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

TY - JOUR

T1 - Heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion, but not insulin action in high fat-fed mice

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.

U2 - 10.2337/db13-1845

DO - 10.2337/db13-1845

M3 - Article

C2 - 24947366

SN - 0012-1797

VL - 63

SP - 3699

EP - 3710

JO - Diabetes

JF - Diabetes

IS - 11

ER -