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:
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
isDerivedFrom
isDescribedBy
hasTaxon
isVersionOf
hasProperty
Mathematical Modelling Ontology
Ordinary differential equation model
Human Disease Ontology type 2 diabetes mellitus
Human Disease Ontology type 2 diabetes mellitus
Curation status
Curated
Tags
| Name | Description | Size | Actions |
|---|---|---|---|
Model files |
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| BIOMD0000000448_url.xml | SBML L2V4 representation of Brännmark2013 - Insulin signalling in human adipocytes (normal condition) | 69.86 KB | Preview | Download |
Additional files |
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| 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
- 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
- Submitted on: 19-Apr-2013 10:08:01
- Submitted by: Elin Nyman
- With comment: Original import of normalmodel
Legends
: Variable used inside SBML models
: Variable used inside SBML models
Species
| Species | Initial Concentration/Amount |
|---|---|
| PKB473p RAC-beta serine/threonine-protein kinase ; Phosphoprotein |
16.8171941560617 mol |
| PKB308p473p RAC-beta serine/threonine-protein kinase ; Phosphoprotein |
1.70566051030056 mol |
| mTORC2 Serine/threonine-protein kinase mTOR ; Rapamycin-insensitive companion of mTOR |
99.8478148461591 mol |
| AS160p TBC1 domain family member 4 ; phosphorylated |
16.1858981408903 mol |
| GLUT4m Solute carrier family 2, facilitated glucose transporter member 4 ; plasma membrane |
26.523878746229 mol |
| GLUT4 Solute carrier family 2, facilitated glucose transporter member 4 |
73.476121253771 mol |
| S6Kp Ribosomal protein S6 kinase beta-1 ; Phosphoprotein |
0.72680127804522 mol |
| S6 40S ribosomal protein S6 |
92.7596420796038 mol |
| S6p 40S ribosomal protein S6 ; Phosphoprotein |
7.24035792039603 mol |
| IRS1 Insulin receptor substrate 1 |
82.9671997523599 mol |
| IRS1p Insulin receptor substrate 1 ; Phosphoprotein |
0.00119481841136737 mol |
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)
(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.