Abstract
Dysmetabolism of branched-chain amino acid (BCAA) causes insulin resistance in type 2 diabetes, yet its effect on insulin-producing β-cells remains unclear. Here, we demonstrate that branched-chain α-ketoacids (BCKAs), derived from BCAAs, inhibited glucose-stimulated insulin secretion (GSIS) and glucose fluxes across human islets, mouse islets, and mouse β-cells. In diabetic humans, elevated circulating BCKAs negatively correlated with insulin secretory ability. Treatment with BCKA or its impaired catabolism suppressed GSIS in human islets and male mice, while reducing BCKA improved glucose tolerance and GSIS in male and female diabetic mice. Mechanistically, BCKA redirected glucose metabolism from the TCA cycle to the “β-cell disallowed” lactate dehydrogenase A (LDHA)-lactate axis. BCKA directly bound to LDHA, promoting its dimerization and enhancing enzymatic activity. β-cell-specific LDHA ablation restored GSIS and glucose tolerance in BCKA-fed male mice. Our findings demonstrate that BCKA disrupts insulin secretion through LDHA reactivation, linking aberrant BCAA metabolism to β-cell dysfunction in diabetes.
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All experimental data generated in this study are provided in the Supplementary Information/Source Data file. A PDF file with uncropped scans of western blots and source data used to generate the graphs in the paper are provided. The processed transcriptome and proteome datasets for BCAA catabolic enzyme expression were downloaded from Kolic et al. (PMID: 38959864) and are publicly available at www.humanislets.com and were reanalyzed. Additional information can be obtained from the lead contact upon reasonable request. Source data are provided in this paper.
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Acknowledgements
We would like to thank Dr. Xi Chen for her kind help in collecting serum and tissue samples in BCKA-fed mice. We thank the Department of University Life Science at The Hong Kong Polytechnic University for providing instruments and instructions. This project was supported by National Natural Science Foundation of China (81970675 and 92357305), Hong Kong Research Grant Council (RGC) Collaborative Research Fund (C5044-23G) and General Research Fund (15101221), Shenzhen Municipal Science and Technology Innovation Commission Basic Research General Program: 20210324130202006 and PolyU internal funding (P0040979, P0036848 and P0059102) to Dr. Kenneth King-yip Cheng, AoE/M-707/18/RGC Area of Excellence to Dr. Aimin Xu and Department of Defense (W81XWH2010592) to Dr. Chen Cao.
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H.L. and M.Y.H. conducted most of the experiments and drafted and revised the manuscript. Y.Y. and B.W. collected human samples and conducted data analysis. S.M. and A.M.M. performed some immunohistochemical experiments. W.W., P.S., and H.P. helped with LC-MS/MS measurement for BCAA/BCKA and TCA cycle intermediates. A.X. provided LDHA floxed mice and revised the manuscript. S.Y. and J.C. supervised and conducted BCKA-LDHA docking site analysis. C.G. provided PPM1K global KO mice, provided supervision on the animal study and reviewed the manuscript. P.M.S. collected human serum samples and clinical data in Hong Kong. X.L. provided pancreatic slides, islets, serum and clinical data from T2D humans. K.K.C. acquired the funding, provided resources, supervised the project and wrote the manuscript. K.K.C. and X.L. jointly supervised this work. All authors reviewed and approved the final manuscript.
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Lin, H., Ho, M.Y.M., Wang, B. et al. Branched-chain α-keto acids impair glucose-stimulated insulin secretion in pancreatic β-cells under diabetes by reactivating the LDHA-lactate axis. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70004-2
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DOI: https://doi.org/10.1038/s41467-026-70004-2
