title: Insulin signaling in type 2 diabetes: experimental and modeling analyses reveal mechanisms of insulin resistance in human adipocytes.
abstract: Type 2 diabetes originates in an expanding adipose tissue that for unknown reasons becomes insulin resistant. Insulin resistance reflects impairments in insulin signaling, but mechanisms involved are unclear because current research is fragmented. We report a systems level mechanistic understanding of insulin resistance, using systems wide and internally consistent data from human adipocytes. Based on quantitative steady-state and dynamic time course data on signaling intermediaries, normally and in diabetes, we developed a dynamic mathematical model of insulin signaling. The model structure and parameters are identical in the normal and diabetic states of the model, except for three parameters that change in diabetes: (i) reduced concentration of insulin receptor, (ii) reduced concentration of insulin-regulated glucose transporter GLUT4, and (iii) changed feedback from mammalian target of rapamycin in complex with raptor (mTORC1). Modeling reveals that at the core of insulin resistance in human adipocytes is attenuation of a positive feedback from mTORC1 to the insulin receptor substrate-1, which explains reduced sensitivity and signal strength throughout the signaling network. Model simulations with inhibition of mTORC1 are comparable with experimental data on inhibition of mTORC1 using rapamycin in human adipocytes. We demonstrate the potential of the model for identification of drug targets, e.g. increasing the feedback restores insulin signaling, both at the cellular level and, using a multilevel model, at the whole body level. Our findings suggest that insulin resistance in an expanded adipose tissue results from cell growth restriction to prevent cell necrosis.
authors: Department of Clinical and Experimental Medicine, Linköping University, SE58185 Linköping, Sweden.
authors: Cecilia
authors: C
authors: Brännmark
authors: Department of Clinical and Experimental Medicine, Linköping University, SE58185 Linköping, Sweden.
authors: Elin
authors: E
authors: Nyman
authors: Department of Clinical and Experimental Medicine, Linköping University, SE58185 Linköping, Sweden.
authors: Siri
authors: S
authors: Fagerholm
authors: Department of Clinical and Experimental Medicine, Linköping University, SE58185 Linköping, Sweden.
authors: Linnéa
authors: L
authors: Bergenholm
authors: Department of Clinical and Experimental Medicine, Linköping University, SE58185 Linköping, Sweden.
authors: Eva-Maria
authors: EM
authors: Ekstrand
authors: Department of Clinical and Experimental Medicine, Linköping University, SE58185 Linköping, Sweden; Department of Biomedical Engineering, Linköping University, SE58185 Linköping, Sweden.
authors: Gunnar
authors: G
authors: Cedersund
authors: Department of Clinical and Experimental Medicine, Linköping University, SE58185 Linköping, Sweden. Electronic address: peter.stralfors@liu.se.
authors: Peter
authors: P
authors: Strålfors
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008687:Metformin / Q000494:pharmacology; D008962:Models, Theoretical; D046912:Multiprotein Complexes / Q000378:metabolism*; D009132:Muscles / Q000378:metabolism; D009336:Necrosis; D009765:Obesity / Q000378:metabolism; D050177:Overweight; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D051275:Glucose Transporter Type 4; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D046912:Multiprotein Complexes; C495692:SLC2A4 protein, human; D008687:Metformin; D011972:Receptor, Insulin; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D005947:Glucose
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