The role of estrogens in the regulation of peripheral glucose dynamics

While estrogen is an important hormone regulating sexual function and reproduction, it also has numerous nonreproductive functions, including the regulation of glucose homeostasis. Clinical studies indicate that postmenopausal women are at greater risk for the development of type 2 diabetes, and new evidence in the literature supports a direct role for estrogen in regulating glucose metabolism. The primary estrogen receptors, ERα and ERβ, are now thought to play critical roles in the regulation of glucose in insulin-sensitive tissues. Increased adiposity occurs in humans and mice as a result of decreased ERα activation, and mice with global knockout of ERα exhibit impaired glucose tolerance and skeletal muscle insulin resistance. Based on this evidence, the beneficial effects of estrogens on glucose metabolism are thought to be mediated by ERα. ERα may regulate glucose by increasing insulin-signaling and insulin-stimulated glucose uptake, maintaining GLUT4 expression, and mitigating inflammation and oxidative stress implicated in the development of insulin resistance. ERα and ERβ are known to demonstrate a complex inter-regulatory relationship that varies with the target tissue. Both stimulated by estrogen, the ability of ERα or ERβ to regulate glucose may be dependent on the expression levels and activation of the two receptors in various metabolic tissues. ER isoform-specific agonists and antagonists may prove more beneficial in preventing insulin resistance in postmenopausal women than estrogen treatment alone and should be the focus of future research.