title: Increased interaction with insulin receptor substrate 1, a novel abnormality in insulin resistance and type 2 diabetes.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy/Health Sciences, Wayne State University, Detroit, MI.
authors.forename: Michael
authors.initials: M
authors.lastname: Caruso
authors.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy/Health Sciences, Wayne State University, Detroit, MI.
authors.forename: Danjun
authors.initials: D
authors.lastname: Ma
authors.affiliation: Division of Endocrinology, Wayne State University School of Medicine, Wayne State University, Detroit, MI.
authors.forename: Zaher
authors.initials: Z
authors.lastname: Msallaty
authors.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy/Health Sciences, Wayne State University, Detroit, MI.
authors.forename: Monique
authors.initials: M
authors.lastname: Lewis
authors.affiliation: Division of Endocrinology, Wayne State University School of Medicine, Wayne State University, Detroit, MI.
authors.forename: Berhane
authors.initials: B
authors.lastname: Seyoum
authors.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy/Health Sciences, Wayne State University, Detroit, MI.
authors.forename: Wissam
authors.initials: W
authors.lastname: Al-janabi
authors.affiliation: Department of Obstetrics and Gynecology, Wayne State University, Detroit, MIDepartment of Obstetrics and Gynecology, Georgia Regents University, Augusta, GA.
authors.forename: Michael
authors.initials: M
authors.lastname: Diamond
authors.affiliation: Division of Endocrinology, Wayne State University School of Medicine, Wayne State University, Detroit, MIDepartment of Medicine, Hamad Medical Corporation, Doha, Qatar.
authors.forename: Abdul B
authors.initials: AB
authors.lastname: Abou-Samra
authors.affiliation: Diabetes Research Centre, Department of Endocrinology, Odense University Hospital, Odense, Denmark.
authors.forename: Kurt
authors.initials: K
authors.lastname: Højlund
authors.affiliation: Department of Computer Science, College of Engineering, Wayne State University, Detroit, MI.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Tagett
authors.affiliation: Department of Computer Science, College of Engineering, Wayne State University, Detroit, MI.
authors.forename: Sorin
authors.initials: S
authors.lastname: Draghici
authors.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy/Health Sciences, Wayne State University, Detroit, MI.
authors.forename: Xiangmin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: School of Kinesiology, University of Michigan, Ann Arbor, MI.
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Horowitz
authors.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy/Health Sciences, Wayne State University, Detroit, MI zhengping.yi@wayne.edu.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Yi
mesh_terms: D001786:Blood Glucose / Q000378:metabolism*; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin / Q000008:administration & dosage; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger; D012307:Risk Factors; D015398:Signal Transduction; D013851:Thinness / Q000235:genetics / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D012333:RNA, Messenger