Role of UPR transducer Xbp1 in Pancreatic Beta Cell Survival and Function under Metabolic Stress

Beckman Research Institute/City Of Hope, Duarte CA

Investigators

Abstract

Project Summary Diabetes is now a global epidemic. More than 95% of diabetes is type 2 diabetes (T2D), a chronic disease that can cause serious complications, including heart attack, stroke, kidney failure, blindness, and lower limb amputation. Progressive deterioration in pancreatic islet β-cell function is a hallmark of T2D, however, the mechanism of β-cell loss in T2D remains elusive. Βeta cells increase insulin secretion in response to hyperglycemia. If insulin production surpasses the capacity of endoplasmic reticulum (ER) to make functional proteins, misfolded proteins will buildup, a process called the ER stress. Metabolic stress due to obesity, aging, and other lifestyle changes disrupts energy homeostasis, which triggers ER stress in β cells leading to the activation of UPRs. Chronic ER stress under metabolic stress, which is characterized by insulin resistance, turns adaptive UPR to maladaptive UPR, which is believed a driving force for β-cell mass loss in T2D. Our long-term goal is to identify the tilting point of UPR under metabolic stress and to explore its translational potential for therapeutic interventions. Multiple lines of evidence have indicated that Xbp1s, a UPR transducer activated by ER stress, is crucial for β-cell function and survival. Consistent with the requirement for Xbp1s to protect β-cells from dysfunction under metabolic stress, Xbp1s is found elevated in β-cells in preT2D donors and prediabetic models. However, the overexpression of Xbp1s, when studied in vitro showed conflicting results: one showing Xbp1s promotes β- cell apoptosis, and the other showing Xbp1s promotes β-cell proliferation. Despite the controversy about Xbp1s overexpression in positive or negative regulation of β-cell survival, it is clear that the action of Xbp1s in β-cells is complicated and it is insufficient to elucidate the impact of Xbp1s on β-cell integrity under metabolic stress by in vitro studies solely. Regrettably, there has been no in vivo studies about the impact of Xbp1s overexpression on β-cell survival and function. Using a novel mouse model that allows inducible overexpression of Xbp1s selectively in β-cells, we found a striking impact of Xbp1s on β-cell function and survival. Preliminary studies showed that Xbp1s acts as a regulator of β-cell heterogeneity by facilitating reversible state transitions. A novel link of Xbp1s and NeuroD1 was predicted by the multiome data which highlights a potential mechanism for Xbp1s-faciliated state transition. Moreover, the dynamic state transitions of β-cells were halted in obese mice, indicating metabolic stress could adversely affect the state transition facilitated by Xbp1s. Human islets and cell lines will be employed to complement in vivo animal models at the mechanistic level. Elucidation of the role of Xbp1s as an integrative player in adaptive remodeling of β-cells under metabolic stress will advance our understanding of the progressive deterioration in pancreatic islet β-cells in T2D and pave a way for novel, more effective therapeutic design for preventing β-cell loss in T2D progression.