University of Utah School of Medicine, Salt Lake City, UT84112, USA.
authors.forename: Curtis
authors.initials: C
authors.lastname: Olsen
authors.affiliation: Division of Cardiology, University of Utah School of Medicine, Salt Lake City, UT84112, USA.
authors.forename: Sheldon E
authors.initials: SE
authors.lastname: Litwin
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Fraternal Order of Eagles Diabetes Research Center, Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Electronic address: DRCAdmin@uiowa.edu.
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D024821:Metabolic Syndrome / Q000097:blood / Q000188:drug therapy*; D008665:Metalloporphyrins / Q000494:pharmacology* / Q000627:therapeutic use; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008929:Mitochondria, Heart / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D018384:Oxidative Stress; D015398:Signal Transduction
chemical_list: D000975:Antioxidants; D005227:Fatty Acids; D007328:Insulin; D008665:Metalloporphyrins; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin