The Islet Estrogen Receptor-α Is Induced by Hyperglycemia and Protects Against Oxidative Stress-Induced Insulin-Deficient Diabetes

The female steroid, 17 beta-estradiol (E2), is important for pancreatic beta-cell function and acts via at least three estrogen receptors (ER), ER alpha, ER beta, and the G-protein coupled ER (GPER). Using a pancreas-specific ER alpha knockout mouse generated using the Cre-lox-P system and a Pdx1-Cre transgenic line (PER alpha KO-/-), we previously reported that islet ER alpha suppresses islet glucolipotoxicity and prevents beta-cell dysfunction induced by high fat feeding. We also showed that E2 acts via ER alpha to prevent beta-cell apoptosis in vivo. However, the contribution of the islet ER alpha to beta-cell survival in vivo, without the contribution of ER alpha in other tissues is still unclear. Using the PER alpha KO-/- mouse, we show that ER alpha mRNA expression is only decreased by 20% in the arcuate nucleus of the hypothalamus, without a parallel decrease in the VMH, making it a reliable model of pancreas-specific ER alpha elimination. Following exposure to alloxan-induced oxidative stress in vivo, female and male PER alpha KO-/- mice exhibited a predisposition to beta-cell destruction and insulin deficient diabetes. In male PER alpha KO-/- mice, exposure to E2 partially prevented alloxan-induced beta-cell destruction and diabetes. ER alpha mRNA expression was induced by hyperglycemia in vivo in islets from young mice as well as in cultured rat islets. The induction of ER alpha mRNA by hyperglycemia was retained in insulin receptor-deficient beta-cells, demonstrating independence from direct insulin regulation. These findings suggest that induction of ER alpha expression acts to naturally protect beta-cells against oxidative injury.