Genetic Disruption of SOD1 Gene Causes Glucose Intolerance and Impairs β-Cell Function
- Giovanna Muscogiuri1,
- Adam B. Salmon2,3,
- Cristina Aguayo-Mazzucato4,
- Mengyao Li1,
- Bogdan Balas1,
- Rodolfo Guardado-Mendoza1,
- Andrea Giaccari5,
- Robert L. Reddick6,
- Sara M. Reyna1,
- Gordon Weir4,
- Ralph A. DeFronzo1,
- Holly Van Remmen2,3 and
- Nicolas Musi1,2,3⇑
- 1Diabetes Division, University of Texas Health Science Center, San Antonio, Texas
- 2Barshop Institute for Longevity and Aging Studies, San Antonio, Texas
- 3Geriatric Research, Education, and Clinical Center, South Texas Veterans Health Care System, San Antonio, Texas
- 4Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts
- 5Division of Endocrinology and Metabolic Diseases, Università Cattolica del Sacro Cuore, Policlinico “A. Gemelli,” Rome, and Fondazione Don Gnocchi, Milan, Italy
- 6Department of Pathology, University of Texas Health Science Center, San Antonio, Texas
- Corresponding author: Nicolas Musi, .
G.M. and A.B.S. contributed equally to this study.
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0314/-/DC1.
- Received March 2, 2013.
- Accepted August 27, 2013.
- © 2013 by the American Diabetes Association.
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