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

Abstract

Cardiovascular disease in postmenopausal women represents a major health care concern because a third of all women between the ages of 50 and 75 are thought to be affected and a sixth die of the consequences of artherosclerosis. Recent studies have clearly shown a strong correlation between insulin sensitivity and the development of cardiovascular disease [1±3]: thus factors that diminish insulin sensitivity in women have been the subject of considerable interest [4,5]. Evidence for an association between sex hormones and insulin sensitivity is provided by studies of women with hyperandrogenic conditions, such as polycystic ovary syndrome [6,7]. These studies have argued strongly for a link between sex hormones and insulin resistance, as an improvement of insulin sensitivity is often observed upon correction of the hyperandrogenism [8±10]. Further correlative evidence for a link between insulin sensitivity and sex hormones is provided by other studies, including the induction of insulin resistance in the surgically Diabetologia (2000) Abstract Aim/hypothesis. Numerous studies have suggested a relation between sex hormones and insulin sensitivity but the ability of sex hormones to directly influence 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 stimulate glucose transport independently of a reduction in total cellular GLUT-4 content. This diminished ability of insulin to stimulate glucose transport was accompanied by a reduction in the total cellular content of insulin receptor substrates ±1 and ±2 and the p85a subunit of phosphatidylinositol 3'-kinase. By contrast, cellular content of protein kinase B was unchanged by hormone treatment but the magnitude of insulin-stimulated kinase activity was statistically significantly reduced after incubation with each of the sex hormones tested. We have further shown that treatment of 3T3-L1 adipocytes 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 induce a state of insulin resistance in 3T3-L1 adipocytes in culture. The mechanism of this defect seems to be at least in part due to decreased cellular content and altered subcellular distribution of insulin receptor substrate proteins which in turn results in a reduction in proximal insulin-stimulated signalling cascades. [Diabetologia (2000

Association of alcohol dehydrogenase 2*1 allele with liver damage and insulin concentration in the Japanese

“…We previously reported that, in the same population study, the ADH2*1 allele is associated with increased levels of LDL-cholesterol and high blood pressure, and an increased risk of cerebral infarction (Suzuki et al 2004). The concentration of insulin or resistance to insulin could be affected by sex hormones, sex hormone-binding globulin or obesity (Falkner et al 1999;Collison et al 2000). Therefore, as another possibility, the interaction of the ADH2*1 allele with several hormones associated with sex or lipids may decrease the insulin resistance in target tissues (Harada et al 1998).…”

Release and regulation of leptin, resistin and adiponectin from human placenta, fetal membranes, and maternal adipose tissue and skeletal muscle from normal and gestational diabetes mellitus-complicated pregnancies

“…Dexamethasone, progesterone and estrogen have been proposed to cause insulin resistance by reducing the cellular content of insulin receptor substrate proteins which, in turn, results in a reduction in proximal insulin-stimulated signaling cascades (Collison et al 2000, Buren et al 2002, Garcia-Arencibia et al 2005. Several studies have provided evidence that glucocorticoids may play an important role in the physiological modulation of adipocyokines, and thus insulin resistance.…”

Estrogen Receptor .ALPHA. Regulates Insulin Sensitivity through IRS-1 Tyrosine Phosphorylation in Mature 3T3-L1 Adipocytes

“…The molecular mechanisms by which estrogen modulates glucose uptake in mature adipocytes have not been well established. Collison et al previously showed, using fully differentiated 3T3-L1 adipocytes, that the decreased glucose uptake associated with estrogens (estrone, estradiol or estriol) was due at least in part to decreased cellular contents and an altered subcellular distribution of IRS proteins, in turn resulting in a reduction in proximal insulin signaling cascades [15]. However, under our experimental conditions, decreased tyrosine phosphorylation of IRS-1 protein occurred without IRS-1 protein degradation even during treatment with high doses of E2 or PPT.…”

“…In vitro, culture of 3T3-L1 adipocytes with high concentrations of estrogens (estrone, estradiol or estriol) resulted in a reduced ability of insulin to stimulate glucose uptake by attenuating insulin signaling events, leading to GLUT4 translocation to the plasma membrane [15]. This study suggests that these estrogens can modulate insulin sensitivity and contribute to the development of insulin resistance by acting directly on adipocytes, but the precise role of ER subtypes was not examined.…”