The Influence of Ovarian Sex Steroids on Insulin Receptor Status in Mice

Abstract

The hypoglycaemic action of exogenously administered insulin was significantly increased in mice at oestrus compared to mice at dioestrus, two stages of the oestrous cycle which represent high and low plasma concentrations of the ovarian sex steroids respectively. Unchanged insulin binding data suggested that this increase in insulin action was mediated at the post-receptor level in both skeletal muscle and liver. Neither 2 weeks ovariectomy nor the 2 week oral administration of oestradiol (5 ug/kg/day) to ovariectomised mice had any significant effect on the insulin binding capacity of hepatocytes in the presence of insulin concentrations ranging from 0 to 1000 ng/ml. The insulin binding capacity of hepatocytes was, however, significantly reduced by the 2 week oral administration of oestradiol at 500 µg/kg/day and either progesterone alone (1 mg/kg/day) or in combination with oestradiol (5 µg/kg/day). This observation suggested a possible short-term antagonism to insulin action in the liver induced by these hormone replacement regimes. The maximum specific 125I-insulin binding capacity of soleus muscle was not significantly altered either by 2 weeks ovariectomy or any of the above 2 week hormone replacement regimes. Ovariectomy for 10 weeks resulted in a reduced hypoglycaemic action of exogenously administered insulin, partially mediated via a post-receptor reduction in the ability of insulin to promote glucose oxidation in skeletal muscle. This effect might also have been due to a reduction in insulin action in the liver, a possibility that was suggested by the reduced insulin binding capacity of hepatocytes and a reduction in liver glycogen content. All the reductions in parameters observed after ovariectomy were either partially or totally redressed by 10 weeks oral administration of either oestradiol (5 ug/kg/day), progesterone (1 mg/kg/day), the two in combination or oestradiol at 500 ug/kg/day. These observations support the hypothesis that natural oestrogens and progestogens, at least in the long-term, act on peripheral insulin target tissues to increase the action of insulin.