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Molecular Mechanisms of Insulin Resistance

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Insulin Resistance

Part of the book series: Contemporary Endocrinology ((COE))

Abstract

Initial attempts to unravel the molecular mechanism of insulin resistance have strongly suggested that a defect responsible for insulin resistance in the majority of patients lies at the post-receptor level of insulin signaling. Subsequent studies in insulin-resistant animal models and humans have consistently demonstrated a reduced strength of insulin signaling via the IRS-1–PI 3-kinase pathway, resulting in diminished glucose uptake and utilization in insulin target tissues. However, the nature of the triggering event(s) remains largely enigmatic. Two separate, but likely complementary, mechanisms have recently emerged as a potential explanation. First, it became apparent that serine phosphorylation of IRS proteins can reduce their ability to attract PI 3-kinase, thereby minimizing its activation. A number of serine kinases that phosphorylate serine residues of IRS-1 and weaken insulin signal transduction have been identified. Additionally, mitochondrial dysfunction has been suggested to trigger activation of several serine kinases, leading to a serine phosphorylation of IRS-1. Second, a distinct mechanism involving increased expression of p85α(alpha) has also been found to play an important role in the pathogenesis of insulin resistance. Conceivably, a combination of both increased expression of p85α(alpha) and increased serine phosphorylation of IRS-1is needed to induce clinically apparent insulin resistance.

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  1. Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado, Aurora, CO, USA

    Boris Draznin

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  1. Section of Pediatric Endocrinology, Children’s Hospital Colorado, Aurora, CO, USA

    Philip S. Zeitler

  2. Department of Pediatrics, Children’s Hospital Colorado, Aurora, CO, USA

    Kristen J. Nadeau

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Draznin, B. (2020). Molecular Mechanisms of Insulin Resistance. In: Zeitler, P., Nadeau, K. (eds) Insulin Resistance. Contemporary Endocrinology. Humana, Cham. https://doi.org/10.1007/978-3-030-25057-7_4

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