MECHANISMS BEHIND INSULIN-RESISTANCE IN RAT SKELETAL-MUSCLE AFTER OOPHORECTOMY AND ADDITIONAL TESTOSTERONE TREATMENT

The absence of female sex hormones, as well as testosterone treatment of oophorectomized (OVX) female rats, has been demonstrated to result in decreased whole-body insulin-mediated glucose uptake. The cellular mechanism behind this insulin resistance and the role of low levels of female sex hormones as a risk factor for development of peripheral in sulin resistance are not yet fully clarified. We assessed the protein expression of GLUT4 and glycogen synthase, as web as insulin-induced t ranslocation of GLUT4 to the plasma membrane, in soleus skeletal muscl e from control rats, OVX rats, and OVX rats treated for 8 weeks with t estosterone (OVX + T). Whole-body insulin-mediated glucose uptake asse ssed by the hyperinsulinemic-euglycemic clamp procedure was 25% lower in OVX rats (P < 0.001) and addition of testosterone treatment further decreased insulin-mediated glucose uptake in OVX + T rats by 48% (P < 0.001) compared with controls. GLUT4 protein expression in soleus mus cles was unaltered in the OVX and OVX + T rats compared with controls. Insulin induced a 3.7-fold increase (P < 0.05) in the plasma membrane content of GLUT4 in soleus muscle from control rats, whereas plasma m embrane content of GLUT4 in soleus muscle from OVX or OVX + T rats was unaltered in response to insulin. Glycogen synthase protein expressio n in muscle homogenates was decreased by 25% in the OVX group (P < 0.0 5) and by 37% in the OVX + T group (P < 0.05) when compared with the c ontrol group. Insulin receptor and tyrosine kinase activities in the b asal and insulin-stimulated states did not differ between the OVX and OVX + T rats. In conclusion, the absence of female sex hormones appear s to decrease insulin-mediated whole-body glucose uptake via an impair ed insulin-stimulated translocation of GLUT4 to the plasma membrane an d by decreased protein expression of glycogen synthase. Testosterone t reatment further impairs whole-body insulin-mediated glucose uptake, p resumably by additional impairment of glycogen synthase expression.