title: Heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion, but not insulin action, in high-fat-fed mice.
abstract: Elevated reactive oxygen species (ROS) are linked to insulin resistance and islet dysfunction. Manganese superoxide dismutase (SOD2) is a primary defense against mitochondrial oxidative stress. To test the hypothesis that heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion (GSIS) and insulin action, wild-type (sod2(+/+)) and heterozygous knockout mice (sod2(+/-)) were fed a chow or high-fat (HF) diet, which accelerates ROS production. Hyperglycemic (HG) and hyperinsulinemic-euglycemic (HI) clamps were performed to assess GSIS and insulin action in vivo. GSIS during HG clamps was equal in chow-fed sod2(+/-) and sod2(+/+) but was markedly decreased in HF-fed sod2(+/-). Remarkably, this impairment was not paralleled by reduced HG glucose infusion rate (GIR). Decreased GSIS in HF-fed sod2(+/-) was associated with increased ROS, such as superoxide ion. Surprisingly, insulin action determined by HI clamps did not differ between sod2(+/-) and sod2(+/+) of either diet. Since insulin action was unaffected, we hypothesized that the unchanged HG GIR in HF-fed sod2(+/-) was due to increased glucose effectiveness. Increased GLUT-1, hexokinase II, and phospho-AMPK protein in muscle of HF-fed sod2(+/-) support this hypothesis. We conclude that heterozygous SOD2 deletion in mice, a model that mimics SOD2 changes observed in diabetic humans, impairs GSIS in HF-fed mice without affecting insulin action.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, TN Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, U.K. l.kang@dundee.ac.uk.
authors.forename: Li
authors.initials: L
authors.lastname: Kang
authors.affiliation: Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University, Nashville, TN.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Dai
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Lustig
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Bonner
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
authors.forename: Wesley H
authors.initials: WH
authors.lastname: Mayes
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Mokshagundam
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
authors.forename: Freyja D
authors.initials: FD
authors.lastname: James
authors.affiliation: Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University, Nashville, TN.
authors.forename: Courtney S
authors.initials: CS
authors.lastname: Thompson
authors.affiliation: East Carolina Diabetes and Obesity Institute and Departments of Physiology and Kinesiology, East Carolina University, Greenville, NC.
authors.forename: Chien-Te
authors.initials: CT
authors.lastname: Lin
authors.affiliation: East Carolina Diabetes and Obesity Institute and Departments of Physiology and Kinesiology, East Carolina University, Greenville, NC.
authors.forename: Christopher G R
authors.initials: CG
authors.lastname: Perry
authors.affiliation: East Carolina Diabetes and Obesity Institute and Departments of Physiology and Kinesiology, East Carolina University, Greenville, NC.
authors.forename: Ethan J
authors.initials: EJ
authors.lastname: Anderson
authors.affiliation: East Carolina Diabetes and Obesity Institute and Departments of Physiology and Kinesiology, East Carolina University, Greenville, NC.
authors.forename: P Darrell
authors.initials: PD
authors.lastname: Neufer
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, TN.
authors.forename: David H
authors.initials: DH
authors.lastname: Wasserman
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University, Nashville, TN Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN.
authors.forename: Alvin C
authors.initials: AC
authors.lastname: Powers
mesh_terms: D000818:Animals; D015153:Blotting, Western; D059305:Diet, High-Fat; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000235:genetics; D013481:Superoxides / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D005947:Glucose; D007328:Insulin; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D013481:Superoxides; D000099156:Superoxide Dismutase 2