High selenium impairs hepatic insulin sensitivity through opposite regulation of ROS

Abstract

Insulin resistance is the hallmark of type 2 diabetes. As an essential trace element, selenium (Se) is recommended worldwide for supplementation to prevent Se-deficient pathological conditions, including diabetes and insulin resistance. However, recent evidence has shown that supra-nutritional Se intake is positively associated with the prevalence of diabetes. In the present research, we examined the effect of high Se on insulin sensitivity, and studied possible mechanisms in rats and in rat hepatocytes. Insulin sensitivity and glucose/lipid metabolism were determined by glucose/insulin tolerance test, western blot, immunofluorescence, specific probes and other biochemical assays. We show that high Se activates selenoproteins, including glutathione peroxidase and selenoprotein P, and depletes chromium, leading to a common metabolic intersection-lipolysis in adipose tissue and influx of fatty acids in liver. Fatty acid β-oxidation generates acetyl-CoA, which is metabolized in trichloroacetic acid cycle, supplying excessive electrons for mitochondrial oxidative phosphorylation and leading to increased "bad" reactive oxygen species (ROS) production in mitochondria and final disturbance of insulin signaling. Furthermore, high Se-activated selenoproteins also weaken insulin-stimulated "good" ROS signal generated by NAD(P)H oxidase, leading to attenuation of insulin signaling. Taken together, these data suggest that excessive intake of Se induces hepatic insulin resistance through opposite regulation of ROS.

Keywords: AUC; Akt; CCCP; CPT1; CREB; Chromium; CrPic; DPI; ETO; FAO; FFAs; G6P; GPx; HSL; Hepatic insulin resistance; IPGTT; IPITT; MSA; MitoQ; MitoQuinone; OXPHOS; Oligo; PEPCK; PPARγ; ROS; Rot; SS; Se; SeP; Selenium; Selenoprotein; T2DM; TCA; area under the curve; cAMP response element binding protein; carbonyl cyanide 3-chlorophenylhydrazone; carnitine palmitoyltransferase 1; chromium picolinate; diphenyliodonium; etomoxir; fatty acid oxidation; free fatty acids; glucose-6-phosphate; glutathione peroxidases; hormone-sensitive lipase; intraperitoneal glucose tolerance test; intraperitoneal insulin tolerance test; mercaptosuccinic acid; mitochondrial oxidative phosphorylation; oligomycin; peroxisome proliferator-activated receptor; phosphoenolpyruvate carboxykinase; protein kinase B; reactive oxygen species; rotenone; selenium; selenoprotein P; sodium salicylate; trichloroacetic acid; type 2 diabetes mellitus.