17β-Estradiol Modulates Apoptosis in Pancreatic β-Cells by Specific Involvement of the Sulfonylurea Receptor (SUR) Isoform SUR1

Abstract Apoptosis of pancreatic β-cells is an important factor in the pathophysiology of diabetes. Previously, we have shown that the “phytoestrogen” resveratrol can induce β-cell apoptosis dependent on the expression of sulfonylurea receptor (SUR) 1, the regulatory subunit of pancreatic ATP-sensitive K+ channels. Here, we investigate whether 17β-estradiol also influences β-cell apoptosis in a SUR1-dependent manner. Therefore, islets from wild type or SUR1 knock-out mice, clonal β-cells, or HEK293 cells expressing different SUR forms were treated with 17β-estradiol or estrone. Different apoptotic parameters were determined and estrogen binding to SUR was analyzed. In murine islets, 17β-estradiol treatment resulted in significant apoptotic changes, which in their nature (either apoptotic or anti-apoptotic) were dependent on the age of the animal. These effects were not observed in SUR1 knock-out mice. Furthermore, 17β-estradiol, which specifically binds to SUR, induced enhanced apoptosis in SUR1-expressing HEK293 cells and clonal β-cells, whereas apoptosis in recombinant cells expressing SUR2A or SUR2B (cardiac or vascular SUR-isoforms) or sham-transfected control cells was significantly lower. The apoptotic potency of 17β-estradiol was much higher than that of resveratrol or estrone. SUR1-specific 17β-estradiol-induced apoptosis was either abolished by the mutation M1289T in transmembrane helix 17 of SUR1 or clearly enhanced by two mutations in nucleotide binding fold 2 (R1379C, R1379L). In conclusion, 17β-estradiol treatment modulates β-cell apoptosis under specific involvement of SUR1 in an age-dependent manner. 17β-Estradiol-induced apoptosis can be influenced by certain SUR1 mutations. These findings may contribute to the understanding of pathophysiological changes in β-cell mass and could, for instance, provide interesting aspects concerning the etiology of gestational diabetes.