Sex hormones induce insulin resistance in 3T3-L1 adipocytes by reducing cellular content of IRS proteins

Aim/hypothesis. Numerous studies have suggested a relation between sex horm ones and insulin sensitivity but the ability of sex hormones to directly in fluence insulin action in peripheral tissues has not been investigated. Methods. We have examined the effects of estriol, estradiol and estrone on insulin action in cultured 3T3-L1 adipocytes, a useful model of adipocytes. Results. Treatment of these cells with each of these sex hormones resulted in a statistically significant reduction in the ability of insulin to stimu late glucose transport independently of a reduction in total cellular GLUT- 4 content. This diminished ability of insulin to stimulate glucose transpor t was accompanied by a reduction in the total cellular content of insulin r eceptor substrates -1 and -2 and the p85 alpha subunit of phosphatidylinosi tol 3'-kinase. By contrast, cellular content of protein kinase B was unchan ged by hormone treatment but the magnitude of insulin-stimulated kinase act ivity was statistically significantly reduced after incubation with each of the sex hormones tested. We have further shown that treatment of 3T3-L1 ad ipocytes with these hormones alters the subcellular distribution of insulin receptor substrate proteins such that the particulate and soluble pools of these proteins were differentially affected by hormone treatment. Conclusion/interpretation. These data show that sex hormones can directly i nduce a state of insulin resistance in 3T3-L1 adipocytes in culture. The me chanism of this defect seems to be at least in part due to decreased cellul ar content and altered subcellular distribution of insulin receptor substra te proteins which in turn results in a reduction in proximal insulin-stimul ated signalling cascades.