Increased Interaction With Insulin Receptor Substrate 1, a Novel Abnormality in Insulin Resistance and Type 2 Diabetes

  1. Zhengping Yi1
  1. 1Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy/Health Sciences, Wayne State University, Detroit, MI
  2. 2Division of Endocrinology, Wayne State University School of Medicine, Wayne State University, Detroit, MI
  3. 3Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI
  4. 4Department of Obstetrics and Gynecology, Georgia Regents University, Augusta, GA
  5. 5Department of Medicine, Hamad Medical Corporation, Doha, Qatar
  6. 6Diabetes Research Centre, Department of Endocrinology, Odense University Hospital, Odense, Denmark
  7. 7Department of Computer Science, College of Engineering, Wayne State University, Detroit, MI
  8. 8School of Kinesiology, University of Michigan, Ann Arbor, MI
  1. Corresponding author: Zhengping Yi, zhengping.yi{at}
  1. M.C. and D.M. contributed equally to this work.


Insulin receptor substrate 1 (IRS1) is a key mediator of insulin signal transduction. Perturbations involving IRS1 complexes may lead to the development of insulin resistance and type 2 diabetes (T2D). Surprisingly little is known about the proteins that interact with IRS1 in humans under health and disease conditions. We used a proteomic approach to assess IRS1 interaction partners in skeletal muscle from lean healthy control subjects (LCs), obese insulin-resistant nondiabetic control subjects (OCs), and participants with T2D before and after insulin infusion. We identified 113 novel endogenous IRS1 interaction partners, which represents the largest IRS1 interactome in humans and provides new targets for studies of IRS1 complexes in various diseases. Furthermore, we generated the first global picture of IRS1 interaction partners in LCs, and how they differ in OCs and T2D patients. Interestingly, dozens of proteins in OCs and/or T2D patients exhibited increased associations with IRS1 compared with LCs under the basal and/or insulin-stimulated conditions, revealing multiple new dysfunctional IRS1 pathways in OCs and T2D patients. This novel abnormality, increased interaction of multiple proteins with IRS1 in obesity and T2D in humans, provides new insights into the molecular mechanism of insulin resistance and identifies new targets for T2D drug development.


  • Received December 12, 2013.
  • Accepted February 18, 2014.

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  1. Diabetes vol. 63 no. 6 1933-1947
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