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The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes

Nature volume 510, pages 84–91 (2014)Cite this article

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Abstract

Non-alcoholic fatty liver disease and its downstream sequelae, hepatic insulin resistance and type 2 diabetes, are rapidly growing epidemics, which lead to increased morbidity and mortality rates, and soaring health-care costs. Developing interventions requires a comprehensive understanding of the mechanisms by which excess hepatic lipid develops and causes hepatic insulin resistance and type 2 diabetes. Proposed mechanisms implicate various lipid species, inflammatory signalling and other cellular modifications. Studies in mice and humans have elucidated a key role for hepatic diacylglycerol activation of protein kinase Cε in triggering hepatic insulin resistance. Therapeutic approaches based on this mechanism could alleviate the related epidemics of non-alcoholic fatty liver disease and type 2 diabetes.

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Figure 1: Molecular mechanism by which excess diacylglycerol leads to hepatic insulin resistance and hyperglycaemia.
Figure 2: NAFLD develops due to an imbalance between lipid supply and demand.
Figure 3: Mechanism by which selective skeletal muscle insulin resistance contributes to hepatic insulin resistance.

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Authors and Affiliations

  1. Department of Internal Medicine, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Rachel J. Perry, Varman T. Samuel, Kitt F. Petersen & Gerald I. Shulman

  2. VA Connecticut Healthcare System West Haven, 06516, Connecticut, USA

    Varman T. Samuel

  3. Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK-2200, Denmark

    Kitt F. Petersen & Gerald I. Shulman

  4. Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Gerald I. Shulman

  5. Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, 06535-8012, Connecticut, USA

    Gerald I. Shulman

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  1. Rachel J. Perry
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  2. Varman T. Samuel
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  3. Kitt F. Petersen
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  4. Gerald I. Shulman
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Correspondence to Gerald I. Shulman.

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Perry, R., Samuel, V., Petersen, K. et al. The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature 510, 84–91 (2014). https://doi.org/10.1038/nature13478

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