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Severe insulin resistance syndromes
Angeliki M. Angelidi, … , Andreas Filippaios, Christos S. Mantzoros
Angeliki M. Angelidi, … , Andreas Filippaios, Christos S. Mantzoros
Published February 15, 2021
Citation Information: J Clin Invest. 2021;131(4):e142245. https://doi.org/10.1172/JCI142245.
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Review Series Article has an altmetric score of 36

Severe insulin resistance syndromes

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Abstract

Severe insulin resistance syndromes are a heterogeneous group of rare disorders characterized by profound insulin resistance, substantial metabolic abnormalities, and a variety of clinical manifestations and complications. The etiology of these syndromes may be hereditary or acquired, due to defects in insulin potency and action, cellular responsiveness to insulin, and/or aberrations in adipose tissue function or development. Over the past decades, advances in medical technology, particularly in genomic technologies and genetic analyses, have provided insights into the underlying pathophysiological pathways and facilitated the more precise identification of several of these conditions. However, the exact cellular and molecular mechanisms of insulin resistance have not yet been fully elucidated for all syndromes. Moreover, in clinical practice, many of the syndromes are often misdiagnosed or underdiagnosed. The majority of these disorders associate with an increased risk of severe complications and mortality; thus, early identification and personalized clinical management are of the essence. This Review aims to categorize severe insulin resistance syndromes by disease process, including insulin receptor defects, signaling defects, and lipodystrophies. We also highlight several complex syndromes and emphasize the need to identify patients, investigate underlying disease mechanisms, and develop specific treatment regimens.

Authors

Angeliki M. Angelidi, Andreas Filippaios, Christos S. Mantzoros

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Figure 1

Insulin and IGF-1 signaling pathways intersect.

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Insulin and IGF-1 signaling pathways intersect.
Insulin receptor and IGF...
Insulin receptor and IGF-1 receptor activation initiates a cascade of phosphorylation events. At the time of ligand binding the receptors change conformation and autophosphorylate, leading to the recruitment and phosphorylation of receptor substrates, such as IRS and Shc proteins. Shc activates the Ras/MAPK pathway, whereas IRS protein recruits PI3K to activate the PI3K/AKT pathway, leading to the generation of the second messenger PIP3. Membrane-bound PIP3 then recruits and activates PDK1, which phosphorylates and activates AKT and atypical PKCs (aPKC). AKT mediates most of insulin’s metabolic effects and regulates the cell cycle and cell survival. The Shc/Grb2/SOS/Ras/Raf/MAPK pathway controls cellular proliferation and gene transcription.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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