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BIOMD0000000449 - Brännmark2013 - Insulin signalling in human adipocytes (diabetic condition)

 

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Reference Publication
Publication ID: 23400783
Brännmark C, Nyman E, Fagerholm S, Bergenholm L, Ekstrand EM, Cedersund G, Strålfors P.
Insulin signaling in type 2 diabetes: experimental and modeling analyses reveal mechanisms of insulin resistance in human adipocytes.
J. Biol. Chem. 2013 Apr; 288(14): 9867-9880
Department of Clinical and Experimental Medicine, Linköping University, SE58185 Linköping, Sweden.  [more]
Model
Original Model: supplement to the article
Submitter: Elin Nyman
Submission ID: MODEL1304160000
Submission Date: 16 Apr 2013 08:57:30 UTC
Last Modification Date: 16 Jun 2017 20:21:27 UTC
Creation Date: 19 Apr 2013 15:43:57 UTC
Encoders:  Vijayalakshmi Chelliah
   Elin Nyman
set #1
bqbiol:hasVersion Human Disease Ontology type 2 diabetes mellitus
set #2
bqbiol:hasProperty Mathematical Modelling Ontology ordinary differential equation model
set #3
bqmodel:isDerivedFrom BioModels Database Brannmark2010_InsulinSignalling_Mifamodel
set #4
bqbiol:isVersionOf Gene Ontology cellular response to insulin stimulus
set #5
bqbiol:hasTaxon Taxonomy Homo sapiens
Notes
Brännmark2013 - Insulin signalling in human adipocytes (diabetic 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 diabetic 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.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Model
Publication ID: 23400783 Submission Date: 16 Apr 2013 08:57:30 UTC Last Modification Date: 16 Jun 2017 20:21:27 UTC Creation Date: 19 Apr 2013 15:43:57 UTC
Mathematical expressions
Reactions
v1a v1basal v1c v1d
v1e v1g v1r v2a
v2b v2c v2d v2f
v2basal v2g v3a v3b
v5a v5b v5c v5d
v4a v4b v4c v4e
v4f v4h v6f1 v6b1
v7f v7b v9f1 v9b1
v9f2 v9b2    
Rules
Assignment Rule (variable: measuredIRp) Assignment Rule (variable: measuredIRint) Assignment Rule (variable: measuredIRS1p) Assignment Rule (variable: measuredIRS1307)
Assignment Rule (variable: measuredPKB308p) Assignment Rule (variable: measuredPKB473p) Assignment Rule (variable: measuredAS160p) Assignment Rule (variable: measuredmTORC1a)
Assignment Rule (variable: measuredS6Kp) Assignment Rule (variable: measuredS6p) Assignment Rule (variable: measuredmTORC2a) Assignment Rule (variable: glucoseuptake)
Physical entities
Compartments Species
cellvolume IR IRp IRins
IRip IRi IRS1
IRS1p IRS1p307 IRS1307
X Xp PKB
PKB308p PKB473p PKB308p473p
mTORC1 mTORC1a mTORC2
mTORC2a AS160 AS160p
GLUT4m GLUT4 S6K
S6Kp S6 S6p
Global parameters
diabetes k1a k1basal k1c
k1d k1f k1g k1r
k2a k2c k2basal k2b
k2d k2f k2g k3a
k3b k4a k4b k4c
k4e k4f k4h k5a1
k5a2 k5b k5d km5
k5c k6f1 k6f2 km6
n6 k6b k7f k7b
k8 glut1 k9f1 k9b1
k9f2 k9b2 km9 n9
scaleIR scaleIRS1 scaleIRS1ds scaleIRS1307
scalePKB308 scalePKB473 scaleAS160 scaleGLUCOSE
scaleS6K scaleS6 gluc insulin
measuredIRp measuredIRint measuredIRS1p measuredIRS1307
measuredPKB308p measuredPKB473p measuredAS160p measuredmTORC1a
measuredS6Kp measuredS6p measuredmTORC2a glucoseuptake
Reactions (34)
 
 v1a [IR] → [IRins];   {IR}
 
 v1basal [IR] → [IRp];   {IR}
 
 v1c [IRins] → [IRp];   {IRins}
 
 v1d [IRp] → [IRip];   {IRp}
 
 v1e [IRip] → [IRi];   {Xp} , {IRip} , {Xp}
 
 v1g [IRp] → [IR];   {IRp}
 
 v1r [IRi] → [IR];   {IRi}
 
 v2a [IRS1] → [IRS1p];   {IRip} , {IRS1} , {IRip}
 
 v2b [IRS1p] → [IRS1];   {IRS1p}
 
 v2c [IRS1p] → [IRS1p307];   {mTORC1a} , {IRS1p} , {mTORC1a}
 
 v2d [IRS1p307] → [IRS1p];   {IRS1p307}
 
 v2f [IRS1p307] → [IRS1307];   {IRS1p307}
 
 v2basal [IRS1] → [IRS1307];   {IRS1}
 
 v2g [IRS1307] → [IRS1];   {IRS1307}
 
 v3a [X] → [Xp];   {IRS1p} , {X} , {IRS1p}
 
 v3b [Xp] → [X];   {Xp}
 
 v5a [mTORC1] → [mTORC1a];   {PKB308p} , {PKB308p473p} , {mTORC1} , {PKB308p473p} , {PKB308p}
 
 v5b [mTORC1a] → [mTORC1];   {mTORC1a}
 
 v5c [mTORC2] → [mTORC2a];   {IRip} , {mTORC2} , {IRip}
 
 v5d [mTORC2a] → [mTORC2];   {mTORC2a}
 
 v4a [PKB] → [PKB308p];   {IRS1p} , {PKB} , {IRS1p}
 
 v4b [PKB308p] → [PKB];   {PKB308p}
 
 v4c [PKB308p] → [PKB308p473p];   {mTORC2a} , {PKB308p} , {mTORC2a}
 
 v4e [PKB473p] → [PKB308p473p];   {IRS1p307} , {PKB473p} , {IRS1p307}
 
 v4f [PKB308p473p] → [PKB473p];   {PKB308p473p}
 
 v4h [PKB473p] → [PKB];   {PKB473p}
 
 v6f1 [AS160] → [AS160p];   {PKB308p473p} , {PKB473p} , {AS160} , {PKB308p473p} , {PKB473p}
 
 v6b1 [AS160p] → [AS160];   {AS160p}
 
 v7f [GLUT4] → [GLUT4m];   {AS160p} , {GLUT4} , {AS160p}
 
 v7b [GLUT4m] → [GLUT4];   {GLUT4m}
 
 v9f1 [S6K] → [S6Kp];   {mTORC1a} , {S6K} , {mTORC1a}
 
 v9b1 [S6Kp] → [S6K];   {S6Kp}
 
 v9f2 [S6] → [S6p];   {S6Kp} , {S6} , {S6Kp}
 
 v9b2 [S6p] → [S6];   {S6p}
 
Rules (12)
 
 Assignment Rule (name: measuredIRp) measuredIRp = scaleIR*(IRp+IRip)
 
 Assignment Rule (name: measuredIRint) measuredIRint = IRi+IRip
 
 Assignment Rule (name: measuredIRS1p) measuredIRS1p = scaleIRS1*(IRS1p+IRS1p307)
 
 Assignment Rule (name: measuredIRS1307) measuredIRS1307 = scaleIRS1307*(IRS1p307+IRS1307)
 
 Assignment Rule (name: measuredPKB308p) measuredPKB308p = scalePKB308*(PKB308p+PKB308p473p)
 
 Assignment Rule (name: measuredPKB473p) measuredPKB473p = scalePKB473*(PKB473p+PKB308p473p)
 
 Assignment Rule (name: measuredAS160p) measuredAS160p = scaleAS160*AS160p
 
 Assignment Rule (name: measuredmTORC1a) measuredmTORC1a = mTORC1a
 
 Assignment Rule (name: measuredS6Kp) measuredS6Kp = scaleS6K*S6Kp
 
 Assignment Rule (name: measuredS6p) measuredS6p = scaleS6*S6p
 
 Assignment Rule (name: measuredmTORC2a) measuredmTORC2a = mTORC2a
 
 Assignment Rule (name: glucoseuptake) glucoseuptake = k8*GLUT4m*gluc+glut1*gluc
 
 cellvolume Spatial dimensions: 3.0  Compartment size: 1.0
 
 IR
Compartment: cellvolume
Initial concentration: 49.9344643421136
 
 IRp
Compartment: cellvolume
Initial concentration: 9.31221500588088E-4
 
 IRins
Compartment: cellvolume
Initial concentration: 0.0
 
 IRip
Compartment: cellvolume
Initial concentration: 0.011815001204792
 
 IRi
Compartment: cellvolume
Initial concentration: 0.0527894351383809
 
 IRS1
Compartment: cellvolume
Initial concentration: 86.2418960059256
 
 IRS1p
Compartment: cellvolume
Initial concentration: 9.5272377217019E-4
 
 IRS1p307
Compartment: cellvolume
Initial concentration: 0.00891531075576947
 
 IRS1307
Compartment: cellvolume
Initial concentration: 13.7482359094757
 
 X
Compartment: cellvolume
Initial concentration: 99.9986712896423
 
 Xp
Compartment: cellvolume
Initial concentration: 0.00132871035763352
 
 PKB
Compartment: cellvolume
Initial concentration: 78.0219322115859
 
 PKB308p
Compartment: cellvolume
Initial concentration: 12.2197372437326
 
 PKB473p
Compartment: cellvolume
Initial concentration: 9.6963389945784
 
 PKB308p473p
Compartment: cellvolume
Initial concentration: 0.061992532897245
 
 mTORC1
Compartment: cellvolume
Initial concentration: 96.927052256569
 
 mTORC1a
Compartment: cellvolume
Initial concentration: 3.07294774343092
 
 mTORC2
Compartment: cellvolume
Initial concentration: 99.9045223943705
 
 mTORC2a
Compartment: cellvolume
Initial concentration: 0.0954776056294795
 
 AS160
Compartment: cellvolume
Initial concentration: 95.4699007486273
 
 AS160p
Compartment: cellvolume
Initial concentration: 4.53009925137289
 
 GLUT4m
Compartment: cellvolume
Initial concentration: 4.5880858350243
 
 GLUT4
Compartment: cellvolume
Initial concentration: 45.4119141649757
 
 S6K
Compartment: cellvolume
Initial concentration: 99.8296860066098
 
 S6Kp
Compartment: cellvolume
Initial concentration: 0.170313993390069
 
 S6
Compartment: cellvolume
Initial concentration: 98.2037625421647
 
 S6p
Compartment: cellvolume
Initial concentration: 1.79623745783512
 
Global Parameters (68)
 
   diabetes
Value: 0.15
Constant
 
   k1a
Value: 0.6331
Constant
 
   k1basal
Value: 0.03683
Constant
 
   k1c
Value: 0.8768
Constant
 
   k1d
Value: 31.01
Constant
 
   k1f
Value: 1840.0
Constant
 
   k1g
Value: 1944.0
Constant
 
   k1r
Value: 0.5471
Constant
 
   k2a
Value: 3.227
Constant
 
   k2c
Value: 5759.0
Constant
 
   k2basal
Value: 0.04228
Constant
 
   k2b
Value: 3424.0
Constant
 
   k2d
Value: 280.8
Constant
 
   k2f
Value: 2.913
Constant
 
   k2g
Value: 0.2671
Constant
 
   k3a
Value: 0.001377
Constant
 
   k3b
Value: 0.09876
Constant
 
   k4a
Value: 5790.0
Constant
 
   k4b
Value: 34.8
Constant
 
   k4c
Value: 4.456
Constant
 
   k4e
Value: 42.84
Constant
 
   k4f
Value: 143.6
Constant
 
   k4h
Value: 0.5361
Constant
 
   k5a1
Value: 1.842
Constant
 
   k5a2
Value: 0.05506
Constant
 
   k5b
Value: 24.83
Constant
 
   k5d
Value: 1.06
Constant
 
   km5
Value: 2.65
Constant
 
   k5c
Value: 0.08575
Constant
 
   k6f1
Value: 2.652
Constant
 
   k6f2
Value: 36.93
Constant
 
   km6
Value: 30.54
Constant
 
   n6
Value: 2.137
Constant
 
   k6b
Value: 65.18
Constant
 
   k7f
Value: 50.98
Constant
 
   k7b
Value: 2286.0
Constant
 
   k8
Value: 724.2
Constant
 
   glut1
Value: 7042.0
Constant
 
   k9f1
Value: 0.1298
Constant
 
   k9b1
Value: 0.04441
Constant
 
   k9f2
Value: 3.329
Constant
 
   k9b2
Value: 31.0
Constant
 
   km9
Value: 5873.0
Constant
 
   n9
Value: 0.9855
Constant
 
   scaleIR
Value: 5.202
Constant
 
   scaleIRS1
Value: 0.3761
Constant
 
   scaleIRS1ds
Value: 14.89
Constant
 
   scaleIRS1307
Value: 0.05866
Constant
 
   scalePKB308
Value: 0.04356
Constant
 
   scalePKB473
Value: 0.013
Constant
 
   scaleAS160
Value: 0.026656
Constant
 
   scaleGLUCOSE
Value: 0.04051
Constant
 
   scaleS6K
Value: 0.7465
Constant
 
   scaleS6
Value: 0.1149
Constant
 
   gluc
Value: 0.05
Constant
 
   insulin
Value: 10.0
Constant
 
   measuredIRp  
 
   measuredIRint  
 
   measuredIRS1p  
 
   measuredIRS1307  
 
   measuredPKB308p  
 
   measuredPKB473p  
 
   measuredAS160p  
 
   measuredmTORC1a  
 
   measuredS6Kp  
 
   measuredS6p  
 
   measuredmTORC2a  
 
   glucoseuptake  
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000449

Curator's comment: (updated: 19 Apr 2013 15:42:27 GMT)

Performance of different species at diabetic condition in Figure 5 (red 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.

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