Mechanisms of estrogen protection in diabetes and metabolic disease

Until menopause, women are largely protected against several metabolic disorders, implicating a role for sex hormones. Adiposity and insulin resistance are fundamental features in the pathogenesis of type 2 diabetes mellitus. Emerging data suggest that sex-steroid hormones and adipocyte-derived hormones and cytokines could be associated with type 2 diabetes risk and that some of these novel markers can exhibit a sexual dimorphism with regard to this risk. Evidence suggests that the female hormone, 17β-estradiol protects insulin production and prevents diabetes. Although 17β-estradiol acts primarily via two distinct estrogen receptors (ERs), ERα and ERβ, it appears that ERα protects β-cell survival, whereas ERβ reduces ERα function and provokes β-cell apoptosis. Accordingly, use of menopausal hormone therapy has been shown to reduce diabetes incidence and weight gain. Recent findings that benefits of menopausal hormone therapy might not outweigh the risks in some women do not negate the importance of identifying mechanisms by which 17β-estradiol attenuates the development and progression of metabolic disease. This could lay the ground to the design of pharmacological treatments for the prevention of menopause-associated metabolic disorders that are safer and more efficacious than current hormone-based regimens.