Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 Diabetes

Authors

  • Andreas L. Birkenfeld,

    Corresponding author
    1. Charité-University School of Medicine, Department of Endocrinology Diabetes and Nutrition, Center for Cardiovascular Research, Berlin, Germany
    2. Howard Hughes Medical Institute and the Departments of Internal Medicine and Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT
    • Address reprint requests to: Gerald I. Shulman, M.D., Ph.D., Howard Hughes Medical Institute and the Departments of Internal Medicine and Cellular & Molecular Physiology, Yale University School of Medicine, P.O. Box 9812, New Haven, CT. E-mail: gerald.shulman@yale.edu; fax: 203-737-4059; or Andreas Birkenfeld, M.D., E-mail: andreas.birkenfeld@charite.de.

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  • Gerald I. Shulman

    Corresponding author
    1. Howard Hughes Medical Institute and the Departments of Internal Medicine and Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT
    2. Novo-Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
    • Address reprint requests to: Gerald I. Shulman, M.D., Ph.D., Howard Hughes Medical Institute and the Departments of Internal Medicine and Cellular & Molecular Physiology, Yale University School of Medicine, P.O. Box 9812, New Haven, CT. E-mail: gerald.shulman@yale.edu; fax: 203-737-4059; or Andreas Birkenfeld, M.D., E-mail: andreas.birkenfeld@charite.de.

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  • Potential conflict of interest: Nothing to report.

  • This work was supported by grants from the U.S. Public Health Service (R24 DK-085638, R01 DK-40936, DK-49230, U24 DK-059635, P30 DK-45735, and P30 DK-034989) and grants from the German Research Foundation (DFG; Bl1292/4-1 and BI1292/5-1) and the Fritz-Thyssen-Foundation (Az 10.12.2.140) and grants from the NIH.

Abstract

Nonalcoholic fatty liver disease (NAFLD), hepatic insulin resistance, and type 2 diabetes are all strongly associated and are all reaching epidemic proportions. Whether there is a causal link between NAFLD and hepatic insulin resistance is controversial. This review will discuss recent studies in both humans and animal models of NAFLD that have implicated increases in hepatic diacylglycerol (DAG) content leading to activation of novel protein kinase Cϵ (PKCϵ) resulting in decreased insulin signaling in the pathogenesis of NAFLD-associated hepatic insulin resistance and type 2 diabetes. The DAG-PKCϵ hypothesis can explain the occurrence of hepatic insulin resistance observed in most cases of NAFLD associated with obesity, lipodystrophy, and type 2 diabetes. (Hepatology 2014;59:713-723)

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