352-OR: Selective Loss of the Spliced Form of Xbp1 Causes Early-Onset Diabetes in Male but Not Female Mice

Endoplasmic reticulum (ER) stress is associated with progressive deterioration in pancreatic islet beta cell function, a hallmark of type 2 diabetes. Adaptive unfolded protein response (UPR) is critical for mature beta cells to resolve ER stress due to aging and obesity. X-box binding protein 1 (Xbp1) is an essential, evolutionarily conserved transducer of the UPR. In response to ER stress, the full-length Xbp1 mRNA undergoes noncanonical splicing catalyzed by Ire1, which leads to a frame-shift and the generation of spliced Xbp1 (Xbp1s), a potent transcription factor. Recently, Xbp1 expression was shown to be increased in less mature beta cells from young individuals (<30 y) compared to beta cells from middle-aged adults (30-59 y). The physiological relevance of Xbp1s activation in the early development of the pancreas remains elusive due to the lack of a proper in vivo model; the constitutive Xbp1 KO model is embryonic lethal in rodents, whereas the Cre-loxP-mediated tissue selective Xbp1 KO model ablates both full-length and spliced-form of Xbp1. To fulfill the knowledge gap, we generated a knock-in mutant form of Xbp1 to ablate only the spliced form of Xbp1. We found that homozygous Xbp1s KO mice are born at a rate below the Mendelian ratio, indicating that selective loss of Xbp1s is not developmentally lethal in mammals despite lowering the rate of live births. Strikingly, Xbp1s ablation leads to abnormal islet architecture in both males and females, but only male mice exhibit hyperglycemia and glucose intolerance due to insulin insufficiency. The female Xbp1s KO mice maintain normoglycemia and glucose tolerance due to enhanced insulin sensitivity. Our findings suggest that Xbp1s is essential for the early development of pancreatic islets and beta cell mass, and there are sex-specific mechanisms contributing to adulthood diabetes under Xbp1s deficiency.