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Fat-Induced Insulin Resistance and Atherosclerosis

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Principles of Molecular Medicine

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Abstract

Physiological elevations of plasma free fatty acid (FFA) levels cause peripheral (muscle), hepatic, and vascular insulin resistance, whereas lowering of plasma FFA levels improves peripheral insulin sensitivity in diabetic and nondiabetic subjects. FFA-induced insulin resistance in muscle is produced by defects in insulin-stimulated glucose transport and/or phosphorylation and in glycogen synthesis, which develop over 2–6 h. Development of these defects is temporally associated with accumulation in liver and in muscle cells of diacylglycerol (DAG) and activation of serine/threonine kinases including protein kinase C (PKC) and inhibitor of κB-kinase. In nondiabetic, obese subjects, FFA-induced insulin resistance is fully or nearly fully compensated by FFA-mediated stimulation of insulin secretion. In patients with type 2 diabetes mellitus (T2DM), FFA-mediated stimulation of insulin secretion is impaired; hence, FFA-induced insulin resistance needs to be compensated by hype glycemia. Acute elevation of plasma FFA levels also activate the proinflammatory and proatherosclerotic inhibitor of κB/nuclear factor κB pathway in muscle and liver and this might play a role in the pathogenesis of atherosclerotic vascular disease and nonalcoholic fatty liver disease. Normalizing plasma FFA levels is, therefore, proposed as an approach to reduce insulin resistance and the risk for type 2 diabetes, atherosclerotic vascular diseases and nonalcoholic fatty liver disease.

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Authors and Affiliations

  1. Department of Medicine, Section of Metabolism, Diabetes and Endocrinology, Temple University Hospital, Philadelphia, PA

    Guenther Boden

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  1. Guenther Boden
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Editors and Affiliations

  1. Department of Medicine, Division of Cardiology Carolina Cardiovascular Biology Center, University of North Carolina School of Medicine, Chapel Hill, NC

    Marschall S. Runge MD, PhD  & Cam Patterson MD  & 

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© 2006 Humana Press Inc.

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Boden, G. (2006). Fat-Induced Insulin Resistance and Atherosclerosis. In: Runge, M.S., Patterson, C. (eds) Principles of Molecular Medicine. Humana Press. https://doi.org/10.1007/978-1-59259-963-9_49

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  • DOI: https://doi.org/10.1007/978-1-59259-963-9_49

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-202-5

  • Online ISBN: 978-1-59259-963-9

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