title: A novel regulation of IRS1 (insulin receptor substrate-1) expression following short term insulin administration.
abstract: Reduced insulin-mediated glucose transport in skeletal muscle is a hallmark of the pathophysiology of T2DM (Type II diabetes mellitus). Impaired intracellular insulin signalling is implicated as a key underlying mechanism. Attention has focused on early signalling events such as defective tyrosine phosphorylation of IRS1 (insulin receptor substrate-1), a major target for the insulin receptor tyrosine kinase. This is required for normal induction of signalling pathways key to many of the metabolic actions of insulin. Conversely, increased serine/threonine phosphorylation of IRS1 following prolonged insulin exposure (or in obesity) reduces signalling capacity, partly by stimulating IRS1 degradation. We now show that IRS1 levels in human muscle are actually increased 3-fold following 1 h of hyperinsulinaemic euglycaemia. Similarly, transient induction of IRS1 (3-fold) in the liver or muscle of rodents occurs following feeding or insulin injection respectively. The induction by insulin is also observed in cell culture systems, although to a lesser degree, and is not due to reduced proteasomal targeting, increased protein synthesis or gene transcription. Elucidation of the mechanism by which insulin promotes IRS1 stability will permit characterization of the importance of this novel signalling event in insulin regulation of liver and muscle function. Impairment of this process would reduce IRS1 signalling capacity, thereby contributing to the development of hyperinsulinaemia/insulin resistance prior to the appearance of T2DM.
authors.affiliation: Division of Pathology and Neurosciences, University of Dundee, Dundee DD1 9SY, Scotland, UK.
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Ruiz-Alcaraz
authors.forename: Hui-Kang
authors.initials: HK
authors.lastname: Liu
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Cuthbertson
authors.forename: Edward J
authors.initials: EJ
authors.lastname: McManus
authors.forename: Simeen
authors.initials: S
authors.lastname: Akhtar
authors.forename: Christopher
authors.initials: C
authors.lastname: Lipina
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Morris
authors.forename: John R
authors.initials: JR
authors.lastname: Petrie
authors.forename: Hari S
authors.initials: HS
authors.lastname: Hundal
authors.forename: Calum
authors.initials: C
authors.lastname: Sutherland
mesh_terms: D000328:Adult; D000818:Animals; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D015854:Up-Regulation
chemical_list: C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases