title: A single mechanism can explain network-wide insulin resistance in adipocytes from obese patients with type 2 diabetes.
abstract: The response to insulin is impaired in type 2 diabetes. Much information is available about insulin signaling, but understanding of the cellular mechanisms causing impaired signaling and insulin resistance is hampered by fragmented data, mainly obtained from different cell lines and animals. We have collected quantitative and systems-wide dynamic data on insulin signaling in primary adipocytes and compared cells isolated from healthy and diabetic individuals. Mathematical modeling and experimental verification identified mechanisms of insulin control of the MAPKs ERK1/2. We found that in human adipocytes, insulin stimulates phosphorylation of the ribosomal protein S6 and hence protein synthesis about equally via ERK1/2 and mTORC1. Using mathematical modeling, we examined the signaling network as a whole and show that a single mechanism can explain the insulin resistance of type 2 diabetes throughout the network, involving signaling both through IRS1, PKB, and mTOR and via ERK1/2 to the nuclear transcription factor Elk1. The most important part of the insulin resistance mechanism is an attenuated feedback from the protein kinase mTORC1 to IRS1, which spreads signal attenuation to all parts of the insulin signaling network. Experimental inhibition of mTORC1 using rapamycin in adipocytes from non-diabetic individuals induced and thus confirmed the predicted network-wide insulin resistance.
authors.affiliation: From the Department of Clinical and Experimental Medicine and.
authors.forename: Elin
authors.initials: E
authors.lastname: Nyman
authors.affiliation: From the Department of Clinical and Experimental Medicine and.
authors.forename: Meenu Rohini
authors.initials: MR
authors.lastname: Rajan
authors.affiliation: From the Department of Clinical and Experimental Medicine and.
authors.forename: Siri
authors.initials: S
authors.lastname: Fagerholm
authors.affiliation: From the Department of Clinical and Experimental Medicine and.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Brännmark
authors.affiliation: From the Department of Clinical and Experimental Medicine and the Department of Biomedical Engineering, Linköping University, SE58185 Linköping, Sweden.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Cedersund
authors.affiliation: From the Department of Clinical and Experimental Medicine and peter.stralfors@liu.se.
authors.forename: Peter
authors.initials: P
authors.lastname: Strålfors
mesh_terms: D017667:Adipocytes / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D048909:Diabetes Complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D020935:MAP Kinase Signaling System; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: Adipocyte; Elk1; Extracellular Signal-regulated Kinase (ERK); Human; Insulin Resistance; MAPK; Mathematical Modeling; Protein Phosphorylation; Signal Transduction; Type 2 Diabetes