Type 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia, hyperinsulinemia, and insulin resistance (IR). During the early phase of T2D, insulin synthesis and secretion by pancreatic β cells is enhanced, which can lead to proinsulin misfolding that aggravates endoplasmic reticulum (ER) protein homeostasis in β cells. Moreover, increased circulating insulin may contribute to fatty liver disease. Medical interventions aimed at alleviating ER stress in β cells while maintaining optimal insulin secretion are therefore an attractive therapeutic strategy for T2D. Previously, we demonstrated that germline Chop gene deletion preserved β cells in high-fat diet (HFD)–fed mice and in leptin receptor–deficient db/db mice. In the current study, we further investigated whether targeting Chop/Ddit3 specifically in murine β cells conferred therapeutic benefits. First, we showed that Chop deletion in β cells alleviated β cell ER stress and delayed glucose-stimulated insulin secretion (GSIS) in HFD-fed mice. Second, β cell–specific Chop deletion prevented liver steatosis and hepatomegaly in aged HFD-fed mice without affecting basal glucose homeostasis. Third, we provide mechanistic evidence that Chop depletion reduces ER Ca²⁺ buffering capacity and modulates glucose-induced islet Ca²⁺ oscillations, leading to transcriptional changes of ER chaperone profile (“ER remodeling”). Last, we demonstrated that a GLP1-conjugated Chop antisense oligonucleotide strategy recapitulated the reduction in liver triglycerides and pancreatic insulin content. In summary, our results demonstrate that Chop depletion in β cells provides a therapeutic strategy to alleviate dysregulated insulin secretion and consequent fatty liver disease in T2D.

2 型糖尿病 (T2D) 是一种以高血糖、高胰岛素血症和胰岛素抵抗 (IR) 为特征的代谢性疾病。在 T2D 早期，胰腺 β 细胞的胰岛素合成和分泌增强，可导致胰岛素原错误折叠，加重 β 细胞内质网 (ER) 蛋白稳态。此外，增加的循环胰岛素可能会导致脂肪肝。因此，旨在减轻 β 细胞 ER 应激同时维持最佳胰岛素分泌的医学干预措施是 T2D 的一种有吸引力的治疗策略。以前，我们证明了生殖系Chop基因缺失在高脂饮食 (HFD) 喂养的小鼠和瘦素受体缺陷的db/db中保留了 β 细胞老鼠。在目前的研究中，我们进一步研究了在小鼠 β 细胞中特异性靶向Chop/Ddit3是否具有治疗益处。首先，我们发现β 细胞中的Chop缺失减轻了 HFD 喂养小鼠的 β 细胞 ER 应激并延迟了葡萄糖刺激的胰岛素分泌 (GSIS)。其次，β 细胞特异性Chop缺失可防止老年 HFD 喂养小鼠的肝脏脂肪变性和肝肿大，而不影响基础葡萄糖稳态。第三，我们提供了机械证据表明Chop消耗降低了 ER Ca ²⁺缓冲能力并调节葡萄糖诱导的胰岛 Ca ²⁺振荡，导致 ER 伴侣谱的转录变化（“ER 重塑”）。最后，我们证明了 GLP1 缀合的Chop反义寡核苷酸策略概括了肝脏甘油三酯和胰腺胰岛素含量的减少。总之，我们的结果表明β 细胞中的Chop消耗提供了一种治疗策略，以减轻 T2D 中胰岛素分泌失调和随之而来的脂肪肝疾病。