Effect of dehydroepiandrosterone on insulin sensitivity in Otsuka Long-Evans Tokushima-fatty rats

In order to clarify the effect of dehydroepiandrosterone (DHEA) on improvement of insulin resistance, we examined the effects of overexpression of wild-type protein kinase C-ζ (wt-PKCζ)/3-phosphoinositide-dependent protein kinase-1 (wt-PDK1) and kinase-inactive PKCζ/PDK1 (ΔPKCζ/ΔPDK1) on DHEA-induced [3H]2-deoxyglucose (DOG) uptake using the electroporation method in rat adipocytes. Overexpression of wt-PKCζ and wt-PDK1 significantly increased in DHEA-induced [3H]2-DOG uptake. Wortmannin completely suppressed DHEA-induced [3H]2-DOG uptake in wt-PKCζ- and wt-PDK1-transfected adipocytes. Overexpression of neither ΔPKCζ nor ΔPDK1 increased DHEA-induced [3H]2-DOG uptake. Otsuka Long-Evans fatty rats (OLETF), animal models of type 2 diabetes, and Long-Evans Tokushima rats (LETO) as control, were treated with 0.4% DHEA for 2 weeks. Insulin-induced [3H]2-DOG uptakes, activations of PI 3-kinase and PKCζ of adipocytes were significantly increased in DHEA-treated OLETF rats. Moreover, plasma glucose levels in OLETF rats after treatment with DHEA for 2 weeks were significantly lower than treatment without DHEA, but not in LETO rats. These results indicate that DHEA treatment may improve glucose tolerance through a PI 3-kinase-PKCζ pathway and downregulates adiposity in OLETF rats.