Journal
DIABETES
Volume 62, Issue 12, Pages 4201-4207Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db13-0314
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Funding
- Fondazione Don Gnocchi
- Italian Ministry of Education, University and Research [PRIN 2010JS3PMZ_011]
- National Institutes of Health [R01DK66056, DK93909, P30DK36836]
- JDRF
- Diabetes Research and Wellness Foundation
- National Institute on Aging [P01AG020591, K23AG030979]
- American Federation for Aging Research
- National Institute of Diabetes and Digestive and Kidney Diseases [RO1DK089229, R01DK089229]
- American Diabetes Association
- Universita Cattolica del Sacro Cuore (Fondi Ateneo Linea D.3.2 Sindrome Metabolica)
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Oxidative stress has been associated with insulin resistance and type 2 diabetes. However, it is not clear whether oxidative damage is a cause or a consequence of the metabolic abnormalities present in diabetic subjects. The goal of this study was to determine whether inducing oxidative damage through genetic ablation of superoxide dismutase 1 (SOD1) leads to abnormalities in glucose homeostasis. We studied SOD1-null mice and wild-type (WT) littermates. Glucose tolerance was evaluated with intraperitoneal glucose tolerance tests. Peripheral and hepatic insulin sensitivity was quantitated with the euglycemic-hyperinsulinemic clamp. -Cell function was determined with the hyperglycemic clamp and morphometric analysis of pancreatic islets. Genetic ablation of SOD1 caused glucose intolerance, which was associated with reduced in vivo -cell insulin secretion and decreased -cell volume. Peripheral and hepatic insulin sensitivity were not significantly altered in SOD1-null mice. High-fat diet caused glucose intolerance in WT mice but did not further worsen the glucose intolerance observed in standard chow-fed SOD1-null mice. Our findings suggest that oxidative stress per se does not play a major role in the pathogenesis of insulin resistance and demonstrate that oxidative stress caused by SOD1 ablation leads to glucose intolerance secondary to -cell dysfunction.
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