title: Genetic disruption of SOD1 gene causes glucose intolerance and impairs β-cell function.
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.
authors.affiliation: Diabetes Division, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Muscogiuri
authors.forename: Adam B
authors.initials: AB
authors.lastname: Salmon
authors.forename: Cristina
authors.initials: C
authors.lastname: Aguayo-Mazzucato
authors.forename: Mengyao
authors.initials: M
authors.lastname: Li
authors.forename: Bogdan
authors.initials: B
authors.lastname: Balas
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Guardado-Mendoza
authors.forename: Andrea
authors.initials: A
authors.lastname: Giaccari
authors.forename: Robert L
authors.initials: RL
authors.lastname: Reddick
authors.forename: Sara M
authors.initials: SM
authors.lastname: Reyna
authors.forename: Gordon
authors.initials: G
authors.lastname: Weir
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Defronzo
authors.forename: Holly
authors.initials: H
authors.lastname: Van Remmen
authors.forename: Nicolas
authors.initials: N
authors.lastname: Musi
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D059305:Diet, High-Fat; D018149:Glucose Intolerance / Q000235:genetics* / Q000378:metabolism; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000235:genetics*; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D001786:Blood Glucose; D007328:Insulin; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1