Genetic Disruption of SOD1 Gene Causes Glucose Intolerance and Impairs β-Cell Function

  1. Nicolas Musi1,2,3
  1. 1Diabetes Division, University of Texas Health Science Center, San Antonio, Texas
  2. 2Barshop Institute for Longevity and Aging Studies, San Antonio, Texas
  3. 3Geriatric Research, Education, and Clinical Center, South Texas Veterans Health Care System, San Antonio, Texas
  4. 4Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts
  5. 5Division of Endocrinology and Metabolic Diseases, Università Cattolica del Sacro Cuore, Policlinico “A. Gemelli,” Rome, and Fondazione Don Gnocchi, Milan, Italy
  6. 6Department of Pathology, University of Texas Health Science Center, San Antonio, Texas
  1. Corresponding author: Nicolas Musi, musi{at}uthscsa.edu.
  1. G.M. and A.B.S. contributed equally to this study.

Abstract

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. β-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 β-cell insulin secretion and decreased β-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 β-cell dysfunction.

Footnotes

  • Received March 2, 2013.
  • Accepted August 27, 2013.

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  1. Diabetes vol. 62 no. 12 4201-4207
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