AIMS/HYPOTHESIS During the onset of type 2 diabetes, excessive dietary intake of saturated NEFA and fructose lead to impaired insulin production and secretion by insulin-producing pancreatic beta cells. The majority of data on the deleterious effects of lipids on functional beta cell mass were obtained either in vivo in rodent models or in vitro using rodent islets and beta cell lines. Translating data from rodent to human beta cells remains challenging. Here, we used the human beta cell line EndoC-βH1 and analysed its sensitivity to a lipotoxic and glucolipotoxic (high palmitate with or without high glucose) insult, as a way to model human beta cells in a type 2 diabetes environment. METHODS EndoC-βH1 cells were exposed to palmitate after knockdown of genes related to saturated NEFA metabolism. We analysed whether and how palmitate induces apoptosis, stress and inflammation and modulates beta cell identity. RESULTS EndoC-βH1 cells were insensitive to the deleterious effects of saturated NEFA (palmitate and stearate) unless stearoyl CoA desaturase (SCD) was silenced. SCD was abundantly expressed in EndoC-βH1 cells, as well as in human islets and human induced pluripotent stem cell-derived beta cells. SCD silencing induced markers of inflammation and endoplasmic reticulum stress and also IAPP mRNA. Treatment with the SCD products oleate or palmitoleate reversed inflammation and endoplasmic reticulum stress. Upon SCD knockdown, palmitate induced expression of dedifferentiation markers such as SOX9, MYC and HES1. Interestingly, SCD knockdown by itself disrupted beta cell identity with a decrease in mature beta cell markers INS, MAFA and SLC30A8 and decreased insulin content and glucose-stimulated insulin secretion. CONCLUSIONS/INTERPRETATION The present study delineates an important role for SCD in the protection against lipotoxicity and in the maintenance of human beta cell identity. DATA AVAILABILITY Microarray data and all experimental details that support the findings of this study have been deposited in in the GEO database with the GSE130208 accession code.

中文翻译：

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硬脂酰CoA去饱和酶是一种保护人β细胞免于脂毒性并保持其身份的守门员。

目的/假设在2型糖尿病发作期间，过多的饮食中饱和NEFA和果糖的饮食摄入会导致胰岛素生产和产生胰岛素的胰岛β细胞分泌受损。关于脂质对功能性β细胞质量的有害作用的大多数数据是在啮齿动物模型中体内获得的，或在体外使用啮齿动物胰岛和β细胞系获得的。将数据从啮齿动物转化为人类β细胞仍然具有挑战性。在这里，我们使用人类β细胞系EndoC-βH1并分析了其对脂毒性和糖脂毒性（高棕榈酸酯有或无高葡萄糖）的敏感性，以此作为在2型糖尿病环境中建模人β细胞的方法。方法敲除与饱和NEFA代谢相关的基因后，将EndoC-βH1细胞暴露于棕榈酸酯。我们分析了棕榈酸酯是否以及如何诱导凋亡，压力和炎症并调节β细胞的特性。结果除非将硬脂酰CoA去饱和酶（SCD）沉默，EndoC-βH1细胞对饱和NEFA（棕榈酸酯和硬脂酸酯）的有害作用不敏感。SCD在EndoC-βH1细胞以及人类胰岛和人类诱导的多能干细胞衍生的β细胞中大量表达。SCD沉默诱导炎症和内质网应激以及IAPP mRNA的标志物。用SCD产品油酸盐或棕榈油酸酯治疗可逆转炎症和内质网应激。击倒SCD后，棕榈酸酯诱导去分化标记（如SOX9，MYC和HES1）的表达。有趣的是，SCD自身敲低破坏了β细胞的身份，而成熟β细胞标志物INS的减少，MAFA和SLC30A8以及降低的胰岛素含量和葡萄糖刺激的胰岛素分泌。结论/解释本研究描述了SCD在防止脂毒性和维持人β细胞特性中的重要作用。数据可用性微阵列数据和支持该研究结果的所有实验细节已与GSE130208登录号一起存储在GEO数据库中。