Abstract
Apoptosis of pancreatic beta-cells is an important factor in the pathophysiology of diabetes. Previously, we have shown that the "phytoestrogen" resveratrol can induce beta-cell apoptosis dependent on the expression of sulfonylurea receptor (SUR) 1, the regulatory subunit of pancreatic ATP-sensitive K(+) channels. Here, we investigate whether 17beta-estradiol also influences beta-cell apoptosis in a SUR1-dependent manner. Therefore, islets from wild type or SUR1 knock-out mice, clonal beta-cells, or HEK293 cells expressing different SUR forms were treated with 17beta-estradiol or estrone. Different apoptotic parameters were determined and estrogen binding to SUR was analyzed. In murine islets, 17beta-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, 17beta-estradiol, which specifically binds to SUR, induced enhanced apoptosis in SUR1-expressing HEK293 cells and clonal beta-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 17beta-estradiol was much higher than that of resveratrol or estrone. SUR1-specific 17beta-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, 17beta-estradiol treatment modulates beta-cell apoptosis under specific involvement of SUR1 in an age-dependent manner. 17beta-Estradiol-induced apoptosis can be influenced by certain SUR1 mutations. These findings may contribute to the understanding of pathophysiological changes in beta-cell mass and could, for instance, provide interesting aspects concerning the etiology of gestational diabetes.
Highlights
FEBRUARY 20, 2009 VOLUME 284 NUMBER 8 channels)
By analysis of several apoptotic parameters, we have previously shown that sulfonylurea receptor (SUR) ligands that act as KATP channel blockers such as the synthetic insulinotropic sulfonylurea glibenclamide or the “phytoestrogen” trans-resveratrol can induce apoptotic cell death depending on SUR1, the SUR isoform present in the pancreatic KATP channel [3, 4]
Enhanced apoptosis induced by these substances is not mediated by the electrical activity of KATP channels as it is observed in recombinant SUR1-expressing cells in the absence of the pore forming pancreatic channel subunit Kir6.2
Summary
FEBRUARY 20, 2009 VOLUME 284 NUMBER 8 channels). These channels act as metabolic sensors due to their nucleotide sensitivity and play a key role in important cellular processes like, for instance, the triggering of insulin secretion. Enhanced apoptosis induced by these substances is not mediated by the electrical activity of KATP channels as it is observed in recombinant SUR1-expressing cells in the absence of the pore forming pancreatic channel subunit Kir6.2. These findings point to an additional function of SUR apart from regulating electrical activity of KATP channels. 17-estradiol concentrations are clearly elevated, especially during the third trimester At this stage, gestational diabetes mellitus (GDM) is diagnosed in about 1–16% of pregnant women with the figures depending on the study conditions [12,13,14]. The aim of this study was to investigate whether 17-estradiol affects apoptotic cell death in -cells
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