Brännmark2013 - Insulin signalling in human adipocytes (normal condition)

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Model Identifier
BIOMD0000000448
Short description
Brännmark2013 - Insulin signalling in human adipocytes (normal condition)

The paper describes insulin signalling in human adipocytes under normal and diabetic states using mathematical models based on experimental data. This model corresponds to insulin signalling under normal condtion

This model is described in the article:

Brännmark C, Nyman E, Fagerholm S, Bergenholm L, Ekstrand EM, Cedersund G, Strålfors P.
J Biol Chem. 2013 Apr 5;288(14):9867-80.

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.

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Format
SBML (L2V4)
Related Publication
  • Insulin signaling in type 2 diabetes: experimental and modeling analyses reveal mechanisms of insulin resistance in human adipocytes.
  • Brännmark C, Nyman E, Fagerholm S, Bergenholm L, Ekstrand EM, Cedersund G, Strålfors P
  • The Journal of biological chemistry , 4/ 2013 , Volume 288 , pages: 9867-9880 , PubMed ID: 23400783
  • Department of Clinical and Experimental Medicine, Linköping University, SE58185 Linköping, Sweden.
  • 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.
Contributors
Elin Nyman

Metadata information

is
BioModels Database MODEL1304190000
BioModels Database BIOMD0000000448
isDerivedFrom
BioModels Database BIOMD0000000343
isDescribedBy
PubMed 23400783
hasTaxon
Taxonomy Homo sapiens
isVersionOf
hasProperty
Mathematical Modelling Ontology Ordinary differential equation model
Human Disease Ontology type 2 diabetes mellitus

Curation status
Curated

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  • Model originally submitted by : Elin Nyman
  • Submitted: Apr 19, 2013 10:08:01 AM
  • Last Modified: Apr 8, 2016 6:27:04 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: Apr 8, 2016 6:27:04 PM
    • Submitted by: Elin Nyman
    • With comment: Current version of Brännmark2013 - Insulin signalling in human adipocytes (normal condition)
  • Version: 1 public model Download this version
    • Submitted on: Apr 19, 2013 10:08:01 AM
    • Submitted by: Elin Nyman
    • With comment: Original import of normalmodel

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Legends
: Variable used inside SBML models


Species
Reactions
Reactions Rate Parameters
PKB => PKB308p; IRS1p, PKB, IRS1p k4a*PKB*IRS1p k4a = 5790.0
PKB308p => PKB; PKB308p k4b*PKB308p k4b = 34.8
PKB308p => PKB308p473p; mTORC2a, PKB308p, mTORC2a k4c*PKB308p*mTORC2a k4c = 4.456
PKB473p => PKB308p473p; IRS1p307, PKB473p, IRS1p307 k4e*PKB473p*IRS1p307 k4e = 42.84
PKB308p473p => PKB473p; PKB308p473p k4f*PKB308p473p k4f = 143.6
mTORC1 => mTORC1a; PKB308p, PKB308p473p, mTORC1, PKB308p473p, PKB308p mTORC1*(k5a1*PKB308p473p+k5a2*PKB308p) k5a2 = 0.05506; k5a1 = 1.842
mTORC1a => mTORC1; mTORC1a mTORC1a*k5b k5b = 24.83
mTORC2 => mTORC2a; IRip, mTORC2, IRip mTORC2*k5c*IRip k5c = 0.08575
mTORC2a => mTORC2; mTORC2a k5d*mTORC2a k5d = 1.06
AS160 => AS160p; PKB308p473p, PKB473p, AS160, PKB308p473p, PKB473p AS160*(k6f1*PKB308p473p+k6f2*PKB473p^n6/(km6^n6+PKB473p^n6)) k6f1 = 2.652; k6f2 = 36.93; km6 = 30.54; n6 = 2.137
IR => IRins; IR IR*k1a*insulin k1a = 0.6331; insulin = 10.0
IR => IRp; IR k1basal*IR k1basal = 0.03683
IRp => IR; IRp IRp*k1g k1g = 1944.0
Curator's comment:
(added: 19 Apr 2013, 15:40:13, updated: 19 Apr 2013, 15:40:13)
Performance of different species at normal condition in Figure 5 (blue plots) of the reference publication has been reproduced. The model simulation was performed using COPASI v4.8 (Build 38). The plots were generated using Gnuplot.