复旦大学黄林章小组开发出乳酸激活的GPR81/FARP1信号驱动胰岛素不依赖的葡萄糖摄取和代谢控制。相关论文于2026年1月13日发表在《细胞研究》杂志上。

该课题组研究人员确定l -乳酸作为胰岛素不依赖的葡萄糖摄取调节剂，减轻高血糖。细胞中LDHA的损失减少了乳酸的产生，损害了小鼠的葡萄糖稳态。相比之下，乳酸管理或乳酸产生的基因上调可改善葡萄糖控制。骨骼肌中乳酸受体GPR81的敲除会恶化葡萄糖耐量，而其异位表达或药理激活则会增强碳水化合物代谢。在机制上，GPR81招募FARP1激活RAC1，独立于胰岛素信号传导促进GLUT4易位。值得注意的是，运动后LDHA、GPR81和FARP1的表达上调，GPR81变异体与人体空腹胰岛素水平高度相关，强调了GPR81-FARP1-GLUT4轴与胰岛素在葡萄糖调节中的协同作用。他们的研究结果表明，靶向GPR81代表了治疗高血糖的潜在胰岛素不依赖型策略。

据悉，胰岛素刺激的葡萄糖摄取是全球碳水化合物代谢的核心，然而，独立于胰岛素而增强葡萄糖摄取的代谢物仍未明确。

附：英文原文

Title: Lactate-activated GPR81/FARP1 signaling drives insulin-independent glucose uptake and metabolic control

Author: Niu, Yaxin, Hu, Shengmin, Zhang, Yanfeng, Yang, Jinbao, Zhang, Jiarui, He, Ruiping, Chen, Li, Xu, Lin, Zhao, Hongfang, Gan, Bing, Ren, Ruobing, Loos, Ruth J. F., Ye, Haobin, Du, Xingrong, Zhao, Tongjin, Li, Peng, Vidal-Puig, Antonio, Huang, Linzhang

Issue&Volume: 2026-01-13

Abstract: Insulin-stimulated glucose uptake is central to global carbohydrate metabolism, yet metabolites that enhance glucose uptake independently of insulin remain undefined. Here, we identify L-lactate as an insulin-independent regulator of glucose uptake that mitigates hyperglycemia. Loss of LDHA in muscle reduces lactate production, impairing glucose homeostasis in mice. By contrast, lactate administration or genetic upregulation of lactate production improves glucose control. Knockout of the lactate receptor GPR81 in skeletal muscle worsens glucose tolerance, whereas its ectopic expression or pharmacological activation enhances carbohydrate metabolism. Mechanistically, GPR81 recruits FARP1 to activate RAC1, promoting GLUT4 translocation independently of insulin signaling. Notably, the expression of LDHA, GPR81, and FARP1 is upregulated after exercise, and GPR81 variants are highly correlated with fasting insulin levels in humans, underscoring the synergy of the GPR81-FARP1-GLUT4 axis with insulin in glucose regulation. Our findings suggest that targeting GPR81 represents a potential insulin-independent strategy for the treatment of hyperglycemia.

DOI: 10.1038/s41422-025-01207-3

Source: https://www.nature.com/articles/s41422-025-01207-3