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
Connected external resources
SBGN view in Newt Editor
| 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-biopax2.owl | Auto-generated BioPAX (Level 2) | 47.59 KB | Preview | Download |
| BIOMD0000000448-biopax3.owl | Auto-generated BioPAX (Level 3) | 75.39 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.png | Auto-generated Reaction graph (PNG) | 516.27 KB | Preview | Download |
| BIOMD0000000448.sci | Auto-generated Scilab file | 10.18 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.xpp | Auto-generated XPP file | 12.47 KB | Preview | Download |
| BIOMD0000000448_urn.xml | Auto-generated SBML file with URNs | 68.87 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
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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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: Variable used inside SBML models
| Species | Initial Concentration/Amount |
|---|---|
| PKB RAC-beta serine/threonine-protein kinase |
68.1806649661901 mol |
| PKB308p RAC-beta serine/threonine-protein kinase ; Phosphoprotein |
13.2964849666951 mol |
| PKB473p RAC-beta serine/threonine-protein kinase ; Phosphoprotein |
16.8171941560617 mol |
| PKB308p473p RAC-beta serine/threonine-protein kinase ; Phosphoprotein |
1.70566051030056 mol |
| mTORC1 Serine/threonine-protein kinase mTOR ; Regulatory-associated protein of mTOR |
86.5002472240273 mol |
| mTORC2a Serine/threonine-protein kinase mTOR ; Rapamycin-insensitive companion of mTOR |
0.152185153840861 mol |
| AS160p TBC1 domain family member 4 ; phosphorylated |
16.1858981408903 mol |
| IR Insulin receptor |
99.8737104842408 mol |
| 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 |
(added: 19 Apr 2013, 15:40:13, updated: 19 Apr 2013, 15:40:13)