Precision-cut liver slices as an ex vivo model to assess impaired hepatic glucose production

• Published in: Communications biology 2024-11, Vol.7 (1), p.1479-13, Article 1479
• Main Authors: Kiyuna, Ligia Akemi, Krishnamurthy, Kishore Alagere, Homan, Esther B., Langelaar-Makkinje, Miriam, Gerding, Albert, Bos, Trijnie, Oosterhuis, Dorenda, Overduin, Ruben J., Schreuder, Andrea B., de Meijer, Vincent E., Olinga, Peter, Derks, Terry G. J., van Eunen, Karen, Bakker, Barbara M., Oosterveer, Maaike H.
• Format: Article
• Language: English
• Subjects: 13; 13/106; 38/1; 631/1647/767; 631/443/319/1642; 64/60; 692/308/575; 692/4020/2741/288; 692/4020/4021/1607; 82/80; Adult; Animals; Biomedical and Life Sciences; Dihydroxyacetone; Female; Forskolin; Gluconeogenesis; Glucose; Glucose - metabolism; Glucose transporter; Glycogen; Glycogen Storage Disease Type I - metabolism; Humans; Hypoglycemia; Inborn errors of metabolism; Life Sciences; Liver - metabolism; Liver diseases; Male; Metabolism; Mice; Mice, Inbred C57BL; Phosphate transporter; Storage diseases
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-024-07070-z

Fasting hypoglycemia is a severe and incompletely understood symptom of various inborn errors of metabolism (IEM). Precision-cut liver slices (PCLS) represent a promising model for studying glucose production ex vivo. This study quantified the net glucose production of human and murine PCLS in the presence of different gluconeogenic precursors. Dihydroxyacetone-supplemented slices from the fed mice yielded the highest rate, further stimulated by forskolin and dibutyryl-cAMP. Moreover, using 13 C isotope tracing, we assessed the contribution of glycogenolysis and gluconeogenesis to net glucose production over time. Pharmacological inhibition of the glucose 6-phosphate transporter SLC37A4 markedly reduced net glucose production and increased lactate secretion and glycogen storage, while glucose production was completely abolished in PCLS from glycogen storage disease type Ia and Ib patients. In conclusion, this study identifies PCLS as an effective ex vivo model to study hepatic glucose production and opens opportunities for its future application in IEM research and beyond. Ex vivo precision-cut liver slices allow glucose production quantification to model glycogen storage disease and inborn errors of metabolism.