Selective estrogen receptor modulation in pancreatic β-cells and the prevention of type 2 diabetes

We recently showed that the female hormone 17 beta-estradiol (E2) protects against beta-cell failure in rodent models of type 2 diabetes (T2D) by suppressing islet fatty acids and glycerolipids synthesis, thus preventing lipotoxic beta-cell failure. E2 anti-lipogenic actions were recapitulated by pharmacological activation of the estrogen receptor (ER)alpha, ER beta and the G-protein coupled ER (GPER) in cultured rodent and human beta-cells. In vivo, in mouse islets, ER alpha activation inhibited beta-cell lipogenesis by suppressing fatty acid synthase expression (and activity) via an extranuclear, estrogen response element (ERE)-independent pathway requiring the signal transducer and activator of transcription 3. Here, we show that in INS-1 insulin-secreting cells, the selective ER modulator (SERM), Raloxifene, behaves both as ER antagonist with regard to nuclear ERE-dependent actions and as an ER agonist with regard to suppressing triglyceride accumulation. This additional finding opens the perspective that SERMs harboring ER agonistic activity in beta-cells could have application in postmenopausal prevention of T2D. Additional studies using novel generation SERMs are needed to address this issue.