Volume 36, No 2, Feb 2026

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 36 Issue 2, February 2026: 137-151

ORIGINAL ARTICLES

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

Yaxin Niu^1,† , Shengmin Hu^1,† , Yanfeng Zhang² , Jinbao Yang¹ , Jiarui Zhang¹ , Ruiping He¹ , Li Chen¹ , Lin Xu² , Hongfang Zhao¹ , Bing Gan¹ , Ruobing Ren¹ , Ruth J. F. Loos^3,4 , Haobin Ye¹ , Xingrong Du¹ , Tongjin Zhao^1,5 , Peng Li⁵ , Antonio Vidal-Puig^6,7,8 , Linzhang Huang^1,*

¹State Key Laboratory of Genetics and Development of Complex Phenotypes, Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Drug Clinical Trial Center, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, China
²Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Public Health, and Department of Pediatrics, Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
³Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Kobenhavn, Denmark
⁴The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
⁵Innovation Center of Basic Research for MetabolicAssociated Fatty Liver Disease, Ministry of Education of China, Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
⁶Wellcome-MRC Institute of Metabolic Science and MRC Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
⁷Cambridge University Nanjing Centre of Technology and Innovation, Nanjing, Jiangsu, China
⁸Centro de Investigacion Principe Felipe, Valencia, Spain
^†These authors contributed equally: Yaxin Niu, Shengmin Hu
Correspondence: Linzhang Huang(Linzhang_huang@fudan.edu.cn)

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.

https://doi.org/10.1038/s41422-025-01207-3

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