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

Tags
Name Description Size Actions

Model files

BIOMD0000000448_url.xml SBML L2V4 representation of Brännmark2013 - Insulin signalling in human adipocytes (normal condition) 69.86 KB Preview | Download

Additional files

BIOMD0000000448-biopax3.owl Auto-generated BioPAX (Level 3) 75.39 KB Preview | Download
BIOMD0000000448_urn.xml Auto-generated SBML file with URNs 68.87 KB Preview | Download
BIOMD0000000448.xpp Auto-generated XPP file 12.47 KB Preview | Download
BIOMD0000000448.png Auto-generated Reaction graph (PNG) 516.27 KB Preview | Download
BIOMD0000000448.vcml Auto-generated VCML file 89.52 KB Preview | Download
BIOMD0000000448-biopax2.owl Auto-generated BioPAX (Level 2) 47.59 KB Preview | Download
BIOMD0000000448.svg Auto-generated Reaction graph (SVG) 102.40 KB Preview | Download
BIOMD0000000448.m Auto-generated Octave file 15.43 KB Preview | Download
BIOMD0000000448.pdf Auto-generated PDF file 316.18 KB Preview | Download
BIOMD0000000448.sci Auto-generated Scilab file 10.18 KB Preview | Download

  • 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

(*) You might be seeing discontinuous revisions as only public revisions are displayed here. Any private revisions unpublished model revision of this model will only be shown to the submitter and their collaborators.

Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
IR

Insulin receptor
99.8737104842408 mol
IRp

Insulin receptor ; Phosphoprotein
0.00186253217635894 mol
IRip

Insulin receptor ; Phosphoprotein
0.0188430465801578 mol
IRS1

Insulin receptor substrate 1
82.9671997523599 mol
IRS1p

Insulin receptor substrate 1 ; Phosphoprotein
0.00119481841136737 mol
IRS1p307

Insulin receptor substrate 1 ; Phosphoprotein ; MOD:00046
0.327454355438396 mol
IRS1307

Insulin receptor substrate 1
16.7041510257561 mol
X

protein ; Intermediate
99.9983336594667 mol
Xp

Phosphoprotein ; Intermediate
0.00166634053318549 mol
PKB

RAC-beta serine/threonine-protein kinase
68.1806649661901 mol
Reactions
Reactions Rate Parameters
IR*k1a*insulin

IR*k1a*insulin
k1a = 0.6331; insulin = 10.0
k1basal*IR

k1basal*IR
k1basal = 0.03683
IRp*k1d

IRp*k1d
k1d = 31.01
IRip*k1f*Xp

IRip*k1f*Xp
k1f = 1840.0
IRS1*k2a*IRip

IRS1*k2a*IRip
k2a = 3.227
IRS1p*k2b

IRS1p*k2b
k2b = 3424.0
IRS1p307*k2d

IRS1p307*k2d
k2d = 280.8
IRS1p307*k2f

IRS1p307*k2f
k2f = 2.913
IRS1307*k2g

IRS1307*k2g
k2g = 0.2671
Xp*k3b

Xp*k3b
k3b = 0.09876
k4b*PKB308p

k4b*PKB308p
k4b = 34.8
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.