Targeting the NLRP3 inflammasome–IL-1β pathway in type 2 diabetes and obesity

• Published in: Diabetologia
• Main Authors: Meier, Daniel T., de Paula Souza, Joyce, Donath, Marc Y.
• Format: Journal Article
• Language: English
• Published: 04-11-2024
• ISSN: 0012-186X; 1432-0428; 1432-0428
• DOI: 10.1007/s00125-024-06306-1

Abstract 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