1723-P: ATF6α Is Required for Pancreatic Beta-Cell Proliferation during Acute Severe Insulin Resistance

Introduction: Developing tools to expand beta cell mass is a critical goal towards a true solution to insulin-dependent diabetes. Sub-threshold activation of the UPR increases beta cell proliferation in hyperglycemic conditions via the Activating Transcription Factor 6 (ATF6) arm of UPR. ATF6α overexpression is sufficient to increase beta cell proliferation in high glucose in ex vivo islet cell cultures, and knockdown of ATF6α reduces glucose-induced proliferation. However, chronic beta cell deletion of ATF6α has been reported to cause minimal disruption to healthy biology. It is unknown if ATF6α participates in stress-induced beta cell proliferation in vivo. Methods: Healthy C57BL/6N, or conditional beta cell ATF6α deletion (with Ins1cre: +/+Cre+, F/+Cre+ or F/FCre+ genotypes studied) male and female mice aged 10-15 weeks were implanted with Alzet minipumps containing 10nmol of S961 (insulin receptor antagonist) or vehicle for 7 days. Metabolic testing was performed, and pancreatic islets were isolated for qPCR analysis. Results: Under unstressed conditions, beta cell ATF6α deletion did not alter systemic glucose metabolism. Healthy C57BL/6N mice treated with S961 developed marked hyperinsulinemia, hyperglycemia, and glucose intolerance. RNA from pancreatic islets isolated after 7 days of S961 showed molecular evidence of ER stress and increased proliferation markers; male and female mice were similar. Beta cell ATF6α deletion did not impact circulating metabolic parameters during severe insulin resistance, or surprisingly, the islet response to insulin resistance stress. However, the induction of proliferation markers in islets by S961 was significantly impaired in ATF6α deleted mice. Conclusion: Chronic deletion of ATF6α in beta cells from development through adulthood does not impair beta cell homeostasis under unstressed conditions, but beta cell ATF6α is required for the proliferation response to acute severe insulin resistance in live mice. Disclosure C.O. Darko: None. Y. Wang: None. T.A. Castro: None. L.C. Alonso: None. Funding National Institutes of Health (R01DK135304, R01DK124906, and R01DK114686)