Meier Daniel T, de Paula Souza Joyce, Donath Marc Y
Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.
Department of Biomedicine, University of Basel, Basel, Switzerland.
Diabetologia. 2025 Jan;68(1):3-16. doi: 10.1007/s00125-024-06306-1. Epub 2024 Nov 4.
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.
在肥胖症中观察到含NACHT、LRR和PYD结构域的蛋白3（NLRP3）炎性小体-白细胞介素-1β（IL-1β）途径的活性增加，这有助于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、衰老和微生物群对IL-1β的病理激活，并展示了IL-1β在代谢中的作用的数据。我们探讨了IL-1β途径在胰岛素分泌中的生理作用以及循环中IL-1β水平与糖尿病及相关疾病发展之间的关系。我们强调了IL-1β在血糖调节中既是“朋友”又是“敌人”这一矛盾性质，并详细介绍了临床转化情况，包括IL-1拮抗作用的降糖效果及其对疾病改善的影响。我们还讨论了IL-1β在肥胖症、阿尔茨海默病、疲劳、性腺功能障碍以及类风湿关节炎和痛风等相关疾病中的潜在作用。最后，我们阐述了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。
