The endoplasmic reticulum (ER) is the entry site into the secretory pathway for newly synthesized proteins destined for the cell surface or released into the extracellular milieu. The study of protein folding and trafficking within the ER is an extremely active area of research that has provided novel insights into many disease processes. Cells have evolved mechanisms to modulate the capacity and quality of the ER protein-folding machinery to prevent the accumulation of unfolded or misfolded proteins. These signaling pathways are collectively termed the unfolded protein response (UPR). The UPR sensors signal a transcriptional response to expand the ER folding capacity, increase degradation of malfolded proteins, and limit the rate of mRNA translation to reduce the client protein load. Recent genetic and biochemical evidence in both humans and mice supports a requirement for the UPR to preserve ER homeostasis and prevent the beta-cell failure that may be fundamental in the etiology of diabetes. Chronic or overwhelming ER stress stimuli associated with metabolic syndrome can disrupt protein folding in the ER, reduce insulin secretion, invoke oxidative stress, and activate cell death pathways. Therapeutic interventions to prevent polypeptide-misfolding, oxidative damage, and/or UPR-induced cell death have the potential to improve beta-cell function and/or survival in the treatment of diabetes.

中文翻译：

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未折叠蛋白反应：将胰岛素需求与 β 细胞衰竭和糖尿病联系起来的途径。

内质网 (ER) 是新合成的蛋白质进入分泌途径的进入位点，这些蛋白质运往细胞表面或释放到细胞外环境中。内质网内蛋白质折叠和运输的研究是一个非常活跃的研究领域，它为许多疾病过程提供了新的见解。细胞已经进化出调节内质网蛋白折叠机制的能力和质量的机制，以防止未折叠或错误折叠蛋白的积累。这些信号通路统称为未折叠蛋白反应 (UPR)。UPR 传感器发出转录反应信号，以扩大 ER 折叠能力，增加错误折叠蛋白质的降解，并限制 mRNA 翻译的速度以减少客户蛋白质负载。最近人类和小鼠的遗传和生化证据支持 UPR 的要求，以保持内质网稳态并防止 β 细胞衰竭，这可能是糖尿病病因的基础。与代谢综合征相关的慢性或压倒性内质网应激刺激可以破坏内质网中的蛋白质折叠，减少胰岛素分泌，引发氧化应激，并激活细胞死亡途径。预防多肽错误折叠、氧化损伤和/或 UPR 诱导的细胞死亡的治疗干预有可能改善 β 细胞功能和/或糖尿病治疗中的存活率。与代谢综合征相关的慢性或压倒性内质网应激刺激可以破坏内质网中的蛋白质折叠，减少胰岛素分泌，引发氧化应激，并激活细胞死亡途径。预防多肽错误折叠、氧化损伤和/或 UPR 诱导的细胞死亡的治疗干预有可能改善 β 细胞功能和/或糖尿病治疗中的存活率。与代谢综合征相关的慢性或压倒性内质网应激刺激可以破坏内质网中的蛋白质折叠，减少胰岛素分泌，引发氧化应激，并激活细胞死亡途径。预防多肽错误折叠、氧化损伤和/或 UPR 诱导的细胞死亡的治疗干预有可能改善 β 细胞功能和/或糖尿病治疗中的存活率。