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

Li Kang (Lead / Corresponding author), 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

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    20 Citations (Scopus)

    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 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 O2?-. 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 GLUT1, 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.
    Original languageEnglish
    Pages (from-to)3699-3710
    Number of pages12
    JournalDiabetes
    Volume63
    Issue number11
    Early online date19 Jun 2014
    DOIs
    Publication statusPublished - Nov 2014

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    Fats
    Insulin
    Glucose
    Reactive Oxygen Species
    Glucose Clamp Technique
    AMP-Activated Protein Kinases
    Hexokinase
    Muscle Proteins
    High Fat Diet
    Knockout Mice
    Superoxide Dismutase
    Insulin Resistance
    Oxidative Stress
    Diet

    Cite this

    Kang, L., Dai, C., Lustig, M. E., Bonner, J. S., Mayes, W. H., Mokshagundam, S., ... Powers, A. C. (2014). Heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion, but not insulin action in high fat-fed mice. Diabetes, 63(11), 3699-3710. https://doi.org/10.2337/db13-1845
    Kang, Li ; Dai, Chunhua ; Lustig, Mary E. ; Bonner, Jeffrey S. ; Mayes, Wesley H. ; Mokshagundam, Shilpa ; James, Freyja D. ; Thompson, Courtney S. ; Lin, Chien-Te ; Perry, Christopher G. R. ; Anderson, Ethan J. ; Neufer, P. Darrell ; Wasserman, David H. ; Powers, Alvin C. / Heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion, but not insulin action in high fat-fed mice. In: Diabetes. 2014 ; Vol. 63, No. 11. pp. 3699-3710.
    @article{7587abd5eb204017a4855199ecdd01a6,
    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 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 O2?-. 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 GLUT1, 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.",
    author = "Li Kang and Chunhua Dai and Lustig, {Mary E.} and Bonner, {Jeffrey S.} and Mayes, {Wesley H.} and Shilpa Mokshagundam and James, {Freyja D.} and Thompson, {Courtney S.} and Chien-Te Lin and Perry, {Christopher G. R.} and Anderson, {Ethan J.} and Neufer, {P. Darrell} and Wasserman, {David H.} and Powers, {Alvin C.}",
    note = "{\circledC} 2014 by the American Diabetes Association.",
    year = "2014",
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    language = "English",
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    Kang, L, Dai, C, Lustig, ME, Bonner, JS, Mayes, WH, Mokshagundam, S, James, FD, Thompson, CS, Lin, C-T, Perry, CGR, Anderson, EJ, Neufer, PD, Wasserman, DH & Powers, AC 2014, 'Heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion, but not insulin action in high fat-fed mice', Diabetes, vol. 63, no. 11, pp. 3699-3710. https://doi.org/10.2337/db13-1845

    Heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion, but not insulin action in high fat-fed mice. / Kang, Li (Lead / Corresponding author); Dai, Chunhua; Lustig, Mary E.; Bonner, Jeffrey S.; Mayes, Wesley H.; Mokshagundam, Shilpa; James, Freyja D.; Thompson, Courtney S.; Lin, Chien-Te; Perry, Christopher G. R.; Anderson, Ethan J.; Neufer, P. Darrell; Wasserman, David H.; Powers, Alvin C.

    In: Diabetes, Vol. 63, No. 11, 11.2014, p. 3699-3710.

    Research output: Contribution to journalArticle

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    AU - Kang, Li

    AU - Dai, Chunhua

    AU - Lustig, Mary E.

    AU - Bonner, Jeffrey S.

    AU - Mayes, Wesley H.

    AU - Mokshagundam, Shilpa

    AU - James, Freyja D.

    AU - Thompson, Courtney S.

    AU - Lin, Chien-Te

    AU - Perry, Christopher G. R.

    AU - Anderson, Ethan J.

    AU - Neufer, P. Darrell

    AU - Wasserman, David H.

    AU - Powers, Alvin C.

    N1 - © 2014 by the American Diabetes Association.

    PY - 2014/11

    Y1 - 2014/11

    N2 - 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 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 O2?-. 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 GLUT1, 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.

    AB - 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 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 O2?-. 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 GLUT1, 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.

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