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

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, Charalampos Lazaris, Hannah K. Drescher, Lea M. Bartsch, Henry R. Kilgore, Rudolf Jaenisch, Linda G. Griffith, Ibrahim I. Cisse, Jacob F. Jeppesen, Tong I. Lee () and Richard A. Young ()
Additional contact information
Alessandra Dall’Agnese: Whitehead Institute for Biomedical Research
Jesse M. Platt: Whitehead Institute for Biomedical Research
Ming M. Zheng: Whitehead Institute for Biomedical Research
Max Friesen: Whitehead Institute for Biomedical Research
Giuseppe Dall’Agnese: Whitehead Institute for Biomedical Research
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
Linda G. Griffith: Massachusetts Institute of Technology
Ibrahim I. Cisse: Massachusetts Institute of Technology
Jacob F. Jeppesen: Whitehead Institute for Biomedical Research
Tong I. Lee: Whitehead Institute for Biomedical Research
Richard A. Young: Whitehead Institute for Biomedical Research

Nature Communications, 2022, vol. 13, issue 1, 1-22

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-35176-7

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