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

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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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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