2672-P: Global Loss of CREBRF in Mice Results in Hyperglycemia Despite Resistance to Diet-Induced Obesity in Part Due to Reduced Functional Beta-Cell Mass

Introduction and Objective: Obesity and diabetes are global health threats. A BMI-increasing variant in CREBRF [rs373863828, R457Q] protects against diabetes despite increasing obesity in humans. The mechanisms by which CREBRF and its R457Q variant mediate these effects are unknown. Since beta cell failure is the common pathway to diabetes, we tested the hypothesis that CREBRF is required for functional beta cell mass (BCM). Methods: We generated mice with global deletion of Crebrf (gCrebrfKO). We then evaluated the impact of CREBRF on mechanistic determinants of functional BCM in mice in vivo, islets ex vivo, and INS-1 832/13 cells. Results: In contrast to human carriers of the CREBRF variant, gCrebrfKO mice have impaired fasting glucose and glucose tolerance despite lower total body and fat mass compared to wild-type. BCM, size, and insulin content per beta cell were decreased in gCrebrfKO mice. In addition, ex vivo glucose-stimulated insulin secretion was reduced in gCrebrfKO islets. Gene expression analysis of islets revealed differential expression of genes involved in proliferation, cell cycle progression, cytoskeleton, and secretion. The cell autonomous effect of Crebrf was confirmed by demonstrating reduced proliferation in INS-1 cells following knockdown. Conclusion: These data suggest that CREBRF is critical in maintaining functional BCM, and that the R457Q variant may be a gain-rather than loss-of-function with respect to energy and glucose homeostasis. gCrebrfKO mice exhibit a dramatic decrease in serum insulin, and our results confirm reduction of beta cell size, insulin content, and stimulated insulin secretion in gCrebrfKO islets. We also show the cell autonomous effect of Crebrf by demonstrating reduced proliferation in a beta cell line following its knockdown. CREBRF is required for glucose homeostasis despite lower body weight primarily through effects on functional BCM and regulation of key genes in beta cell proliferation and cell cycle progression. Disclosure M.G. Rossillo: None. P.E. Mattila: None. Z. Ross: None. A. Wood: None. G. Schoiswohl: None. R. Liu: None. F. Shah: None. B. Chuan: None. M.K. Basantani: None. D. Gupta: None. D.E. Weeks: None. S.T. McGarvey: None. L. Heinsberg: None. M. Jurczak: None. V. Yechoor: None. E.E. Kershaw: Consultant; Ended; Novo Nordisk. Consultant; Current; NodThera, Sparrow Pharmaceuticals. Research Support; Current; Pfizer Inc., Arrowhead Pharmaceuticals, Inc. Funding American Diabetes Association (1-17-PMF-02), National Institutes of Health (T32DK007052), National Institutes of Health (K01DK115543), National Institutes of Health (R21KD121266), Winters Foundation Award HHMI Pittsburgh Foundation (MR2018-98421), National Institutes of Health (HL093093)