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BIOMD0000000356 - Nyman2011_M3Hierarachical_InsulinGlucosedynamics

 

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Reference Publication
Publication ID: 21572040
Nyman E, Brännmark C, Palmér R, Brugård J, Nyström FH, Strålfors P, Cedersund G.
A hierarchical whole-body modeling approach elucidates the link between in Vitro insulin signaling and in Vivo glucose homeostasis.
J. Biol. Chem. 2011 Jul; 286(29): 26028-26041
Department of Clinical and Experimental Medicine, Diabetes and Integrative Systems Biology, Linköping University, SE58185 Linköping, Sweden.  [more]
Model
Original Model: BIOMD0000000356.xml.origin
Submitter: Ishan Ajmera
Submission ID: MODEL1108190000
Submission Date: 19 Aug 2011 11:46:43 UTC
Last Modification Date: 28 May 2014 19:12:13 UTC
Creation Date: 19 Aug 2011 12:51:27 UTC
Encoders:  Ishan Ajmera
   Elin Nyman
set #1
bqmodel:isDerivedFrom BioModels Database Sedaghat2002_InsulinSignalling_noFeedback
BioModels Database Brannmark2010_InsulinSignalling_Mifamodel
BioModels Database DallaMan2007_MealModel_GlucoseInsulinSystem
PubMed 19225456
set #2
bqbiol:hasTaxon Taxonomy Homo sapiens
set #3
bqbiol:occursIn Brenda Tissue Ontology BTO:0000443
set #4
bqbiol:isVersionOf Gene Ontology regulation of insulin secretion involved in cellular response to glucose stimulus
Notes

This a model from the article:
A Hierarchical Whole-body Modeling Approach Elucidates the Link between in Vitro Insulin Signaling and in Vivo Glucose Homeostasis.
Nyman E, Brannmark C, Palmer R, Brugard J, Nystrom FH, Stralfors P, Cedersund G.J Biol Chem.2011 Jul 22;286(29):26028-41. 21572040,
Abstract:
Type 2 diabetes is a metabolic disease that profoundly affects energy homeostasis. The disease involves failure at several levels and subsystems and is characterized by insulin resistance in target cells and tissues (i.e. by impaired intracellular insulin signaling). We have previously used an iterative experimental-theoretical approach to unravel the early insulin signaling events in primary human adipocytes. That study, like most insulin signaling studies, is based on in vitro experimental examination of cells, and the in vivo relevance of such studies for human beings has not been systematically examined. Herein, we develop a hierarchical model of the adipose tissue, which links intracellular insulin control of glucose transport in human primary adipocytes with whole-body glucose homeostasis. An iterative approach between experiments and minimal modeling allowed us to conclude that it is not possible to scale up the experimentally determined glucose uptake by the isolated adipocytes to match the glucose uptake profile of the adipose tissue in vivo. However, a model that additionally includes insulin effects on blood flow in the adipose tissue and GLUT4 translocation due to cell handling can explain all data, but neither of these additions is sufficient independently. We also extend the minimal model to include hierarchical dynamic links to more detailed models (both to our own models and to those by others), which act as submodules that can be turned on or off. The resulting multilevel hierarchical model can merge detailed results on different subsystems into a coherent understanding of whole-body glucose homeostasis. This hierarchical modeling can potentially create bridges between other experimental model systems and the in vivo human situation and offers a framework for systematic evaluation of the physiological relevance of in vitro obtained molecular/cellular experimental data.

This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
For more information see the terms of use.
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Model
Publication ID: 21572040 Submission Date: 19 Aug 2011 11:46:43 UTC Last Modification Date: 28 May 2014 19:12:13 UTC Creation Date: 19 Aug 2011 12:51:27 UTC
Mathematical expressions
Reactions
R1 R2 R3 R4
R5 R6 R7 R8
R9 R10 R11 R12
R13 R14 R15 R16
R17 R18 R19 R20
R21 R22 R23 R24
R25 R26 R27 R28
R29 R30 R31 R32
R33 R34 R35 R36
R37 R38 R39 R40
R41 R42 R43 R44
R45 R46 R47 R48
v2f v2b v3f v3b
v4f v4b v5f v5b
v6f v6b v7f v7b
v8f v8b v9f v9b
Rules
Assignment Rule (variable: vglucoseuptake) Assignment Rule (variable: KD) Assignment Rule (variable: S2) Assignment Rule (variable: S1)
Assignment Rule (variable: K4) Assignment Rule (variable: K8) Assignment Rule (variable: aa) Assignment Rule (variable: cc)
Assignment Rule (variable: EGP) Assignment Rule (variable: V_mmax) Assignment Rule (variable: E) Assignment Rule (variable: S)
Assignment Rule (variable: I) Assignment Rule (variable: G) Assignment Rule (variable: HE) Assignment Rule (variable: m_3)
Assignment Rule (variable: Q_sto) Assignment Rule (variable: Ra) Assignment Rule (variable: k_empt) Assignment Rule (variable: U_idm)
Assignment Rule (variable: U_id) Assignment Rule (variable: U) Assignment Rule (variable: S_po) Rate Rule (variable: G_p)
Rate Rule (variable: G_t) Rate Rule (variable: I_l) Rate Rule (variable: I_p) Rate Rule (variable: Q_sto1)
Rate Rule (variable: Q_sto2) Rate Rule (variable: Q_gut) Rate Rule (variable: I_1) Rate Rule (variable: I_d)
Rate Rule (variable: INS) Rate Rule (variable: I_po) Rate Rule (variable: Y)  
Physical entities
Compartments Species
default r0 r1 r2
r11 r12 r22
r1x2 r11x2 r1x22
r1x22d r11x22 rend
rendP iendIR iend
rPbasal IRS IRSiP
X X_P PI3K
PI3K_ PDK1 PDK1_
PKC PKC_P PKB
PKB_P mTOR mTOR_
GLUT4_C GLUT4_M  
Global parameters
a1 a2 d1 d2
Kcr Kex Kend Kdp
Kcat Km kfbasal krbasal
k21 k22 k23 k24
k2b k3f k3b k4f
k4b k5f k5b k6f
k6b k7f k7b k8f
k8b k91 k92 k9b
k5Basic k5BasicWb k_glut4 k_glut1
KmG1 KmG4 kbf V_G
k_1 k_2 G_b V_I
m_1 m_2 m_4 m_5
m_6 HE_b I_b S_b
S_b_minus k_max k_min k_abs
k_gri f b d
BW k_p1 k_p2 k_p3
k_p4 k_i U_ii V_m0
V_mX K_m0 p_2U part
K alpha beta gamma
k_e1 k_e2 D vglucoseuptake
KD S2 S1 K4
K8 aa cc EGP
V_mmax E S I
G HE m_3 Q_sto
Ra k_empt U_idm U_id
U S_po G_p G_t
I_l I_p Q_sto1 Q_sto2
Q_gut I_1 I_d INS
I_po Y    
Reactions (64)
 
 R1 [r0] → [r1];  
 
 R2 [r0] → [r2];  
 
 R3 [r1] → [r11];  
 
 R4 [r2] → [r12];  
 
 R5 [r1] → [r0];  
 
 R6 [r1] → [r12];  
 
 R7 [r2] → [r22];  
 
 R8 [r2] → [r0];  
 
 R9 [r1] → [r1x2];  
 
 R10 [r2] → [r1x2];  
 
 R11 [r1x2] → [r11x2];  
 
 R12 [r11] → [r1];  
 
 R13 [r12] → [r2];  
 
 R14 [r1x2] → [r1x22];  
 
 R15 [r12] → [r1];  
 
 R16 [r22] → [r2];  
 
 R17 [r11] → [r11x2];  
 
 R18 [r12] → [r1x22];  
 
 R19 [r1x2] → [r1];  
 
 R20 [r12] → [r11x2];  
 
 R21 [r22] → [r1x22];  
 
 R22 [r1x2] → [r2];  
 
 R23 [r1x2] → [r1x22d];  
 
 R24 [r11x2] → [r1x2];  
 
 R25 [r1x22] → [r1x2];  
 
 R26 [r11x2] → [r11];  
 
 R27 [r1x22] → [r12];  
 
 R28 [r11x2] → [r12];  
 
 R29 [r1x22] → [r22];  
 
 R30 [r1x22] → [r11x22];  
 
 R31 [r11x2] → [r11x22];  
 
 R32 [r1x22] → [r1x22d];  
 
 R33 [r1x22d] → [r1x22];  
 
 R34 [r1x22d] → [r1x2];  
 
 R35 [r11x22] → [r1x22];  
 
 R36 [r11x22] → [r11x2];  
 
 R37 [rend] → [r0];  
 
 R38 [iend] → ;  
 
 R39 [r1x2] → [rendP] + [iendIR];  
 
 R40 [r11x2] → [rendP] + 2.0 × [iendIR];  
 
 R41 [r1x22] → [rendP] + 2.0 × [iendIR];  
 
 R42 [r1x22d] → [rendP] + 3.0 × [iendIR];  
 
 R43 [r11x22] → [rendP] + 3.0 × [iendIR];  
 
 R44 [rendP] → [rend];   {X_P}
 
 R45 [iendIR] → [iend];   {X_P}
 
 R46 [r0] → [rPbasal];  
 
 R47 [rPbasal] → [r0];  
 
 R48 [rPbasal] → [rendP];  
 
 v2f [IRS] → [IRSiP];   {PKC_P} , {mTOR} , {r11x2} , {r11x22} , {r1x2} , {r1x22} , {r1x22d} , {rPbasal} , {rendP}
 
 v2b [IRSiP] → [IRS];  
 
 v3f [X] → [X_P];   {IRSiP}
 
 v3b [X_P] → [X];  
 
 v4f [PI3K] → [PI3K_];   {IRSiP}
 
 v4b [PI3K_] → [PI3K];  
 
 v5f [PDK1] → [PDK1_];   {PI3K_}
 
 v5b [PDK1_] → [PDK1];  
 
 v6f [PKC] → [PKC_P];   {PDK1_}
 
 v6b [PKC_P] → [PKC];  
 
 v7f [PKB] → [PKB_P];   {PDK1_}
 
 v7b [PKB_P] → [PKB];  
 
 v8f [mTOR] → [mTOR_];   {PKB_P}
 
 v8b [mTOR_] → [mTOR];  
 
 v9f [GLUT4_C] → [GLUT4_M];   {PKB_P} , {PKC_P}
 
 v9b [GLUT4_M] → [GLUT4_C];  
 
Rules (35)
 
 Assignment Rule (name: vglucoseuptake) vglucoseuptake = k_glut1*G_t/(KmG1+G_t)+k_glut4*GLUT4_M*G_t/(KmG4+G_t)+kbf*(INS+5)
 
 Assignment Rule (name: KD) KD = 7E-6
 
 Assignment Rule (name: S2) S2 = 0
 
 Assignment Rule (name: S1) S1 = (INS+5)*1E-12
 
 Assignment Rule (name: K4) K4 = 1400
 
 Assignment Rule (name: K8) K8 = 0.01
 
 Assignment Rule (name: aa) aa = 5/2/(1-b)/D
 
 Assignment Rule (name: cc) cc = 5/2/d/D
 
 Assignment Rule (name: EGP) EGP = k_p1-k_p2*G_p-k_p3*I_d-k_p4*I_po
 
 Assignment Rule (name: V_mmax) V_mmax = (1-part)*(V_m0+V_mX*INS)
 
 Assignment Rule (name: E) E = 0
 
 Assignment Rule (name: S) S = gamma*I_po
 
 Assignment Rule (name: I) I = I_p/V_I
 
 Assignment Rule (name: G) G = G_p/V_G
 
 Assignment Rule (name: HE) HE = (-m_5)*S+m_6
 
 Assignment Rule (name: m_3) m_3 = HE*m_1/(1-HE)
 
 Assignment Rule (name: Q_sto) Q_sto = Q_sto1+Q_sto2
 
 Assignment Rule (name: Ra) Ra = f*k_abs*Q_gut/BW
 
 Assignment Rule (name: k_empt) k_empt = k_min+(k_max-k_min)/2*(tanh(aa*(Q_sto-b*D))-tanh(cc*(Q_sto-d*D))+2)
 
 Assignment Rule (name: U_idm) U_idm = V_mmax*G_t/(K_m0+G_t)
 
 Assignment Rule (name: U_id) U_id = U_idm+vglucoseuptake
 
 Assignment Rule (name: U) U = U_ii+U_id
 
 Assignment Rule (name: S_po) S_po = Y+K*(EGP+Ra-E-U_ii-k_1*G_p+k_2*G_t)/V_G+S_b
 
 Rate Rule (name: G_p) d [ G_p] / d t= EGP+Ra-E-U_ii-k_1*G_p+k_2*G_t
 
 Rate Rule (name: G_t) d [ G_t] / d t= -U_id+k_1*G_p-k_2*G_t
 
 Rate Rule (name: I_l) d [ I_l] / d t= (-m_1)*I_l-m_3*I_l+m_2*I_p+S
 
 Rate Rule (name: I_p) d [ I_p] / d t= (-m_2)*I_p-m_4*I_p+m_1*I_l
 
 Rate Rule (name: Q_sto1) d [ Q_sto1] / d t= (-k_gri)*Q_sto1
 
 Rate Rule (name: Q_sto2) d [ Q_sto2] / d t= (-k_empt)*Q_sto2+k_gri*Q_sto1
 
 Rate Rule (name: Q_gut) d [ Q_gut] / d t= (-k_abs)*Q_gut+k_empt*Q_sto2
 
 Rate Rule (name: I_1) d [ I_1] / d t= (-k_i)*(I_1-I)
 
 Rate Rule (name: I_d) d [ I_d] / d t= (-k_i)*(I_d-I_1)
 
 Rate Rule (name: INS) d [ INS] / d t= (-p_2U)*INS+p_2U*(I-I_b)
 
 Rate Rule (name: I_po) d [ I_po] / d t= (-gamma)*I_po+S_po
 
 Rate Rule (name: Y) d [ Y] / d t= (-alpha)*(Y-beta*(G-G_b))
 
   default Spatial dimensions: 3.0  Compartment size: 1.0
 
 r0
Compartment: default
Initial amount: 9.96820379306998
 
 r1
Compartment: default
Initial amount: 0.0221366043399864
 
 r2
Compartment: default
Initial amount: 0.00934921094738169
 
 r11
Compartment: default
Initial amount: 1.22886711962222E-5
 
 r12
Compartment: default
Initial amount: 1.0376421415741E-5
 
 r22
Compartment: default
Initial amount: 2.18683301945588E-6
 
 r1x2
Compartment: default
Initial amount: 1.36475817837692E-6
 
 r11x2
Compartment: default
Initial amount: 1.51513915390766E-9
 
 r1x22
Compartment: default
Initial amount: 6.39351849488596E-10
 
 r1x22d
Compartment: default
Initial amount: 5.59231079319369E-20
 
 r11x22
Compartment: default
Initial amount: 1.78725515332219E-14
 
 rend
Compartment: default
Initial amount: 3.31711803810961E-5
 
 rendP
Compartment: default
Initial amount: 2.12533941418487E-4
 
 iendIR
Compartment: default
Initial amount: 7.25519178924707E-6
 
 iend
Compartment: default
Initial amount: 1.13228497567934E-6
 
 rPbasal
Compartment: default
Initial amount: 3.87230309356247E-5
 
 IRS
Compartment: default
Initial amount: 9.99982253600007
 
 IRSiP
Compartment: default
Initial amount: 1.77463999892648E-4
 
 X
Compartment: default
Initial amount: 9.92463241634744
 
 X_P
Compartment: default
Initial amount: 0.0753675836525682
 
 PI3K
Compartment: default
Initial amount: 9.97578356966623
 
 PI3K_
Compartment: default
Initial amount: 0.0242164303337614
 
 PDK1
Compartment: default
Initial amount: 8.65876984730663
 
 PDK1_
Compartment: default
Initial amount: 1.34123015269338
 
 PKC
Compartment: default
Initial amount: 3.60283594102724E-5
 
 PKC_P
Compartment: default
Initial amount: 9.99996397164059
 
 PKB
Compartment: default
Initial amount: 9.90193143617302
 
 PKB_P
Compartment: default
Initial amount: 0.0980685638269942
 
 mTOR
Compartment: default
Initial amount: 0.0201915011292933
 
 mTOR_
Compartment: default
Initial amount: 9.97980849887072
 
 GLUT4_C
Compartment: default
Initial amount: 9.99316830771855
 
 GLUT4_M
Compartment: default
Initial amount: 0.00683169228144988
 
Global Parameters (114)
 
 a1
Value: 4.4825146271204E8
Constant
 
 a2
Value: 4321891.90327031
Constant
 
 d1
Value: 0.7722612342
Constant
 
 d2
Value: 0.0122057759
Constant
 
 Kcr
Value: 0.0013640432
Constant
 
 Kex
Value: 37.0818924842
Constant
 
 Kend
Value: 30.6825110077
Constant
 
 Kdp
Value: 9.500831E-4
Constant
 
 Kcat
Value: 237.5189220434
Constant
 
 Km
Value: 3.0181933402
Constant
 
 kfbasal
Value: 0.49752158
Constant
 
 krbasal
Value: 128042.884096176
Constant
 
 k21
Value: 0.009645863
Constant
 
 k22
Value: 2374.9773277896
Constant
 
 k23
Value: 0.1199031163
Constant
 
 k24
Value: 0.9430860972
Constant
 
 k2b
Value: 608.5839585406
Constant
 
 k3f
Value: 8.1119350488
Constant
 
 k3b
Value: 0.1895302156
Constant
 
 k4f
Value: 384885.688277883
Constant
 
 k4b
Value: 28137.0701606029
Constant
 
 k5f
Value: 64300.0712750856
Constant
 
 k5b
Value: 10052.5084521206
Constant
 
 k6f
Value: 1.60942017926563E7
Constant
 
 k6b
Value: 77.7712105485
Constant
 
 k7f
Value: 4174.6300598327
Constant
 
 k7b
Value: 565342.162392942
Constant
 
 k8f
Value: 1515762.41887571
Constant
 
 k8b
Value: 300.7511656484
Constant
 
 k91
Value: 8.14E-8
Constant
 
 k92
Value: 0.0280831426
Constant
 
 k9b
Value: 4.0297596909
Constant
 
 k5Basic
Value: 0.2040341054
Constant
 
 k5BasicWb
Value: 2.34E-8
Constant
 
 k_glut4
Value: 31.4211308621
Constant
 
 k_glut1
Value: 0.2966651081
Constant
 
 KmG1
Value: 132.7704719106
Constant
 
 KmG4
Value: 70.4032025464
Constant
 
 kbf
Value: 0.003119389367
Constant
 
 V_G
Value: 1.88
Constant
 
 k_1
Value: 0.065
Constant
 
 k_2
Value: 0.079
Constant
 
 G_b
Value: 95.0
Constant
 
 V_I
Value: 0.05
Constant
 
 m_1
Value: 0.19
Constant
 
 m_2
Value: 0.484
Constant
 
 m_4
Value: 0.194
Constant
 
 m_5
Value: 0.0304
Constant
 
 m_6
Value: 0.6471
Constant
 
 HE_b
Value: 0.6
Constant
 
 I_b
Value: 25.0
Constant
 
 S_b
Value: 1.8
Constant
 
 S_b_minus
Value: -1.8
Constant
 
 k_max
Value: 0.0558
Constant
 
 k_min
Value: 0.0080
Constant
 
 k_abs
Value: 0.057
Constant
 
 k_gri
Value: 0.0558
Constant
 
 f
Value: 0.9
Constant
 
   b
Value: 0.82
Constant
 
   d
Value: 0.01
Constant
 
 BW
Value: 78.0
Constant
 
 k_p1
Value: 2.7
Constant
 
 k_p2
Value: 0.0021
Constant
 
 k_p3
Value: 0.0090
Constant
 
 k_p4
Value: 0.0618
Constant
 
 k_i
Value: 0.0079
Constant
 
 U_ii
Value: 1.0
Constant
 
   V_m0
Value: 2.5
Constant
 
   V_mX
Value: 0.047
Constant
 
   K_m0
Value: 225.59
Constant
 
 p_2U
Value: 0.0331
Constant
 
   part
Value: 0.2
Constant
 
   K
Value: 2.3
Constant
 
 alpha
Value: 0.05
Constant
 
 beta
Value: 0.11
Constant
 
 gamma
Value: 0.5
Constant
 
 k_e1
Value: 5.0E-4
Constant
 
 k_e2
Value: 339.0
Constant
 
   D
Value: 78000.0
Constant
 
   vglucoseuptake  
 
   KD  
 
   S2  
 
   S1  
 
   K4  
 
   K8  
 
   aa  
 
   cc  
 
   EGP  
 
   V_mmax  
 
   E  
 
   S  
 
   I  
 
   G  
 
   HE  
 
   m_3  
 
   Q_sto  
 
   Ra  
 
   k_empt  
 
   U_idm  
 
   U_id  
 
   U  
 
   S_po  
 
 G_p
Value: 178.0
 
 G_t
Value: 135.0
 
 I_l
Value: 4.5
 
 I_p
Value: 1.25
 
   Q_sto1
Value: 78000.0
 
   Q_sto2  
 
   Q_gut  
 
   I_1
Value: 25.0
 
   I_d
Value: 25.0
 
 INS  
 
 I_po
Value: 3.6
 
   Y  
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000356

Curator's comment: (updated: 19 Aug 2011 13:53:26 BST)

The model reproduces fig 9 of the reference publication.
Plot F was found to be inconsistent with the published figure but has been agreed upon by the author.
The model was integrated and simulated using Copasi v4.7 (Build 34).

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