The compensatory proliferation of insulin-producing β cells is critical to maintaining glucose homeostasis at the early stage of type 2 diabetes. Failure of β cells to proliferate results in hyperglycemia and insulin dependence in patients. To understand the effect of the interplay between β cell compensation and lipid metabolism upon obesity and peripheral insulin resistance, we eliminated LDL receptor–related protein 1 (LRP1), a pleiotropic mediator of cholesterol, insulin, energy metabolism, and other cellular processes, in β cells. Upon high-fat diet exposure, LRP1 ablation significantly impaired insulin secretion and proliferation of β cells. The diminished insulin signaling was partly contributed to by the hypersensitivity to glucose-induced, Ca²⁺-dependent activation of Erk and the mTORC1 effector p85 S6K1. Surprisingly, in LRP1-deficient islets, lipotoxic sphingolipids were mitigated by improved lipid metabolism, mediated at least in part by the master transcriptional regulator PPARγ2. Acute overexpression of PPARγ2 in β cells impaired insulin signaling and insulin secretion. Elimination of Apbb2, a functional regulator of LRP1 cytoplasmic domain, also impaired β cell function in a similar fashion. In summary, our results uncover the double-edged effects of intracellular lipid metabolism on β cell function and viability in obesity and type 2 diabetes and highlight LRP1 as an essential regulator of these processes.

中文翻译：

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饮食引起的肥胖症中细胞内脂质代谢损害β细胞补偿

产生胰岛素的β细胞的代偿性增殖对于维持2型糖尿病早期的葡萄糖稳态是至关重要的。β细胞增殖失败会导致患者出现高血糖和胰岛素依赖。为了了解β细胞补偿与脂质代谢之间的相互作用对肥胖症和外周胰岛素抵抗的影响，我们在研究中消除了LDL受体相关蛋白1（LRP1），它是胆固醇，胰岛素，能量代谢和其他细胞过程的多效介质。 β细胞。高脂饮食暴露后，LRP1消融显着损害胰岛素分泌和β细胞增殖。胰岛素信号减弱的部分原因是对葡萄糖诱导的Ca ²⁺过敏依赖性激活Erk和mTORC1效应子p85 S6K1。令人惊讶地，在缺乏LRP1的胰岛中，脂质毒性的鞘脂通过改善的脂质代谢而减轻，脂质代谢的改变至少部分地由主转录调节因子PPARγ2介导。β细胞中PPARγ2的急性过表达会损害胰岛素信号传导和胰岛素分泌。消除Lbb1胞质域的功能性调节剂Apbb2，也以类似的方式损害了β细胞的功能。总之，我们的结果揭示了肥胖和2型糖尿病中细胞内脂质代谢对β细胞功能和生存能力的双重影响，并强调LRP1是这些过程的重要调节剂。