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:
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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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.
Metadata information
Human Disease Ontology type 2 diabetes mellitus
Name | Description | Size | Actions |
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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_urn.xml | Auto-generated SBML file with URNs | 68.87 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.vcml | Auto-generated VCML file | 89.52 KB | Preview | Download |
BIOMD0000000448.sci | Auto-generated Scilab file | 10.18 KB | Preview | Download |
BIOMD0000000448-biopax3.owl | Auto-generated BioPAX (Level 3) | 75.39 KB | Preview | Download |
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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
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Version: 2
- 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)
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Version: 1
- Submitted on: Apr 19, 2013 10:08:01 AM
- Submitted by: Elin Nyman
- With comment: Original import of normalmodel
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revisions as only public revisions are displayed here. Any private revisions
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: Variable used inside SBML models
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 | 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 |
(added: 19 Apr 2013, 15:40:13, updated: 19 Apr 2013, 15:40:13)