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The dynamic clustering of insulin receptor underlies its signaling and is disrupted in insulin resistance

Author

Listed:
  • Alessandra Dall’Agnese

    (Whitehead Institute for Biomedical Research)

  • Jesse M. Platt

    (Whitehead Institute for Biomedical Research
    Massachusetts General Hospital)

  • Ming M. Zheng

    (Whitehead Institute for Biomedical Research
    Massachusetts Institute of Technology)

  • Max Friesen

    (Whitehead Institute for Biomedical Research)

  • Giuseppe Dall’Agnese

    (Whitehead Institute for Biomedical Research
    University of Udine)

  • Alyssa M. Blaise

    (Whitehead Institute for Biomedical Research)

  • Jessica B. Spinelli

    (Whitehead Institute for Biomedical Research)

  • Jonathan E. Henninger

    (Whitehead Institute for Biomedical Research)

  • Erin N. Tevonian

    (Massachusetts Institute of Technology)

  • Nancy M. Hannett

    (Whitehead Institute for Biomedical Research)

  • Charalampos Lazaris

    (Whitehead Institute for Biomedical Research)

  • Hannah K. Drescher

    (Massachusetts General Hospital)

  • Lea M. Bartsch

    (Massachusetts General Hospital)

  • Henry R. Kilgore

    (Whitehead Institute for Biomedical Research)

  • Rudolf Jaenisch

    (Whitehead Institute for Biomedical Research
    Massachusetts Institute of Technology)

  • Linda G. Griffith

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Ibrahim I. Cisse

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Jacob F. Jeppesen

    (Whitehead Institute for Biomedical Research
    Global Drug Discovery, Novo Nordisk)

  • Tong I. Lee

    (Whitehead Institute for Biomedical Research)

  • Richard A. Young

    (Whitehead Institute for Biomedical Research
    Massachusetts Institute of Technology)

Abstract

Insulin receptor (IR) signaling is central to normal metabolic control and is dysregulated in metabolic diseases such as type 2 diabetes. We report here that IR is incorporated into dynamic clusters at the plasma membrane, in the cytoplasm and in the nucleus of human hepatocytes and adipocytes. Insulin stimulation promotes further incorporation of IR into these dynamic clusters in insulin-sensitive cells but not in insulin-resistant cells, where both IR accumulation and dynamic behavior are reduced. Treatment of insulin-resistant cells with metformin, a first-line drug used to treat type 2 diabetes, can rescue IR accumulation and the dynamic behavior of these clusters. This rescue is associated with metformin’s role in reducing reactive oxygen species that interfere with normal dynamics. These results indicate that changes in the physico-mechanical features of IR clusters contribute to insulin resistance and have implications for improved therapeutic approaches.

Suggested Citation

  • Alessandra Dall’Agnese & Jesse M. Platt & Ming M. Zheng & Max Friesen & Giuseppe Dall’Agnese & Alyssa M. Blaise & Jessica B. Spinelli & Jonathan E. Henninger & Erin N. Tevonian & Nancy M. Hannett & Ch, 2022. "The dynamic clustering of insulin receptor underlies its signaling and is disrupted in insulin resistance," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35176-7
    DOI: 10.1038/s41467-022-35176-7
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    References listed on IDEAS

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    1. Yu-San Huoh & Bin Wu & Sehoon Park & Darren Yang & Kushagra Bansal & Emily Greenwald & Wesley P. Wong & Diane Mathis & Sun Hur, 2020. "Dual functions of Aire CARD multimerization in the transcriptional regulation of T cell tolerance," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    2. Javier Emperador-Melero & Man Yan Wong & Shan Shan H. Wang & Giovanni de Nola & Hajnalka Nyitrai & Tom Kirchhausen & Pascal S. Kaeser, 2021. "PKC-phosphorylation of Liprin-α3 triggers phase separation and controls presynaptic active zone structure," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    3. Anila K. Madiraju & Derek M. Erion & Yasmeen Rahimi & Xian-Man Zhang & Demetrios T. Braddock & Ronald A. Albright & Brett J. Prigaro & John L. Wood & Sanjay Bhanot & Michael J. MacDonald & Michael J. , 2014. "Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase," Nature, Nature, vol. 510(7506), pages 542-546, June.
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