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

Ligia Akemi Kiyuna; Kishore Alagere Krishnamurthy; Esther B. Homan; Miriam Langelaar-Makkinje; Albert Gerding; Trijnie Bos; Dorenda Oosterhuis; Ruben J. Overduin; Andrea B. Schreuder; Vincent E. de Meijer; Peter Olinga; Terry G.J. Derks; Karen van Eunen; Barbara M. Bakker; Maaike H. Oosterveer

doi:10.1038/s42003-024-07070-z

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

Ligia Akemi Kiyuna, Kishore Alagere Krishnamurthy, Esther B. Homan, Miriam Langelaar-Makkinje, Albert Gerding, Trijnie Bos, Dorenda Oosterhuis, Ruben J. Overduin, Andrea B. Schreuder, Vincent E. de Meijer, Peter Olinga, Terry G.J. Derks, Karen van Eunen, Barbara M. Bakker, Maaike H. Oosterveer

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

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 13C 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.

Original language	English
Article number	1479
Pages (from-to)	1-13
Number of pages	13
Journal	Communications biology
Volume	7
Early online date	9 Nov 2024
DOIs	https://doi.org/10.1038/s42003-024-07070-z
Publication status	Published - 2024

Bibliographical note

Publisher Copyright:
© 2024. The Author(s).

Funding

This project is supported by European Union\u2019s Horizon 2020 research and innovation program under the Marie Sk\u0142odowska-Curie Actions PoLiMeR Innovative Training Network (Grant Agreement No 812616) and a grant from Stichting De Cock\u2013Hadders. E.B.H. is funded by the University Medical Center Groningen. We thank Mitchel Ruigrok, Yvette Jansen and Hermien Hartog for excellent technical assistance and Sanofi for kindly providing S4048.

Funders	Funder number
Horizon 2020 Framework Programme
Universitair Medisch Centrum Groningen
Stichting De Cock-Hadders
Marie Skłodowska-Curie Actions PoLiMeR Innovative Training Network	812616

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Kiyuna, L. A., Krishnamurthy, K. A., Homan, E. B., Langelaar-Makkinje, M., Gerding, A., Bos, T., Oosterhuis, D., Overduin, R. J., Schreuder, A. B., de Meijer, V. E., Olinga, P., Derks, T. G. J., van Eunen, K., Bakker, B. M., & Oosterveer, M. H. (2024). Precision-cut liver slices as an ex vivo model to assess impaired hepatic glucose production. Communications biology, 7, 1-13. Article 1479. https://doi.org/10.1038/s42003-024-07070-z

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abstract = "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 13C 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.",

author = "Kiyuna, {Ligia Akemi} and Krishnamurthy, {Kishore Alagere} and Homan, {Esther B.} and Miriam Langelaar-Makkinje and Albert Gerding and Trijnie Bos and Dorenda Oosterhuis and Overduin, {Ruben J.} and Schreuder, {Andrea B.} and {de Meijer}, {Vincent E.} and Peter Olinga and Derks, {Terry G.J.} and {van Eunen}, Karen and Bakker, {Barbara M.} and Oosterveer, {Maaike H.}",

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Kiyuna, LA, Krishnamurthy, KA, Homan, EB, Langelaar-Makkinje, M, Gerding, A, Bos, T, Oosterhuis, D, Overduin, RJ, Schreuder, AB, de Meijer, VE, Olinga, P, Derks, TGJ, van Eunen, K, Bakker, BM & Oosterveer, MH 2024, 'Precision-cut liver slices as an ex vivo model to assess impaired hepatic glucose production', Communications biology, vol. 7, 1479, pp. 1-13. https://doi.org/10.1038/s42003-024-07070-z

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T1 - Precision-cut liver slices as an ex vivo model to assess impaired hepatic glucose production

AU - Kiyuna, Ligia Akemi

AU - Krishnamurthy, Kishore Alagere

AU - Homan, Esther B.

AU - Langelaar-Makkinje, Miriam

AU - Gerding, Albert

AU - Bos, Trijnie

AU - Oosterhuis, Dorenda

AU - Overduin, Ruben J.

AU - Schreuder, Andrea B.

AU - de Meijer, Vincent E.

AU - Olinga, Peter

AU - Derks, Terry G.J.

AU - van Eunen, Karen

AU - Bakker, Barbara M.

AU - Oosterveer, Maaike H.

PY - 2024

Y1 - 2024

N2 - 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 13C 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.

AB - 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 13C 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.

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

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