Dietary selenium deficiency partially rescues type 2 diabetes-like phenotypes of glutathione peroxidase-1-overexpressing male mice

Abstract

This study was conducted to determine whether dietary Se deficiency precluded overproduction of glutathione peroxidase-1 (GPX1) activity in mice overexpressing (OE) this gene and thus rescued their type 2 diabetes-like phenotypes. A total of 20 male OE and wild-type (WT) mice were fed an Se-deficient (<0.02 mg/kg) diet or an Se-supplemented (0.3 mg/kg as sodium selenite) diet from 1 to 5 mo of age. Dietary Se deficiency eliminated or attenuated (P < 0.05) genotype differences in concentrations of blood glucose, plasma insulin, and/or hepatic lipids, insulin sensitivity, and glucose-stimulated insulin secretion at the end of the study. Dietary Se deficiency decreased (P < 0.05) OE islet mRNA levels of 2 key transcriptional activators (Beta2 and Foxa2) and removed genotype differences in islet mRNA levels of 7 genes (Beta2, Cfos, Foxa2, Pregluc, Ins1, p53, and Sur1) related to insulin synthesis and secretion. Compared with those of the Se-adequate OE mice, the Se-deficient OE mice had lower (P < 0.05) hepatic mRNA levels of 2 key rate-limiting enzymes for lipogenesis (Acc1) and glycolysis (Gk1), along with lower (P < 0.05) activities of hepatic glucokinase and muscle phosphoenolpyruvate carboxykinase. Dietary Se deficiency also decreased (P < 0.05) blood glucose and hepatic lipid concentrations in the WT mice. In conclusion, dietary Se deficiency precluded the overproduction of GPX1 in full-fed OE mice and partially rescued their metabolic syndromes. This alleviation resulted from modulating the expression and/or function of proinsulin genes, lipogenesis rate-limiting enzyme genes, and key glycolysis and gluconeogenesis enzymes in islets, liver, and muscle.

FIGURE 1

Effects of dietary Se concentration on hepatic GPX1 activity (A), body weight (B), blood glucose concentration (C), and postmortem plasma insulin concentration (D) in WT and OE mice at 5 mo of age. Values are means ± SE, n = 3–4 (A and D) or n = 5–10 (B and C). Means for a given measure without a common letter differ, P < 0.05. GPX1, glutathione peroxidase-1; OE, GPX1 overexpressing; OE(+), Se-adequate GPX1 overexpressing mice; OE(−), Se-deficient GPX1 overexpressing mice; WT, wild-type; WT(+), Se-adequate wild-type mice; WT(−), Se-deficient wild-type mice.

FIGURE 2

Effects of dietary Se concentration on body glucose tolerance test (1 g dextrose/kg) (A), body insulin tolerance test (0.5 U insulin/kg) (B), and glucose-stimulated insulin secretion (1 g dextrose/kg) (C) in WT and OE mice at 1 wk prior to the end of the experiment (5 mo of age). Values are means ± SE, n = 5. Means for a given measure at a given time point without a common letter differ, P < 0.05. OE, glutathione peroxidase-1 (GPX1) overexpressing; OE(+), Se-adequate GPX1 overexpressing mice; OE(−), Se-deficient GPX1 overexpressing mice; WT, wild-type; WT(+), Se-adequate wild-type mice; WT(−), Se-deficient wild-type mice.

FIGURE 3

Effects of dietary Se concentration on hepatic concentrations of TG (A), TC (B), and NEFA (C) in WT and OE mice at 5 mo of age. Values are means ± SE, n = 5. Means for a given measure without a common letter differ, P < 0.05. NEFA, nonesterified fatty acid; OE, glutathione peroxidase-1 (GPX1) overexpressing; OE(+), Se-adequate GPX1 overexpressing mice; OE(−), Se-deficient GPX1 overexpressing mice; TC, total cholesterol; WT, wild-type; WT(+), Se-adequate wild-type mice; WT(−), Se-deficient wild-type mice.

FIGURE 4

Effects of dietary Se concentration on pancreatic islet mRNA abundances of insulin-related genes in WT and OE mice at 5 mo of age. The figure shows genes in the OE islets that were responsive to dietary Se deficiency (A) and those genes that were less responsive to the same treatment (B). Values are means ± SE, n = 5. Means for a given gene without a common letter differ, P < 0.05. OE, glutathione peroxidase-1 (GPX1) overexpressing; OE(+), Se-adequate GPX1 overexpressing mice; OE(−), Se-deficient GPX1 overexpressing mice; WT, wild-type; WT(+), Se-adequate wild-type mice; WT(−), Se-deficient wild-type mice.

FIGURE 5

Effects of dietary Se concentration on hepatic mRNA abundances of lipogenesis-related genes in WT and OE mice at 5 mo of age. Values are means ± SE, n = 5. Means for a given gene without a common letter differ, P < 0.05. OE, glutathione peroxidase-1 (GPX1) overexpressing; OE(+), Se-adequate GPX1 overexpressing mice; OE(−), Se-deficient GPX1 overexpressing mice; WT, wild-type; WT(+), Se-adequate wild-type mice; WT(−), Se-deficient wild-type mice.

FIGURE 6

Effects of dietary Se concentration on hepatic GK activity (A), hepatic and muscular PEPCK activities (B), and hepatic p53 protein (C) in WT and OE mice at 5 mo of age. Values are means ± SE, n = 5. The band image of Western blot (C) was a representative of 5 independent experiments. Means for a given measure without a common letter differ, P < 0.05. GK, glucokinase; OE, glutathione peroxidase-1 (GPX1) overexpressing; OE(+), Se-adequate GPX1 overexpressing mice; OE(−), Se-deficient GPX1 overexpressing mice; PEPCK, phosphoenolpyruvate carboxykinase; WT, wild-type; WT(+), Se-adequate wild-type mice; WT(−), Se-deficient wild-type mice.

FIGURE 7

Scheme of potential regulatory pathways and mechanisms for the impacts of dietary Se deficiency on the type 2 diabetes–like phenotypes of OE mice. GK, glucokinase; GPX1, glutathione peroxidase-1; GSIS, glucose-stimulated insulin secretion; NEFA, nonesterified fatty acid; OE, GPX1 overexpressing; OE(+), Se-adequate GPX1 overexpressing mice; OE(−), Se-deficient GPX1 overexpressing mice; PEPCK, phosphoenolpyruvate carboxykinase; TC, total cholesterol; WT, wild-type; WT(+), Se-adequate wild-type mice; WT(−), Se-deficient wild-type mice.