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  • Perspective
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Liver insulinization as a driver of triglyceride dysmetabolism

Nature Metabolism volume 5, pages 1101–1110 (2023)Cite this article

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Abstract

Metabolic dysfunction-associated fatty liver disease (MAFLD) is an increasingly prevalent fellow traveller with the insulin resistance that underlies type 2 diabetes mellitus. However, the mechanistic connection between MAFLD and impaired insulin action remains unclear. In this Perspective, we review data from humans to elucidate insulin’s aetiological role in MAFLD. We focus particularly on the relative preservation of insulin’s stimulation of triglyceride (TG) biosynthesis despite its waning ability to curb hepatic glucose production (HGP). To explain this apparent ‘selective insulin resistance’, we propose that hepatocellular processes that lead to TG accumulation require less insulin signal transduction, or ‘insulinization,’ than do those that regulate HGP. As such, mounting hyperinsulinaemia that barely compensates for aberrant HGP in insulin-resistant states more than suffices to maintain hepatic TG biosynthesis. Thus, even modestly elevated or context-inappropriate insulin levels, when sustained day and night within a heavily pro-lipogenic metabolic milieu, may translate into substantial cumulative TG biosynthesis in the insulin-resistant state.

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Fig. 1: Insulin dose–response profiles.
Fig. 2: Insulinization requires a lipogenic milieu to provoke MAFLD.
Fig. 3: Insulinaemia and insulinization during the day.

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Acknowledgements

This work was supported by the National Institutes of Health (DK069861 to M.A.H., DK103818 to U.B.P.), the Columbia University Department of Medicine (career startup grant to J.R.C.), the Columbia Diabetes Research Center (2P30DK063608) and the Einstein–Mt. Sinai Diabetes Research Center (5P30DK020541).

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  1. Naomi Berrie Diabetes Center, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Columbia University College of Physicians & Surgeons, New York City, NY, USA

    Joshua R. Cook & Utpal B. Pajvani

  2. Diabetes Research and Training Center, Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, New York City, NY, USA

    Meredith A. Hawkins

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J.R.C. conceptualized the project, wrote the manuscript and prepared the figures. M.A.H. and U.B.P. critically reviewed and edited the manuscript and figures. All authors discussed the form and content of the manuscript.

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Cook, J.R., Hawkins, M.A. & Pajvani, U.B. Liver insulinization as a driver of triglyceride dysmetabolism. Nat Metab 5, 1101–1110 (2023). https://doi.org/10.1038/s42255-023-00843-6

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