Having established that ERα is not essential to islet angiogenesis in mice, we focused on the role of ERα in protecting islets from glucotoxicity and oxidative stress in vivo and report that both male and female mice lacking ERα selectively in the pancreas are more susceptible to alloxan-induced β-cell destruction, insulin deficiency, and hyperglycemia. The gene discussed is ESR1; the disease is Hyperglycemia.