Increased activity of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome–IL-1β pathway is observed in obesity and contributes to the development of type 2 diabetes and its complications. In this review, we describe the pathological activation of IL-1β by metabolic stress, ageing and the microbiome and present data on the role of IL-1β in metabolism. We explore the physiological role of the IL-1β pathway in insulin secretion and the relationship between circulating levels of IL-1β and the development of diabetes and associated diseases. We highlight the paradoxical nature of IL-1β as both a friend and a foe in glucose regulation and provide details on clinical translation, including the glucose-lowering effects of IL-1 antagonism and its impact on disease modification. We also discuss the potential role of IL-1β in obesity, Alzheimer’s disease, fatigue, gonadal dysfunction and related disorders such as rheumatoid arthritis and gout. Finally, we address the safety of NLRP3 inhibition and IL-1 antagonists and the prospect of using this therapeutic approach for the treatment of type 2 diabetes and its comorbidities.

Graphical Abstract

中文翻译：

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靶向 2 型糖尿病和肥胖症中的 NLRP3 炎性小体-IL-1β 通路

在肥胖中观察到含有 NACHT、LRR 和 PYD 结构域的蛋白 3 （NLRP3） 炎性小体-IL-1β 通路的活性增加，并导致 2 型糖尿病及其并发症的发展。在这篇综述中，我们描述了代谢应激、衰老和微生物组对 IL-1β 的病理激活，并提供了有关 IL-1β 在新陈代谢中的作用的数据。我们探讨了 IL-1β 通路在胰岛素分泌中的生理作用以及 IL-1β 循环水平与糖尿病和相关疾病发展之间的关系。我们强调了 IL-1β 在葡萄糖调节中既是朋友又是敌人的矛盾性质，并提供了临床转化的详细信息，包括 IL-1 拮抗作用的降糖作用及其对疾病修饰的影响。我们还讨论了 IL-1β 在肥胖、阿尔茨海默病、疲劳、性腺功能障碍和相关疾病（如类风湿性关节炎和痛风）中的潜在作用。最后，我们讨论了 NLRP3 抑制和 IL-1 拮抗剂的安全性以及使用这种治疗方法治疗 2 型糖尿病及其合并症的前景。

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