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<p>Human stem cell-derived β (SC-β) cells still exhibit limited glucose response required for insulin secretion due to glycolytic bottlenecks, yet how these metabolic abnormalities impact glucose response and functional maturation of SC-β cells remains unclear. In this study, we identify a metabolic checkpoint located at PEP accumulation that impedes the functional maturation, which is rescued by restoration of pyruvate kinase M1 (<i>PKM1</i>). Glucose-tracing metabolomics in human stem cell-derived islets reveal abnormal glycolytic PEP accumulation at resting condition, associated with impaired calcium response and insulin secretion upon high glucose or glycolytic metabolite stimulation. Mechanistically, elevated PEP significantly raises intracellular basal calcium levels and downregulates expression of genes involved in TCA cycle as elucidated by single cell transcriptomics. Furthermore, the activity of pyruvate kinase, which metabolizes PEP, is notably reduced due to low <i>PKM1</i> expression. Overexpression of <i>PKM1</i> alleviates PEP accumulation, restores TCA-related gene expression, and enhances glucose-stimulated calcium responses and insulin secretion. Together, our findings reveal a critical role of PKM1-regulated PEP metabolism in SC-β cell functional maturation and highlight the importance of metabolic reprogramming for advancing stem cell-based therapies for diabetes.</p>

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Restoration of PKM1 improves functional maturation of human stem-cell derived-β cell by regulating PEP metabolism

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月21日

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  • Haopeng Lin,
  • Xin Liu,
  • Feng Zhang,
  • Deqi Chen,
  • Xiaoxiao Xie,
  • Qifei Dong,
  • Jiawei Yan,
  • Jiaxiang Yin,
  • Zirong Bi,
  • Zhihua Dou,
  • Yingling Jiang,
  • Kuo Jiang,
  • Tongran Zhang,
  • Peng Xue,
  • Wei Peng,
  • Lihua Chen,
  • Tao Xu,
  • Zonghong Li,
  • Yanying Guo,
  • Huisheng Liu

摘要

Human stem cell-derived β (SC-β) cells still exhibit limited glucose response required for insulin secretion due to glycolytic bottlenecks, yet how these metabolic abnormalities impact glucose response and functional maturation of SC-β cells remains unclear. In this study, we identify a metabolic checkpoint located at PEP accumulation that impedes the functional maturation, which is rescued by restoration of pyruvate kinase M1 (PKM1). Glucose-tracing metabolomics in human stem cell-derived islets reveal abnormal glycolytic PEP accumulation at resting condition, associated with impaired calcium response and insulin secretion upon high glucose or glycolytic metabolite stimulation. Mechanistically, elevated PEP significantly raises intracellular basal calcium levels and downregulates expression of genes involved in TCA cycle as elucidated by single cell transcriptomics. Furthermore, the activity of pyruvate kinase, which metabolizes PEP, is notably reduced due to low PKM1 expression. Overexpression of PKM1 alleviates PEP accumulation, restores TCA-related gene expression, and enhances glucose-stimulated calcium responses and insulin secretion. Together, our findings reveal a critical role of PKM1-regulated PEP metabolism in SC-β cell functional maturation and highlight the importance of metabolic reprogramming for advancing stem cell-based therapies for diabetes.