Genetic disruption of SOD1 gene causes glucose intolerance and impairs β-cell function - PubMed (original) (raw)

. 2013 Dec;62(12):4201-7.

doi: 10.2337/db13-0314. Epub 2013 Sep 5.

Adam B Salmon, Cristina Aguayo-Mazzucato, Mengyao Li, Bogdan Balas, Rodolfo Guardado-Mendoza, Andrea Giaccari, Robert L Reddick, Sara M Reyna, Gordon Weir, Ralph A Defronzo, Holly Van Remmen, Nicolas Musi

Affiliations

Genetic disruption of SOD1 gene causes glucose intolerance and impairs β-cell function

Giovanna Muscogiuri et al. Diabetes. 2013 Dec.

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.

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Figures

FIG. 1.

FIG. 1.

Glucose tolerance in SOD1-null mice. Blood glucose concentration was measured after the administration of intraperitoneal glucose in WT and SOD1-null mice. Data are means ± SE. *P < 0.05. KO, knockout.

FIG. 2.

FIG. 2.

Insulin-stimulated whole-body glucose disposal determined with the euglycemic-hyperinsulinemic clamp technique (A). EGP rate (B). Data are means ± SE. KO, knockout.

FIG. 3.

FIG. 3.

Insulin secretion in vivo during a hyperglycemic clamp. Data are means ± SE. *P < 0.05. KO, knockout.

FIG. 4.

FIG. 4.

Representative microscopic images of insulin, glucagon, and somatostatin immunostaining of pancreatic islets. KO, knockout.

FIG. 5.

FIG. 5.

Morphometric analysis of pancreatic islets. β-Cell volume expressed as the percentage of the pancreas (A), percentage of the islets (B), and islet size (C). Data are means ± SE. *P < 0.05. KO, knockout.

FIG. 6.

FIG. 6.

A: Average fat and lean mass for mice in the indicated diet group; *P < 0.05 between genotypes for indicated diet. B: Glucose tolerance curve in low-fat (LF) and high-fat (HF)-fed mice. C: Area under the curve calculated from glucose tolerance tests; *P < 0.05 vs. WT on low-fat diet. D: Plasma insulin concentration; *P < 0.05 vs. WT mice from corresponding diet assignment. Data are means ± SE. KO, knockout.

FIG. 7.

FIG. 7.

A: H2O2 production of isolated skeletal muscle mitochondria with different (or no) mitochondrial substrates; *P < 0.05 between genotypes for indicated diet. B: F2-isoprostanes content in muscle; *P < 0.05 vs. WT from corresponding diet. C: 4-HNE adducts in muscle; *P < 0.05 vs. WT on low-fat diet. Data are means ± SE. AU, arbitrary units; Glut/Mal, glutamate/malate; HF, high fat; KO, knockout; LF, low fat; Succ/Rot, succinate/rotenone.

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