Heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion, but not insulin action, in high-fat-fed mice

Li Kang; Chunhua Dai; Mary E Lustig; Jeffrey S Bonner; Wesley H Mayes; Shilpa Mokshagundam; Freyja D James; Courtney S Thompson; Chien-Te Lin; Christopher G R Perry; Ethan J Anderson; P Darrell Neufer; David H Wasserman; Alvin C Powers

doi:10.2337/db13-1845

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Heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion, but not insulin action, in high-fat-fed mice

Journal article

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Heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion, but not insulin action, in high-fat-fed mice

Li Kang, Chunhua Dai, Mary E Lustig, Jeffrey S Bonner, Wesley H Mayes, Shilpa Mokshagundam, Freyja D James, Courtney S Thompson, Chien-Te Lin, Christopher G R Perry, …

Diabetes (New York, N.Y.), Vol.63(11), pp.3699-3710

11/2014

DOI: 10.2337/db13-1845

PMCID: PMC4207395

PMID: 24947366

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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.

Superoxide Dismutase - genetics

Reactive Oxygen Species - metabolism

Oxidative Stress - physiology

Oxidative Stress - genetics

Muscle, Skeletal - metabolism

Superoxide Dismutase - deficiency

Glucose - pharmacology

Reverse Transcriptase Polymerase Chain Reaction

Blotting, Western

Insulin - metabolism

Animals

Mice, Mutant Strains

Diet, High-Fat

Superoxides - metabolism

Mice

Details

Title: Subtitle: Heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion, but not insulin action, in high-fat-fed mice
Creators: Li Kang - 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
Chunhua Dai - Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University, Nashville, TN
Mary E Lustig - Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN
Jeffrey S Bonner - Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN
Wesley H Mayes - Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN
Shilpa Mokshagundam - Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN
Freyja D James - Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN
Courtney S Thompson - Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University, Nashville, TN
Chien-Te Lin - East Carolina Diabetes and Obesity Institute and Departments of Physiology and Kinesiology, East Carolina University, Greenville, NC
Christopher G R Perry - East Carolina Diabetes and Obesity Institute and Departments of Physiology and Kinesiology, East Carolina University, Greenville, NC
Ethan J Anderson - East Carolina Diabetes and Obesity Institute and Departments of Physiology and Kinesiology, East Carolina University, Greenville, NC
P Darrell Neufer - East Carolina Diabetes and Obesity Institute and Departments of Physiology and Kinesiology, East Carolina University, Greenville, NC
David H Wasserman - Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, TN
Alvin C Powers - 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
Resource Type: Journal article
Publication Details: Diabetes (New York, N.Y.), Vol.63(11), pp.3699-3710
Publisher: United States
DOI: 10.2337/db13-1845
PMID: 24947366
PMCID: PMC4207395
ISSN: 0012-1797
eISSN: 1939-327X
Grant note: R37 DK050277 / NIDDK NIH HHS R01 DK073488 / NIDDK NIH HHS R56 DK054902 / NIDDK NIH HHS DK-69603 / NIDDK NIH HHS P30 DK020593 / NIDDK NIH HHS DK-059637 / NIDDK NIH HHS DK-072473 / NIDDK NIH HHS P60 DK020593 / NIDDK NIH HHS DK-20593 / NIDDK NIH HHS U01 DK089538 / NIDDK NIH HHS R33 DK066636 / NIDDK NIH HHS DK-66636 / NIDDK NIH HHS R01 DK069603 / NIDDK NIH HHS DK-089572 / NIDDK NIH HHS R21 DK066636 / NIDDK NIH HHS U24 DK059637 / NIDDK NIH HHS DK-054902 / NIDDK NIH HHS DK-089538 / NIDDK NIH HHS I01 BX000666 / BLRD VA R01 DK054902 / NIDDK NIH HHS U01 DK072473 / NIDDK NIH HHS U01 DK089572 / NIDDK NIH HHS
Language: English
Date published: 11/2014
Academic Unit: Pharmaceutical Sciences and Experimental Therapeutics; Fraternal Order of Eagles Diabetes Research Center; Health and Human Physiology
Record Identifier: 9984065690502771

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