Mueller Andreas S, Pallauf Josef
Institute of Animal Nutrition and Nutritional Physiology, Justus Liebig University Giessen, D-35392 Giessen, Germany.
J Nutr Biochem. 2006 Aug;17(8):548-60. doi: 10.1016/j.jnutbio.2005.10.006. Epub 2005 Nov 9.
In recent years, a number of investigations on the antidiabetic effects of supranutritional selenate doses have been carried out. Selenate (selenium oxidation state +VI) was shown to possess regulatory effects on glycolysis, gluconeogenesis and fatty acid metabolism, metabolic pathways which are disturbed in diabetic disorders. An enhanced phosphorylation of single components of the insulin signalling pathway could be shown to be one molecular mechanism responsible for the insulinomimetic properties of selenate. In type II diabetic animals, a reduction of insulin resistance could be shown as an outcome of selenate treatment. The present study with db/db mice was performed to investigate the antidiabetic mechanisms of selenate in type II diabetic animals. Twenty-one young adult female db/db mice were randomly assigned to three experimental groups (selenium deficient=0Se, selenite-treated group=SeIV and selenate-treated group=SeVI) with seven animals each. Mice of all groups were fed a selenium-deficient diet for 8 weeks. The animals of the groups SeIV and SeVI were supplemented with increasing amounts of sodium selenite or sodium selenate up to 35% of the LD50 in week 8 in addition to the diet by tube feeding. Selenate treatment reduced insulin resistance significantly and reduced the activity of liver cytosolic protein tyrosine phosphatases (PTPs) as negative regulators of insulin signalling by about 50%. In an in vitro inhibition test selenate (oxidation state +VI) per se did not inhibit PTP activity. In this test, however, selenium compounds of the oxidation state +IV were found to be the actual inhibitors of PTP activity. Selenate administration in vivo further led to characteristic changes in the selenium-dependent redox system, which could be mimicked in an in vitro assay and provided further evidence for the intermediary formation of SeIV metabolites. The expression of peroxisome proliferator-activated receptor gamma (PPARgamma), another important factor in the context of insulin resistance and lipid metabolism, was significantly increased by selenate application. In particular, liver gluconeogenesis and lipid metabolism were influenced strongly by selenate treatment. In conclusion, our results showed that supranutritional selenate doses influenced two important mechanisms involved in insulin-resistant diabetes, namely, PTPs and PPARgamma, which, in turn, can be assumed as being responsible for the changes in intermediary metabolism, e.g., gluconeogenesis and lipid metabolism. The initiation of these mechanisms thereby seems to be coupled to the intermediary formation of the selenium oxidation state +IV (selenite state) from selenate.
近年来，人们对超营养剂量硒酸盐的抗糖尿病作用进行了多项研究。硒酸盐（硒的氧化态为+VI）已被证明对糖酵解、糖异生和脂肪酸代谢具有调节作用，而这些代谢途径在糖尿病紊乱中会受到干扰。胰岛素信号通路单个成分的磷酸化增强被证明是硒酸盐具有胰岛素模拟特性的一种分子机制。在II型糖尿病动物中，硒酸盐治疗的结果显示胰岛素抵抗有所降低。本研究以db/db小鼠为对象，旨在探究硒酸盐在II型糖尿病动物中的抗糖尿病机制。将21只成年雌性db/db小鼠随机分为三个实验组（缺硒组=0Se、亚硒酸盐处理组=SeIV和硒酸盐处理组=SeVI），每组7只。所有组的小鼠均喂食缺硒饮食8周。在第8周，除饮食外，通过管饲法给SeIV组和SeVI组的动物补充递增剂量的亚硒酸钠或硒酸钠，剂量最高可达半数致死量的35%。硒酸盐治疗显著降低了胰岛素抵抗，并使作为胰岛素信号负调节因子的肝细胞溶质蛋白酪氨酸磷酸酶（PTPs）的活性降低了约50%。在体外抑制试验中，硒酸盐（氧化态为+VI）本身并不抑制PTP活性。然而，在该试验中，氧化态为+IV的硒化合物被发现是PTP活性的实际抑制剂。体内给予硒酸盐还导致了硒依赖性氧化还原系统的特征性变化，这在体外试验中可以模拟，并为SeIV代谢产物的中间形成提供了进一步的证据。过氧化物酶体增殖物激活受体γ（PPARγ）的表达，这是胰岛素抵抗和脂质代谢方面的另一个重要因素，通过施用硒酸盐而显著增加。特别是，硒酸盐治疗对肝脏糖异生和脂质代谢有强烈影响。总之，我们的结果表明，超营养剂量的硒酸盐影响了胰岛素抵抗性糖尿病中涉及的两个重要机制，即PTPs和PPARγ，反过来，可以认为这两个机制是导致中间代谢变化的原因，例如糖异生和脂质代谢。因此，这些机制的启动似乎与从硒酸盐中中间形成氧化态为+IV（亚硒酸盐状态）的硒有关。
