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  • Review Article
  • Published:

Hepatic glucose metabolism in the steatotic liver

Nature Reviews Gastroenterology & Hepatology volume 21, pages 319–334 (2024)Cite this article

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Abstract

The liver is central in regulating glucose homeostasis, being the major contributor to endogenous glucose production and the greatest reserve of glucose as glycogen. It is both a target and regulator of the action of glucoregulatory hormones. Hepatic metabolic functions are altered in and contribute to the highly prevalent steatotic liver disease (SLD), including metabolic dysfunction-associated SLD (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). In this Review, we describe the dysregulation of hepatic glucose metabolism in MASLD and MASH and associated metabolic comorbidities, and how advances in techniques and models for the assessment of hepatic glucose fluxes in vivo have led to the identification of the mechanisms related to the alterations in glucose metabolism in MASLD and comorbidities. These fluxes can ultimately increase hepatic glucose production concomitantly with fat accumulation and alterations in the secretion and action of glucoregulatory hormones. No pharmacological treatment has yet been approved for MASLD or MASH, but some antihyperglycaemic drugs approved for treating type 2 diabetes have shown positive effects on hepatic glucose metabolism and hepatosteatosis. A deep understanding of how MASLD affects glucose metabolic fluxes and glucoregulatory hormones might assist in the early identification of at-risk individuals and the use or development of targeted therapies.

Key points

  • Hepatic glucose metabolism can be studied by measuring metabolite fluxes (fluxomics) based on in vivo infusion of non-radioactive labelled compounds and using metabolic mathematical modelling.

  • The liver is the major contributor to endogenous glucose production via gluconeogenesis and glycogenolysis, and is the greatest reserve of glucose as glycogen.

  • Hepatic glucose metabolism is mainly regulated by glucoregulatory hormones, including insulin and glucagon and by substrate availability.

  • Hepatic extraction and clearance of insulin modulates peripheral insulin action and has a role in hyperinsulinaemia in steatotic liver disease.

  • Abnormal increase in gluconeogenesis and impaired glycogen metabolism are observed in steatotic liver disease and related metabolic conditions such as obesity and type 2 diabetes.

  • Hepatic and peripheral insulin resistance and hyperglucagonaemia contribute to altered glucose metabolism and the pathogenesis of steatotic liver disease.

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Fig. 1: Overview of the techniques currently used to investigate glucose fluxes in humans.
Fig. 2: The role of insulin resistance in altered glucose metabolism in steatotic liver disease.
Fig. 3: Overview of glucose metabolic pathways in the hepatocyte.

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Acknowledgements

A.G. acknowledges the financial support from the European Union’s Horizon 2020 Research and Innovation Programme (IMI) for the projects LITMUS (grant no. 777377) and SOPHIA (grant no. 875534) and Horizon Europe project PAS GRAS (grant no. 101080329). This communication reflects the author’s views. Neither IMI nor the European Union, EFPIA, or any associated partners are responsible for any use that may be made of the information contained herein.

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  1. Institute of Clinical Physiology, National Research Council, Lecce, Italy

    Egeria Scoditti

  2. Institute of Clinical Physiology, National Research Council, Pisa, Italy

    Silvia Sabatini, Fabrizia Carli & Amalia Gastaldelli

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A.G. has served as a consultant for Boehringer Ingelheim, Eli Lilly and Company, Metadeq Diagnostics and Fractyl Health; has participated on advisory boards for Boehringer Ingelheim, Merck Sharp & Dohme, Novo Nordisk, Metadeq Diagnostics and Pfizer; and has received speaker’s honoraria and other fees from Eli Lilly and Company, Merck Sharp & Dohme, Novo Nordisk and Pfizer. The other authors declare no competing interests.

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Scoditti, E., Sabatini, S., Carli, F. et al. Hepatic glucose metabolism in the steatotic liver. Nat Rev Gastroenterol Hepatol 21, 319–334 (2024). https://doi.org/10.1038/s41575-023-00888-8

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