焦亡在胰岛素抵抗发生发展中的作用及研究进展

The role and research progress of pyroptosis in the development and progression of insulin resistance

摘要:

胰岛素抵抗是2型糖尿病、代谢综合征、代谢相关脂肪性肝病及心血管疾病等多种代谢性疾病的共同病理基础,其发生机制包括脂毒性、氧化应激及慢性低度炎症等。细胞焦亡是一种依赖Caspase-1活化的程序性细胞死亡形式。近年来研究表明,细胞焦亡在胰岛素抵抗的发生发展中发挥重要作用。在代谢应激条件下,如高脂饮食、高糖饮食或游离脂肪酸水平升高,可激活脂肪组织、肝脏、骨骼肌及胰岛β细胞中的核苷酸结合结构域富含亮氨酸重复序列和含热蛋白结构域受体3(NLRP3)炎症小体,诱导细胞焦亡,并释放白细胞介素1β(IL-1β)和IL-18等炎症因子,干扰胰岛素信号转导,进而导致糖代谢紊乱。目前,靶向焦亡通路相关分子的干预策略在基础研究中已显示出改善胰岛素敏感性的潜力,但在临床转化层面仍面临安全性及有效性等挑战。本文系统综述了细胞焦亡参与胰岛素抵抗的分子机制及其在不同代谢组织中的作用特点,并进一步梳理了靶向焦亡通路的干预策略,以期为胰岛素抵抗及相关代谢性疾病的防治提供理论依据与潜在靶点。

Abstract:

Insulin resistance is a common pathological basis for multiple metabolic diseases, including type 2 diabetes mellitus, metabolic syndrome, metabolic associated fatty liver disease, and cardiovascular diseases, and its underlying mechanisms involve lipotoxicity, oxidative stress, and chronic low-grade inflammation. Pyroptosis is a programmed cell death pathway that depends on Caspase-1 activation. Recent studies have demonstrated that pyroptosis plays a significant role in the development and progression of insulin resistance. Under metabolic stress conditions, such as high-fat diet, high-glucose diet, or elevated levels of free fatty acids, the nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3 (NLRP3) inflammasome can be activated in adipose tissue, liver, skeletal muscle, and pancreatic β-cells, thereby inducing pyroptosis and promoting the release of inflammatory cytokines including interleukin-1β (IL-1β) and IL-18. These cytokines subsequently interfere with insulin signal transduction, leading to glucose metabolic disorders. Currently, intervention strategies targeting pyroptosis-related molecules have shown potential in improving insulin sensitivity in preclinical studies; however, challenges regarding safety and efficacy remain in clinical translation. This review systematically summarizes the molecular mechanisms by which pyroptosis participates in insulin resistance and its distinctive roles in different metabolic tissues, and further delineates potential therapeutic approaches targeting the pyroptosis pathway, aiming to provide a theoretical foundation and identify promising targets for the prevention and treatment of insulin resistance and its associated metabolic diseases.