Jiang2007 - GSIS system, Pancreatic Beta Cells

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Model Identifier
BIOMD0000000239
Short description
Jiang2007 - GSIS system, Pancreatic Beta Cells
Description of a core kinetic model of the glucose-stimulated insulin secretion system (GSIS) in pancreatic beta cells.

This model is described in the article:

Jiang N, Cox RD, Hancock JM.
Mamm Genome 2007 Jul; 18(6-7):508-20.

Abstract:

The construction and characterization of a core kinetic model of the glucose-stimulated insulin secretion system (GSIS) in pancreatic beta cells is described. The model consists of 44 enzymatic reactions, 59 metabolic state variables, and 272 parameters. It integrates five subsystems: glycolysis, the TCA cycle, the respiratory chain, NADH shuttles, and the pyruvate cycle. It also takes into account compartmentalization of the reactions in the cytoplasm and mitochondrial matrix. The model shows expected behavior in its outputs, including the response of ATP production to starting glucose concentration and the induction of oscillations of metabolite concentrations in the glycolytic pathway and in ATP and ADP concentrations. Identification of choke points and parameter sensitivity analysis indicate that the glycolytic pathway, and to a lesser extent the TCA cycle, are critical to the proper behavior of the system, while parameters in other components such as the respiratory chain are less critical. Notably, however, sensitivity analysis identifies the first reactions of nonglycolytic pathways as being important for the behavior of the system. The model is robust to deletion of malic enzyme activity, which is absent in mouse pancreatic beta cells. The model represents a step toward the construction of a model with species-specific parameters that can be used to understand mouse models of diabetes and the relationship of these mouse models to the human disease state.

The model reproduces Figure 2 of the paper, and is built using files 'ModelNNT11.xml' and 'changed.m' available from http://www.har.mrc.ac.uk/research/bioinformatics/research_areas/systems_biology.html .

A couple of small errors in the model (in the original SBML file 'ModelNNT11.xml') have been corrected. The errors are:

  • v44 now produces Pyr rather than PYR
  • the kinetic law of v27 is now dependent on cytoplasmic (rather than mitochondrial) acetyl CoA and OXA

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.

Format
SBML (L2V4)
Related Publication
  • A kinetic core model of the glucose-stimulated insulin secretion network of pancreatic beta cells.
  • Jiang N, Cox RD, Hancock JM
  • Mammalian genome : official journal of the International Mammalian Genome Society , 7/ 2007 , Volume 18 , pages: 508-520 , PubMed ID: 17514510
  • Bioinformatics Group, MRC Mammalian Genetics Unit, Harwell, Oxfordshire, OX11 0RD, UK.
  • The construction and characterization of a core kinetic model of the glucose-stimulated insulin secretion system (GSIS) in pancreatic beta cells is described. The model consists of 44 enzymatic reactions, 59 metabolic state variables, and 272 parameters. It integrates five subsystems: glycolysis, the TCA cycle, the respiratory chain, NADH shuttles, and the pyruvate cycle. It also takes into account compartmentalization of the reactions in the cytoplasm and mitochondrial matrix. The model shows expected behavior in its outputs, including the response of ATP production to starting glucose concentration and the induction of oscillations of metabolite concentrations in the glycolytic pathway and in ATP and ADP concentrations. Identification of choke points and parameter sensitivity analysis indicate that the glycolytic pathway, and to a lesser extent the TCA cycle, are critical to the proper behavior of the system, while parameters in other components such as the respiratory chain are less critical. Notably, however, sensitivity analysis identifies the first reactions of nonglycolytic pathways as being important for the behavior of the system. The model is robust to deletion of malic enzyme activity, which is absent in mouse pancreatic beta cells. The model represents a step toward the construction of a model with species-specific parameters that can be used to understand mouse models of diabetes and the relationship of these mouse models to the human disease state.
Contributors
Kieran Smallbone

Metadata information

is
BioModels Database MODEL1469251725
BioModels Database BIOMD0000000239
isDescribedBy
PubMed 17514510
hasTaxon
Taxonomy Homo sapiens
hasProperty
Human Disease Ontology diabetes mellitus

Curation status
Curated

Tags
Name Description Size Actions

Model files

BIOMD0000000239_url.xml SBML L2V4 representation of Jiang2007 - GSIS system, Pancreatic Beta Cells 239.65 KB Preview | Download

Additional files

BIOMD0000000239.m Auto-generated Octave file 54.16 KB Preview | Download
BIOMD0000000239.sci Auto-generated Scilab file 82.03 KB Preview | Download
BIOMD0000000239.svg Auto-generated Reaction graph (SVG) 114.33 KB Preview | Download
BIOMD0000000239.vcml Auto-generated VCML file 897.00 Bytes Preview | Download
BIOMD0000000239_urn.xml Auto-generated SBML file with URNs 222.20 KB Preview | Download
BIOMD0000000239.pdf Auto-generated PDF file 444.61 KB Preview | Download
BIOMD0000000239-biopax2.owl Auto-generated BioPAX (Level 2) 116.78 KB Preview | Download
BIOMD0000000239.xpp Auto-generated XPP file 40.21 KB Preview | Download
BIOMD0000000239-biopax3.owl Auto-generated BioPAX (Level 3) 179.51 KB Preview | Download
BIOMD0000000239.png Auto-generated Reaction graph (PNG) 977.07 KB Preview | Download

  • Model originally submitted by : Kieran Smallbone
  • Submitted: 28-Aug-2009 16:20:55
  • Last Modified: 08-Apr-2016 17:06:10
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 08-Apr-2016 17:06:10
    • Submitted by: Kieran Smallbone
    • With comment: Current version of Jiang2007 - GSIS system, Pancreatic Beta Cells
  • Version: 1 public model Download this version
    • Submitted on: 28-Aug-2009 16:20:55
    • Submitted by: Kieran Smallbone
    • With comment: Original import of Jiang et al 2007

(*) You might be seeing discontinuous revisions as only public revisions are displayed here. Any private revisions unpublished model revision of this model will only be shown to the submitter and their collaborators.

Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
DHAP

Glycerone phosphate ; dihydroxyacetone phosphate
0.0076925 mol
OXA cyt

Oxaloacetate ; oxaloacetic acid
4.0E-6 mol
Asp cyt

L-Aspartate ; L-aspartic acid
0.00114 mol
Glu cyt

L-Glutamate ; L-glutamic acid
0.00303 mol
OG cyt

2-Oxoglutarate ; 2-oxoglutaric acid
2.1E-5 mol
Suc

Succinate ; succinic acid
0.00295 mol
GTP

GTP ; GTP
0.0045 mol
Asp

L-Aspartate ; L-aspartic acid
0.00114 mol
Glu

L-Glutamate ; L-glutamic acid
0.00303 mol
H2O

H2O ; water
0.001 mol
CoA

CoA ; coenzyme A
2.72E-4 mol
Acetyl CoA

Acetyl-CoA ; acetyl-CoA
3.0E-5 mol
Pi

Orthophosphate ; phosphate(3-)
0.004 mol
Reactions
Reactions Rate Parameters
NADH_cyt + DHAP => G3P + NAD CYTOPLASM*V*v38_GUT2P*NADH_cyt/(K+NADH_cyt) V=0.0399; K=34.0; v38_GUT2P=0.001
Cit_cyt + CoA_cyt => OXA_cyt + Acetyl_CoA_cyt CYTOPLASM*Kid*Kc*V*Acetyl_CoA_cyt*OXA_cyt*v10_CS/(Acetyl_CoA_cyt*OXA_cyt+Ka*OXA_cyt+Kb*Acetyl_CoA_cyt+Kia*Kib)/(Keq*Kia*Kb) Kb=4.5E-6; v10_CS=3.8617E-7; Kia=5.0E-6; Kc=3.9E-5; Ka=5.0E-6; Keq=1.8E7; Kid=0.0043; V=0.004833; Kib=4.5E-6
NADH_cyt + OXA_cyt => Mal_cyt + NAD CYTOPLASM*v31_MDH*(k1*k2*k3*k4*NADH_cyt*OXA_cyt-kminus1*kminus2*kminus3*kminus4*Mal_cyt*NAD)/(kminus1*(kminus2+k3)*k4+k1*(kminus2+k3)*k4*NADH_cyt+kminus1*(kminus2+k3)*kminus4*NAD+k2*k3*k4*OXA_cyt+kminus1*kminus2*kminus3*Mal_cyt+k1*k2*(k3+k4)*NADH_cyt*OXA_cyt+(kminus1+kminus2)*kminus3*kminus4*Mal_cyt*NAD+k1+kminus2+kminus3*NADH_cyt*Mal_cyt+k1*k2*kminus3*NADH_cyt*OXA_cyt*Mal_cyt+k2*k3*kminus4*OXA_cyt*NAD+k2*kminus3*kminus4*OXA_cyt*Mal_cyt*NAD) kminus2=1400.0; k4=214.0; v31_MDH=3.8617E-7; k3=4650.0; k2=3.5E7; kminus1=26.0; kminus4=260000.0; kminus3=570000.0; k1=3.4E7
Asp_cyt + OG_cyt => OXA_cyt + Glu_cyt CYTOPLASM*KcF*KcR*v32_AspTA*(Asp_cyt*OG_cyt-OXA_cyt*Glu_cyt/Keq)/(KcR*KmS2*Asp_cyt+KcR*KmS1*OG_cyt+KcF*KmP2*OXA_cyt/Keq+KcF*KmP1*Glu_cyt/Keq+KcR*Asp_cyt*OG_cyt+KcF*KmP2*Asp_cyt*OXA_cyt/(Keq*KiS1)+KcF*OXA_cyt*Glu_cyt/Keq+KcR*KmS1*OG_cyt*Glu_cyt/KiP2) KmS1=9.0E-4; v32_AspTA=3.8617E-7; KmP2=0.004; Keq=6.2; KiP2=0.0083; KcF=300.0; KmP1=4.0E-5; KiS1=0.002; KcR=1000.0; KmS2=1.0E-4
Glu_cyt + Asp => Asp_cyt + Glu MATRIX*(Asp*Glu_cyt/alpha/KiS1/KiS2*KcF-Glu*Asp_cyt/beta/KiP1/KiP2*KcR)*v22_AGC/(1+Asp/KiS1+Glu_cyt/KiS2+Glu/KiP1+Asp_cyt/KiP2+Asp*Glu_cyt/alpha/KiS1/KiS2+Glu*Asp_cyt/beta/KiP1/KiP2+Glu_cyt*Asp_cyt/gamma/KiS2/KiP2+Asp*Glu/delta/KiS1/KiP1) KiP2=0.0028; v22_AGC=3.3211E-4; KiS2=0.0032; KcR=10.0; KcF=10.0; alpha=1.0; delta=1.0; KiS1=8.0E-5; KiP1=1.8E-4; beta=1.0; gamma=1.0
IsoCitcyt + NADP_cyt => OG_cyt + NADPH_cyt; CO2 CYTOPLASM*v41_IDHc*(IsoCitcyt*NADP_cyt/(phi0*IsoCitcyt*NADP_cyt+phi1*NADP_cyt+phi2*IsoCitcyt+phi12)-OG_cyt*NADPH_cyt*CO2/(phir0*OG_cyt*NADPH_cyt*CO2+phir1*NADPH_cyt*CO2+phir2*OG_cyt*CO2+phir3*OG_cyt*NADPH_cyt+phir12*CO2+phir13*NADPH_cyt+phir23*OG_cyt+phir123)) v41_IDHc=3.8617E-7; phir13=1.3E-10; phir123=4.6E-14; phi12=9.0E-8; phi0=0.051; phir23=9.4E-8; phi2=9.6E-7; phir1=3.7E-7; phir12=6.0E-12; phir2=2.9E-5; phir3=2.5E-4; phir0=0.066; phi1=9.5E-8
Suc + Q => Fum + QH2 MATRIX*KcF*KcR*v16_SDH*(Suc*Q-Fum*QH2/Keq)/(KcR*KmS2*Suc+KcR*KmS1*Q+KcF*KmP2*Fum/Keq+KcF*KmP1*QH2/Keq+KcR*Suc*Q+KcF*KmP2*Suc*Fum/(Keq*KiS1)+KcF*Fum*QH2/Keq+KcR*KmS1*Q*QH2/KiP2) KmP1=3.0E-7; KmP2=1.5E-6; KmS1=3.0E-5; KiP2=5.6E-6; Keq=0.037; KiS1=4.1E-6; v16_SDH=9.9211E-5; KmS2=6.9E-5; KcR=1.73; KcF=69.3
GDP + SCoA + Pi => Suc + GTP + CoA MATRIX*(GDP*SCoA*pi-Suc*GTP*CoA/Keq)*(Kc1*v15_SCS+Kc2*v15_SCS*(KmC*Suc/KmC2*Kip+pi/KmC2))/(Kia*KmB*pi+KmB*GDP*pi+KmA*SCoA*pi+KmC*GDP*SCoA+GDP*SCoA*pi+GDP*SCoA*pi*pi/KmC2+Kia*KmB*KmC*Suc/Kip+Kia*KmB*KmC*Suc*GTP/Kip/Kiq+Kia*KmB*KmC*Suc*CoA/Kip/Kir+Kia*KmB*Kic*GTP*CoA/KmQ/Kir+Kia*KmB*KmC*Suc*GTP*CoA/Kip/KmQ/Kir+Kia*KmB*KmC*Suc*Suc*GTP*CoA/Kip/KmP2/KmQ/Kir+Kia*KmB*pi*GTP/Kiq+Kia*KmB*pi*CoA/Kir+Kia*KmB*pi*GTP*CoA/KmQ/Kir+Kia*KmB*pi*Suc*GTP*CoA/KmP2/KmQ/Kir+KmB*KmC*GDP*Suc/Kip+KmA*KmC*SCoA*Suc/Kip+KmC*GDP*SCoA*Suc/Kip+KmC*GDP*SCoA*pi*Suc/KmC2/Kip+KmA*SCoA*pi*GTP/Kiq+KmB*GDP*pi*CoA/Kir+KmA*KmC*SCoA*Suc*GTP/Kip/Kiq+KmB*KmC*GDP*Suc*CoA/Kip/Kir) KmQ=7.5E-6; KmC=4.5E-4; Kib=2.0E-5; KmP=6.0E-4; Kip=0.07; Kiq=5.0E-6; Kir=6.7E-6; v15_SCS=3.8617E-7; KmB=3.5E-5; Kc2=100.0; KmA=5.0E-6; KmP2=6.0E-4; Kia=4.0E-4; Keq=8.375; Kic=3.0E-5; Kc1=100.0; KmC2=4.5E-4
ADP + Pi => ATP + H2O MATRIX*v28_Complex_V*V*ADP/(Km+ADP+ADP*ADP/Ki) V=0.075; v28_Complex_V=0.0033211; Km=0.0045; Ki=0.047
Pyr + CoA + NAD_p => CO2 + Acetyl_CoA + NADH MATRIX*KcF*v9_PDC*Pyr*CoA*NAD_p/(KmC*Pyr*CoA+KmB*Pyr*NAD_p+KmA*CoA*NAD_p+Pyr*CoA*NAD_p+KmA*KmP*Kib*Kic/KmR/Kip/Kiq*Acetyl_CoA*NADH+KmC/Kir*Pyr*CoA*NADH+KmB/Kiq*Pyr*NAD_p*Acetyl_CoA+KmA*KmP*Kib*Kic/KmR/Kip/Kia/Kiq*Pyr*Acetyl_CoA*NADH) Kiq=3.5E-5; KmP=5.9E-7; v9_PDC=3.8617E-7; Kic=1.8E-4; KmC=5.0E-5; KmA=2.5E-5; KcF=856.0; KmR=6.9E-7; KmB=1.3E-5; Kip=6.0E-5; Kib=3.0E-4; Kir=3.6E-5; Kia=5.5E-4
Curator's comment:
(added: 01 Dec 2009, 16:35:08, updated: 01 Dec 2009, 16:35:08)
The model reproduces figure 2 of the reference publication. The model was integrated and simulated using Copasi v4.5 (Build 30).