Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes.
Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes.
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IL-1β是2型糖尿病(T2D)的重要炎症介质。在这里，我们展示了胰岛淀粉样多肽的寡聚体，一种在T2D期间在胰腺形成淀粉样沉积的蛋白质，触发Nlrp3炎症体并产生成熟的白介素1β。T2D疗法格列本脲在体外抑制IAPP介导的IL-1β的产生。由IAPP启动的IL-1β的处理首先需要启动，这一过程涉及葡萄糖代谢，最低限度氧化的低密度脂蛋白可以促进这一过程。最后，转基因人IAPP的小鼠增加了胰岛中与淀粉样蛋白和巨噬细胞共存的IL-1β。我们的发现揭示了T2D的发病机制和IAPP引起的病理治疗的新机制。
IL-1β is an important inflammatory mediator of type 2 diabetes (T2D). Here we show that oligomers of islet amyloid polypeptide (IAPP), a protein that forms amyloid deposits in the pancreas during T2D, trigger the Nlrp3 inflammasome and generate mature interleukin (IL)-1β. A T2D therapy, glyburide, suppresses IAPP-mediated IL-1β production in vitro. Processing of IL-1β initiated by IAPP first requires priming, a process that involves glucose metabolism and can be facilitated by minimally oxidized low density lipoprotein. Finally, mice transgenic for human IAPP have increased IL-1β in pancreatic islets, which colocalizes with amyloid and macrophages. Our findings reveal novel mechanisms in the pathogenesis of T2D and treatment of pathology caused by IAPP.