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<p>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.</p>

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Branched-chain α-keto acids impair glucose-stimulated insulin secretion in pancreatic β-cells under diabetes by reactivating the LDHA-lactate axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月2日

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  • Huige Lin,
  • Melody Yuen Man Ho,
  • Baomin Wang,
  • Shama Mansoori,
  • Yumei Yang,
  • Wen Wang,
  • Pui Kin So,
  • Aimin Xu,
  • Shilun Yang,
  • Junlei Chang,
  • Ada Man Hau Man,
  • Hailong Piao,
  • Chen Gao,
  • Parco Ming Fai Siu,
  • Xiaomu Li,
  • Kenneth King Yip Cheng

摘要

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.