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

ABSTRACT: 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 expressi

SUBMITTER: Lin H 

PROVIDER: S-EPMC12830896 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature