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.