Modulation of estrogen receptor sensitizes pancreatic beta cells to apoptosis

In the United States, ~16% of adults have been diagnosed with diabetes mellitus, although prevalence varies between men and women. Previous studies have shown that there is a reduced preponderance of diabetes amongst premenopausal women when compared with age-matched men although severity is greater in women postmenopause. Studies from our lab have shown that female C57BL6 mice are also resistant to the development of type I diabetes using streptozotocin (STZ) (Schiazza et al., 2021). Previously, we found that 4-hydroxytamoxifen, an estrogen receptor α modulator, increased the susceptibility of female mice to STZ leading to the development of hyperglycemia. Taken together, we hypothesize that ERα prevents the destruction of pancreatic beta cells and onset of diabetes, and that modulation with 4-hydroxytamoxifen renders the islet cells more susceptible to mitochondrial dysfunction and endoplasmic reticulum stress. To test this, we have selected two pancreatic beta cell lines, Beta-TC-6 cells, derived from a pancreatic tumor of a transgenic mouse, and HIT T15 cells, isolated from a hamster model. Both cell lines were confirmed to express estrogen receptor α. Additionally, upon exposure to varying concentrations of glucose, both cell lines demonstrated glucose-stimulated insulin secretion (GSIS), confirmed by an insulin ELISA assay. Specifically, the Beta-TC-6 cells showed a dose response to 0, 5, and 20 mM of glucose. Additionally, GSIS doesn’t appear to be modulated by hormone concentrations within the growth media. Current efforts are focused on determining how 4-hydroxytamoxifen impacts GSIS in these cells, and whether estrogen receptor signaling regulates mitochondrial dynamics. Dekkers Endowed Chair of Human Science This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.