2. Academic Validation
  3. The dynamic clustering of insulin receptor underlies its signaling and is disrupted in insulin resistance

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

  • Nat Commun. 2022 Dec 6;13(1):7522. doi: 10.1038/s41467-022-35176-7.
Alessandra Dall'Agnese # 1,  Jesse M Platt # 1 2,  Ming M Zheng 1 3,  Max Friesen 1,  Giuseppe Dall'Agnese 1 4,  Alyssa M Blaise 1,  Jessica B Spinelli 1,  Jonathan E Henninger 1,  Erin N Tevonian 5,  Nancy M Hannett 1,  Charalampos Lazaris 1,  Hannah K Drescher 2,  Lea M Bartsch 2,  Henry R Kilgore 1,  Rudolf Jaenisch 1 6,  Linda G Griffith 5 7 8,  Ibrahim I Cisse 3 6,  Jacob F Jeppesen 1 9,  Tong I Lee 10,  Richard A Young 11 12
Affiliations

Affiliations

  • 1 Whitehead Institute for Biomedical Research, Cambridge, MA, 02142, USA.
  • 2 Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
  • 3 Department of Physics, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
  • 4 Department of Medicine, University of Udine, Udine, 33100, Italy.
  • 5 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
  • 6 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
  • 7 Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 8 Center for Gynepathology Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 9 Global Drug Discovery, Novo Nordisk, Copenhagen, Denmark.
  • 10 Whitehead Institute for Biomedical Research, Cambridge, MA, 02142, USA. tlee@wi.mit.edu.
  • 11 Whitehead Institute for Biomedical Research, Cambridge, MA, 02142, USA. young@wi.mit.edu.
  • 12 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. young@wi.mit.edu.
  • # Contributed equally.
PMID: 36473871 DOI: 10.1038/s41467-022-35176-7
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.

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