BioModels Database logo

BioModels Database

spacer

BIOMD0000000349 - Fridlyand2010_GlucoseSensitivity_B

 

 |   |   |  Send feedback
Reference Publication
Publication ID: 20497556
Fridlyand LE, Philipson LH.
Glucose sensing in the pancreatic beta cell: a computational systems analysis.
Theor Biol Med Model 2010; 7: 15
Department of Medicine, The University of Chicago, Chicago, IL 60637, USA. lfridlia@medicine.bsd.uchicago.edu  [more]
Model
Original Model: BIOMD0000000349.origin
Submitter: Ishan Ajmera
Submission ID: MODEL1108090001
Submission Date: 09 Aug 2011 18:16:18 UTC
Last Modification Date: 10 Oct 2014 10:29:40 UTC
Creation Date: 09 Aug 2011 18:27:55 UTC
Encoders:  Ishan Ajmera
set #1
bqbiol:hasProperty Human Disease Ontology diabetes mellitus
set #2
bqmodel:isDerivedFrom PubMed 9575813
PubMed 9575814
set #3
bqbiol:isVersionOf Gene Ontology regulation of insulin secretion involved in cellular response to glucose stimulus
Gene Ontology type B pancreatic cell proliferation
set #4
bqbiol:occursIn Brenda Tissue Ontology pancreatic beta cell
set #5
bqbiol:hasTaxon Taxonomy Homo sapiens
Notes

This a model from the article:
Glucose sensing in the pancreatic beta cell: a computational systems analysis.
Fridlyand LE, Philipson LH.Theor Biol Med Model.2010 May 24;7:15. 20497556,
Abstract:
BACKGROUND: Pancreatic beta-cells respond to rising blood glucose by increasing oxidative metabolism, leading to an increased ATP/ADP ratio in the cytoplasm. This leads to a closure of KATP channels, depolarization of the plasma membrane, influx of calcium and the eventual secretion of insulin. Such mechanism suggests that beta-cell metabolism should have a functional regulation specific to secretion, as opposed to coupling to contraction. The goal of this work is to uncover contributions of the cytoplasmic and mitochondrial processes in this secretory coupling mechanism using mathematical modeling in a systems biology approach. METHODS: We describe a mathematical model of beta-cell sensitivity to glucose. The cytoplasmic part of the model includes equations describing glucokinase, glycolysis, pyruvate reduction, NADH and ATP production and consumption. The mitochondrial part begins with production of NADH, which is regulated by pyruvate dehydrogenase. NADH is used in the electron transport chain to establish a proton motive force, driving the F1F0 ATPase. Redox shuttles and mitochondrial Ca2+ handling were also modeled. RESULTS: The model correctly predicts changes in the ATP/ADP ratio, Ca2+ and other metabolic parameters in response to changes in substrate delivery at steady-state and during cytoplasmic Ca2+ oscillations. Our analysis of the model simulations suggests that the mitochondrial membrane potential should be relatively lower in beta cells compared with other cell types to permit precise mitochondrial regulation of the cytoplasmic ATP/ADP ratio. This key difference may follow from a relative reduction in respiratory activity. The model demonstrates how activity of lactate dehydrogenase, uncoupling proteins and the redox shuttles can regulate beta-cell function in concert; that independent oscillations of cytoplasmic Ca2+ can lead to slow coupled metabolic oscillations; and that the relatively low production rate of reactive oxygen species in beta-cells under physiological conditions is a consequence of the relatively decreased mitochondrial membrane potential. CONCLUSION: This comprehensive model predicts a special role for mitochondrial control mechanisms in insulin secretion and ROS generation in the beta cell. The model can be used for testing and generating control hypotheses and will help to provide a more complete understanding of beta-cell glucose-sensing central to the physiology and pathology of pancreatic beta-cells.

This model was taken from the Vcell MathModel directory and was converted to SBML

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: 20497556 Submission Date: 09 Aug 2011 18:16:18 UTC Last Modification Date: 10 Oct 2014 10:29:40 UTC Creation Date: 09 Aug 2011 18:27:55 UTC
Mathematical expressions
Rules
Assignment Rule (variable: ACa) Assignment Rule (variable: AD) Assignment Rule (variable: ADP) Assignment Rule (variable: AT)
Assignment Rule (variable: DelJNCa) Assignment Rule (variable: FDe) Assignment Rule (variable: FLNADc) Assignment Rule (variable: FNADc)
Assignment Rule (variable: FPCa) Assignment Rule (variable: FPNAD) Assignment Rule (variable: FPYR) Assignment Rule (variable: FTe)
Assignment Rule (variable: hCa) Assignment Rule (variable: IKCa) Assignment Rule (variable: IVCa) Assignment Rule (variable: JGlu)
Assignment Rule (variable: Jgpd) Assignment Rule (variable: Jhl) Assignment Rule (variable: Jhres) Assignment Rule (variable: JLDH)
Assignment Rule (variable: JNCa) Assignment Rule (variable: JO2) Assignment Rule (variable: Jph) Assignment Rule (variable: JPYR)
Assignment Rule (variable: Jtnadh) Assignment Rule (variable: Juni) Assignment Rule (variable: MgADP) Assignment Rule (variable: NADc)
Assignment Rule (variable: NADm) Assignment Rule (variable: nKCa) Assignment Rule (variable: PVCa) Rate Rule (variable: G3P)
Rate Rule (variable: PYR) Rate Rule (variable: ATP) Rate Rule (variable: NADHm) Rate Rule (variable: NADHc)
Rate Rule (variable: Vm) Rate Rule (variable: Cam) Rate Rule (variable: Vp) Rate Rule (variable: Cac)
Physical entities
Compartments Species
compartment G3P PYR ATP
NADHm NADHc Vm
Cam    
Global parameters
ai am Ao ATP_init
Cac_init Cam_init Cmit Cmp
F fi fm G3P_init
gKCa Glu gmVCa hgl
hp hpc kat kATP
kATPCa kbt kCaA KCaj
KCam KgNc kgpd Klnc
klp Kmadp KmATP Kmg3p
Kmgl KmLD KmNh Kmph
Kmpyr knadhc knadhm KNaj
KpCam KPNm ksg KTNc
KTNm NADHc_init NADHm_init Nam
Ni Ntc Ntm PCa
Plb Plr PYR_init Tnadh
Tv u1 u2 Vci
Vi Vm_init Vme Vmglu
Vmgpd Vmldh Vmmit Vmnc
Vmpdh Vmph Vp_init ZCa
ACa AD ADP AT
DelJNCa FDe FLNADc FNADc
FPCa FPNAD FPYR FTe
hCa IKCa IVCa JGlu
Jgpd Jhl Jhres JLDH
JNCa JO2 Jph JPYR
Jtnadh Juni MgADP NADc
NADm nKCa PVCa Vp
Cac      
Reactions (0)
Rules (40)
 
 Assignment Rule (name: ACa) ACa = 1+(-1*1/exp(Cam*1/KpCam))
 
 Assignment Rule (name: AD) AD = MgADP*MgADP*1/(MgADP*MgADP+Kmadp*Kmadp)
 
 Assignment Rule (name: ADP) ADP = Ao+(-ATP)
 
 Assignment Rule (name: AT) AT = Vm^hp*1/(Kmph^hp+Vm^hp)
 
 Assignment Rule (name: DelJNCa) DelJNCa = 1+Ni^3*1/KNaj^3+Cam*1/KCaj+Ni^3*Cam*1/(KNaj^3*KCaj)+Nam^3*1/KNaj^3+Cac*1/KCaj+Nam^3*Cac*1/(KNaj^3*KCaj)
 
 Assignment Rule (name: FDe) FDe = NADHm*1/(KmNh+NADHm)
 
 Assignment Rule (name: FLNADc) FLNADc = NADHc*1/(Klnc+NADHc*1/NADc)*1/NADc
 
 Assignment Rule (name: FNADc) FNADc = NADHc*1/(KTNc+NADHc*1/NADc)*1/NADc
 
 Assignment Rule (name: FPCa) FPCa = 1*1/(1+u2*(1+u1*1/(1+Cam*1/KCam)^2))
 
 Assignment Rule (name: FPNAD) FPNAD = NADm*1/(KPNm+NADm*1/NADHm)*1/NADHm
 
 Assignment Rule (name: FPYR) FPYR = PYR*1/(Kmpyr+PYR)
 
 Assignment Rule (name: FTe) FTe = (1+kat*Vm)*1/(1+kbt*Vm)
 
 Assignment Rule (name: hCa) hCa = 1*1/(1+exp(0.166666666666667*(15+Vp)))
 
 Assignment Rule (name: IKCa) IKCa = gKCa*nKCa*(75+Vp)
 
 Assignment Rule (name: IVCa) IVCa = gmVCa*PVCa*hCa*(-100+Vp)
 
 Assignment Rule (name: JGlu) JGlu = Vmglu*Glu^hgl*ATP*1/(Kmgl^hgl+Glu^hgl)*1/(KmATP+ATP)
 
 Assignment Rule (name: Jgpd) Jgpd = Vmgpd*G3P*NADc*1/(G3P+Kmg3p)*1/(KgNc+NADc*1/NADHc)*1/NADHc
 
 Assignment Rule (name: Jhl) Jhl = (Plb+Plr)*exp(klp*Vm)
 
 Assignment Rule (name: Jhres) Jhres = Vme*FTe*FDe
 
 Assignment Rule (name: JLDH) JLDH = Vmldh*FLNADc*PYR*1/(KmLD+PYR)
 
 Assignment Rule (name: JNCa) JNCa = Vmnc*(exp(0.5*Vm*Ni^3*Cam*1/(Tv*KNaj^3*KCaj))+(-exp(-0.5*Vm*Nam^3*Cac*1/(Tv*KNaj^3*KCaj))))*1/DelJNCa
 
 Assignment Rule (name: JO2) JO2 = 0.1*Jhres
 
 Assignment Rule (name: Jph) Jph = Vmph*AD*AT*ACa
 
 Assignment Rule (name: JPYR) JPYR = Vmpdh*FPNAD*FPCa*FPYR
 
 Assignment Rule (name: Jtnadh) Jtnadh = Tnadh*FNADc*NADm*1/(KTNm+NADm*1/NADHm)*1/NADHm
 
 Assignment Rule (name: Juni) Juni = PCa*ZCa*Vm*(am*Cam*exp(-Vm*ZCa*1/Tv)+(-ai*Cac))*1/Tv*1/(-1+exp(-Vm*ZCa*1/Tv))
 
 Assignment Rule (name: MgADP) MgADP = 0.055*ADP
 
 Assignment Rule (name: NADc) NADc = Ntc+(-NADHc)
 
 Assignment Rule (name: NADm) NADm = Ntm+(-NADHm)
 
 Assignment Rule (name: nKCa) nKCa = Cac^3*1/(0.015625+Cac^3)
 
 Assignment Rule (name: PVCa) PVCa = 1*1/(1+exp(0.105263157894737*(-19+(-Vp))))
 
 Rate Rule (name: G3P) d [ G3P] / d t= (2*JGlu+(-Jgpd))*1/Vi+(-kgpd*G3P)
 
 Rate Rule (name: PYR) d [ PYR] / d t= (Jgpd+(-JPYR)+(-JLDH))*1/(Vi+Vmmit)
 
 Rate Rule (name: ATP) d [ ATP] / d t= -(kATP+kATPCa*Cac)*ATP+(2*JGlu+0.231*Jph)*1/Vi
 
 Rate Rule (name: NADHm) d [ NADHm] / d t= (4.6*JPYR+(-0.1*Jhres)+Jtnadh)*1/Vmmit+(-knadhm*NADHm)
 
 Rate Rule (name: NADHc) d [ NADHc] / d t= (Jgpd+(-Jtnadh)+(-JLDH))*1/Vi+(-knadhc*NADHc)
 
 Rate Rule (name: Vm) d [ Vm] / d t= (Jhres+(-Jph)+(-Jhl)+(-2*Juni)+(-JNCa))*1/Cmit
 
 Rate Rule (name: Cam) d [ Cam] / d t= fm*(Juni+(-JNCa))*1/Vmmit
 
 Rate Rule (name: Vp) d [ Vp] / d t= -(IVCa+IKCa)*1/Cmp
 
 Rate Rule (name: Cac) d [ Cac] / d t= -fi*IVCa*1/(2*F*Vci)+(-ksg*Cac)
 
   Spatial dimensions: 3.0  Compartment size: NaN
 
 G3P
Compartment: compartment
 
 PYR
Compartment: compartment
 
 ATP
Compartment: compartment
 
 NADHm
Compartment: compartment
 
 NADHc
Compartment: compartment
 
 Vm
Compartment: compartment
 
 Cam
Compartment: compartment
 
Global Parameters (105)
 
 ai
Value: 0.341
Constant
 
 am
Value: 0.2
Constant
 
 Ao
Value: 4000.0
Constant
 
 ATP_init
Value: 3700.0
Constant
 
 Cac_init
Value: 0.1
Constant
 
 Cam_init
Value: 0.2
Constant
 
 Cmit
Value: 1.82
Constant
 
 Cmp
Value: 6158.0
Constant
 
 F
Value: 96480.0
Constant
 
 fi
Value: 0.01
Constant
 
 fm
Value: 3.0E-4
Constant
 
 G3P_init
Value: 30.0
Constant
 
 gKCa
Value: 25.0
Constant
 
 Glu
Value: 8.0
Constant
 
 gmVCa
Value: 20.0
Constant
 
 hgl
Value: 1.7
Constant
 
 hp
Value: 8.0
Constant
 
 hpc
Value: 8.0
Constant
 
 kat
Value: -0.00492
Constant
 
 kATP
Value: 4.0E-5
Constant
 
 kATPCa
Value: 9.0E-5
Constant
 
 kbt
Value: -0.00443
Constant
 
 kCaA
Value: 30.0
Constant
 
 KCaj
Value: 8.0
Constant
 
 KCam
Value: 0.05
Constant
 
 KgNc
Value: 0.09
Constant
 
 kgpd
Value: 1.0E-5
Constant
 
 Klnc
Value: 1.0
Constant
 
 klp
Value: 0.0305
Constant
 
 Kmadp
Value: 20.0
Constant
 
 KmATP
Value: 500.0
Constant
 
 Kmg3p
Value: 200.0
Constant
 
 Kmgl
Value: 7.0
Constant
 
 KmLD
Value: 47.5
Constant
 
 KmNh
Value: 3000.0
Constant
 
 Kmph
Value: 131.4
Constant
 
 Kmpyr
Value: 47.5
Constant
 
 knadhc
Value: 1.0E-4
Constant
 
 knadhm
Value: 1.0E-4
Constant
 
 KNaj
Value: 8000.0
Constant
 
 KpCam
Value: 0.165
Constant
 
 KPNm
Value: 81.0
Constant
 
 ksg
Value: 2.0E-5
Constant
 
 KTNc
Value: 0.0020
Constant
 
 KTNm
Value: 16.78
Constant
 
 NADHc_init
Value: 10.0
Constant
 
 NADHm_init
Value: 50.0
Constant
 
 Nam
Value: 5000.0
Constant
 
 Ni
Value: 10000.0
Constant
 
 Ntc
Value: 2000.0
Constant
 
 Ntm
Value: 2200.0
Constant
 
 PCa
Value: 0.0040
Constant
 
 Plb
Value: 0.0012
Constant
 
 Plr
Value: 0.0012
Constant
 
 PYR_init
Value: 10.0
Constant
 
 Tnadh
Value: 0.05
Constant
 
 Tv
Value: 26.73
Constant
 
 u1
Value: 1.5
Constant
 
 u2
Value: 1.1
Constant
 
 Vci
Value: 0.764
Constant
 
 Vi
Value: 0.53
Constant
 
 Vm_init
Value: 100.0
Constant
 
 Vme
Value: 22.0
Constant
 
 Vmglu
Value: 0.011
Constant
 
 Vmgpd
Value: 0.5
Constant
 
   Vmldh
Value: 1.2
Constant
 
 Vmmit
Value: 0.0144
Constant
 
 Vmnc
Value: 0.025
Constant
 
 Vmpdh
Value: 0.3
Constant
 
 Vmph
Value: 8.0
Constant
 
 Vp_init
Value: -70.0
Constant
 
 ZCa
Value: 2.0
Constant
 
   ACa
Value: NaN
 
   AD
Value: NaN
 
   ADP
Value: NaN
 
   AT
Value: NaN
 
   DelJNCa
Value: NaN
 
   FDe
Value: NaN
 
   FLNADc
Value: NaN
 
   FNADc
Value: NaN
 
   FPCa
Value: NaN
 
   FPNAD
Value: NaN
 
   FPYR
Value: NaN
 
   FTe
Value: NaN
 
   hCa
Value: NaN
 
   IKCa
Value: NaN
 
   IVCa
Value: NaN
 
   JGlu
Value: NaN
 
   Jgpd
Value: NaN
 
   Jhl
Value: NaN
 
   Jhres
Value: NaN
 
   JLDH
Value: NaN
 
   JNCa
Value: NaN
 
   JO2
Value: NaN
 
   Jph
Value: NaN
 
   JPYR
Value: NaN
 
   Jtnadh
Value: NaN
 
   Juni
Value: NaN
 
   MgADP
Value: NaN
 
   NADc
Value: NaN
 
   NADm
Value: NaN
 
   nKCa
Value: NaN
 
   PVCa
Value: NaN
 
 Vp
Value: NaN
 
   Cac
Value: NaN
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000349

Curator's comment: (updated: 09 Aug 2011 19:27:40 BST)

The model reproduces figure 11 of the reference publication. Simulation of the model predicts the dynamics of metabolic and membrane variable in beta cell for independent Ca+2 oscillation.
The model was integrated and simulated using Copasi v4.7 (Build 34).

spacer
spacer