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

  • Model originally submitted by : Elin Nyman
  • Submitted: 19-Apr-2013 10:08:01
  • Last Modified: 08-Apr-2016 18:27:04
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 08-Apr-2016 18:27:04
    • 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: 19-Apr-2013 10:08:01
    • Submitted by: Elin Nyman
    • With comment: Original import of normalmodel
Legends
: Variable used inside SBML models


Species
Reactions
Reactions Rate Parameters
(PKB473p) => (PKB)

([RAC-beta serine/threonine-protein kinase; Phosphoprotein]) => ([RAC-beta serine/threonine-protein kinase])
k4h*PKB473p

k4h*[RAC-beta serine/threonine-protein kinase; Phosphoprotein]
k4h = 0.5361
(PKB308p) => (PKB308p473p)

([RAC-beta serine/threonine-protein kinase; Phosphoprotein]) => ([RAC-beta serine/threonine-protein kinase; Phosphoprotein])
k4c*PKB308p*mTORC2a

k4c*[RAC-beta serine/threonine-protein kinase; Phosphoprotein]*[Serine/threonine-protein kinase mTOR; Rapamycin-insensitive companion of mTOR]
k4c = 4.456
(mTORC2a) => (mTORC2)

([Serine/threonine-protein kinase mTOR; Rapamycin-insensitive companion of mTOR]) => ([Serine/threonine-protein kinase mTOR; Rapamycin-insensitive companion of mTOR])
k5d*mTORC2a

k5d*[Serine/threonine-protein kinase mTOR; Rapamycin-insensitive companion of mTOR]
k5d = 1.06
(AS160) => (AS160p)

([TBC1 domain family member 4]) => ([TBC1 domain family member 4; phosphorylated])
AS160*(k6f1*PKB308p473p+k6f2*PKB473p^n6/(km6^n6+PKB473p^n6))

[TBC1 domain family member 4]*(k6f1*[RAC-beta serine/threonine-protein kinase; Phosphoprotein]+k6f2*[RAC-beta serine/threonine-protein kinase; Phosphoprotein]^n6/(km6^n6+[RAC-beta serine/threonine-protein kinase; Phosphoprotein]^n6))
k6f1 = 2.652; k6f2 = 36.93; km6 = 30.54; n6 = 2.137
(GLUT4m) => (GLUT4)

([Solute carrier family 2, facilitated glucose transporter member 4; plasma membrane]) => ([Solute carrier family 2, facilitated glucose transporter member 4])
GLUT4m*k7b

[Solute carrier family 2, facilitated glucose transporter member 4; plasma membrane]*k7b
k7b = 2286.0
(S6K) => (S6Kp)

([Ribosomal protein S6 kinase beta-1]) => ([Ribosomal protein S6 kinase beta-1; Phosphoprotein])
S6K*k9f1*mTORC1a^n9/(km9^n9+mTORC1a^n9)

[Ribosomal protein S6 kinase beta-1]*k9f1*[Serine/threonine-protein kinase mTOR; Regulatory-associated protein of mTOR]^n9/(km9^n9+[Serine/threonine-protein kinase mTOR; Regulatory-associated protein of mTOR]^n9)
n9 = 0.9855; km9 = 5873.0; k9f1 = 0.1298
(S6Kp) => (S6K)

([Ribosomal protein S6 kinase beta-1; Phosphoprotein]) => ([Ribosomal protein S6 kinase beta-1])
S6Kp*k9b1

[Ribosomal protein S6 kinase beta-1; Phosphoprotein]*k9b1
k9b1 = 0.04441
(S6p) => (S6)

([40S ribosomal protein S6; Phosphoprotein]) => ([40S ribosomal protein S6])
S6p*k9b2

[40S ribosomal protein S6; Phosphoprotein]*k9b2
k9b2 = 31.0
(IRS1p) => (IRS1)

([Insulin receptor substrate 1; Phosphoprotein]) => ([Insulin receptor substrate 1])
IRS1p*k2b

[Insulin receptor substrate 1; Phosphoprotein]*k2b
k2b = 3424.0
(IRS1) => (IRS1p)

([Insulin receptor substrate 1]) => ([Insulin receptor substrate 1; Phosphoprotein])
IRS1*k2a*IRip

[Insulin receptor substrate 1]*k2a*[Insulin receptor; Phosphoprotein]
k2a = 3.227
(IRS1p) => (IRS1p307)

([Insulin receptor substrate 1; Phosphoprotein]) => ([Insulin receptor substrate 1; Phosphoprotein; MOD:00046])
IRS1p*k2c*mTORC1a*diabetes

[Insulin receptor substrate 1; Phosphoprotein]*k2c*[Serine/threonine-protein kinase mTOR; Regulatory-associated protein of mTOR]*diabetes
k2c = 5759.0; diabetes = 1.0
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.