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MODEL1209260000
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reaction: 096723
reaction: 096591
notes: Kinetic Modeling of Human Hepatic Glucose Metabolism in Type 2 Diabetes Mellitus Predicts Higher Risk of Hypoglycemic Events in Rigorous Insulin Therapy* Kinetic Model of Human Hepatic Glucose Metabolism in T2DM Authors Matthias Koenig and Hermann-Georg Holzhuetter Corresponding Author Matthias Koenig matthias.koenig@charite.de Charite Berlin, Computational Systems Biochemistry, Germany Keywords hepatic glucose metabolism; kinetic model; glucose homeostasis; liver, T2DM A major problem in the insulin therapy of patients with diabetes type 2 (T2DM) is the increased occurrence of hypoglycemic events which, if left untreated, may cause confusion or fainting and in severe cases seizures, coma, and even death. To elucidate the potential contribution of the liver to hypoglycemia in T2DM we applied a detailed kinetic model of human hepatic glucose metabolism to simulate changes in glycolysis, gluconeogenesis, and glycogen metabolism induced by deviations of the hormones insulin, glucagon, and epinephrine from their normal plasma profiles. Our simulations reveal in line with experimental and clinical data from a multitude of studies in T2DM, (i) significant changes in the relative contribution of glycolysis, gluconeogenesis, and glycogen metabolism to hepatic glucose production and hepatic glucose utilization; (ii) decreased postprandial glycogen storage as well as increased glycogen depletion in overnight fasting and short term fasting; and (iii) a shift of the set point defining the switch between hepatic glucose production and hepatic glucose utilization to elevated plasma glucose levels, respectively, in T2DM relative to normal, healthy subjects. Intriguingly, our model simulations predict a restricted gluconeogenic response of the liver under impaired hormonal signals observed in T2DM, resulting in an increased risk of hypoglycemia. The inability of hepatic glucose metabolism to effectively counterbalance a decline of the blood glucose level becomes even more pronounce…
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is described by: http://identifiers.org/pubmed/22977253
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species: 096047
type: SpeciesReference

096363
in compartment: 095758
is: SBO:0000299
boundary condition: false
initial concentration: 0.24
type: Species
name: nadh_mito
is: C00004
initial amount: NaN
has only substance units: false
constant: false

096711
product: 168147
reversible: true
product: 168099
is: Q16822
product: 168111
product: 168159
name: PEPCK_mito
product: 168135
fast: false
type: Reaction
is: R00431
is: SBO:0000014
reactant: 168075
reactant: 168087
product: 168123

096291
in compartment: 095758
is: SBO:0000299
is: C00035
initial amount: NaN
constant: false
name: gdp_mito
has only substance units: false
initial concentration: 0.1
boundary condition: false
type: Species

095891
in compartment: 095734
initial concentration: 5.6E-4
is: SBO:0000299
has only substance units: false
name: nadh
type: Species
is: C00004
initial amount: NaN
constant: false
boundary condition: false

167799
is: SBO:0000015
stoichiometry: 1.0
species: 095903
type: SpeciesReference

168099
is: SBO:0000011
stoichiometry: 1.0
species: 096218
type: SpeciesReference

167415
is: SBO:0000015
stoichiometry: 1.0
species: 095866
type: SpeciesReference

168555
is: SBO:0000011
stoichiometry: 1.0
species: 096279
type: SpeciesReference

167223
is: SBO:0000015
stoichiometry: 1.0
species: 095963
type: SpeciesReference

167079
is: SBO:0000015
stoichiometry: 1.0
species: 096158
type: SpeciesReference

096639
reactant: 167787
type: Reaction
fast: false
reactant: 167811
product: 167835
is: P04406
reversible: true
name: GAPDH
is: R01061
is: SBO:0000014
product: 167847
reactant: 167799
product: 167823

095794
constant: false
in compartment: 095734
name: atp
initial concentration: 2.8
is: C00002
initial amount: NaN
type: Species
is: SBO:0000299
has only substance units: false
boundary condition: false

167163
is: SBO:0000015
stoichiometry: 1.0
species: 096023
type: SpeciesReference

167871
is: SBO:0000015
stoichiometry: 1.0
species: 096096
type: SpeciesReference

096194
initial concentration: 0.01
initial amount: NaN
has only substance units: false
is: C00036
in compartment: 095758
is: SBO:0000299
boundary condition: false
constant: false
type: Species
name: oaa_mito

167607
is: SBO:0000011
stoichiometry: 1.0
species: 095903
type: SpeciesReference

168267
is: SBO:0000015
stoichiometry: 1.0
species: 096146
type: SpeciesReference

168495
is: SBO:0000011
stoichiometry: 1.0
species: 096242
type: SpeciesReference

168351
is: SBO:0000015
stoichiometry: 1.0
species: 096254
type: SpeciesReference

096339
name: h_mito
boundary condition: false
initial amount: NaN
is: C00011
is: SBO:0000299
initial concentration: 1.0E-8
has only substance units: false
constant: false
type: Species
in compartment: 095758

168627
is: SBO:0000015
stoichiometry: 1.0
species: 096242
type: SpeciesReference

168291
is: SBO:0000011
stoichiometry: 1.0
species: 096170
type: SpeciesReference

167943
is: SBO:0000011
stoichiometry: 1.0
species: 095927
type: SpeciesReference

095806
is: C00008
has only substance units: false
in compartment: 095734
initial concentration: 0.8
constant: false
initial amount: NaN
is: SBO:0000299
boundary condition: false
name: adp
type: Species

095951
initial concentration: 5.0E-8
is: C00080
constant: false
type: Species
name: h
in compartment: 095734
boundary condition: false
has only substance units: false
is: SBO:0000299
initial amount: NaN

167235
is: SBO:0000011
stoichiometry: 1.0
species: 096023
type: SpeciesReference

167847
is: SBO:0000011
stoichiometry: 1.0
species: 096096
type: SpeciesReference

096423
product: 167091
reactant: 167079
is: P11168
is: SBO:0000284
fast: false
reversible: true
name: GLUT2
type: Reaction

168315
is: SBO:0000015
stoichiometry: 1.0
species: 096206
type: SpeciesReference

096675
reactant: 167931
fast: false
product: 167943
is: R00658
name: EN
is: P06733
type: Reaction
is: P13929
reversible: true
is: P09104
product: 167955
is: SBO:0000014

168567
product: 168579
is: SBO:0000014
fast: false
reversible: true
name: OAAFLX
type: Reaction

167487
is: SBO:0000011
stoichiometry: 1.0
species: 095830
type: SpeciesReference

096133
is: SBO:0000299
initial amount: NaN
in compartment: 095734
is: C00036
has only substance units: false
initial concentration: 0.01
boundary condition: false
type: Species
name: oaa
constant: false

167787
is: SBO:0000015
stoichiometry: 1.0
species: 095878
type: SpeciesReference

095903
initial amount: NaN
in compartment: 095734
is: SBO:0000299
boundary condition: false
type: Species
constant: false
name: p
has only substance units: false
is: C00009
initial concentration: 5.0

168615
reactant: 168627
is: SBO:0000014
fast: false
reversible: true
name: VCITFLX
type: Reaction

096747
is: R00209
fast: false
is: SBO:0000014
product: 168447
type: Reaction
is: P09622
reversible: false
product: 168435
product: 168411
reactant: 168375
is: P08559
is: P11177
reactant: 168399
is: P10515
is: O00330
reactant: 168387
name: PDH
product: 168423

096399
has only substance units: false
is: C00723
constant: false
is: SBO:0000299
boundary condition: false
initial concentration: 7.61E-8
in compartment: 095746
name: insulin_blood
initial amount: NaN
is: P01308
type: Species

096495
is: Q15181
fast: false
name: PPASE
reactant: 167307
product: 167319
reactant: 167295
is: R00004
is: SBO:0000014
type: Reaction
reversible: false

168003
is: SBO:0000011
stoichiometry: 1.0
species: 096146
type: SpeciesReference

167619
is: SBO:0000011
stoichiometry: 1.0
species: 096011
type: SpeciesReference

168255
is: SBO:0000015
stoichiometry: 1.0
species: 095951
type: SpeciesReference

095758
is: GO:0005739
is: SBO:0000290
constant: true
size: 1.0
spatial dimensions: 3.0
name: mito
type: Compartment

095782
is: GO:0005886
is: SBO:0000290
constant: true
size: 0.0
spatial dimensions: 2.0
name: pm
type: Compartment

167175
is: SBO:0000011
stoichiometry: 1.0
species: 095903
type: SpeciesReference

096471
product: 167235
fast: false
name: G16PI
type: Reaction
is: SBO:0000014
reactant: 167223
is: Q96G03
is: P36871
reversible: true
is: R00959

096182
type: Species
has only substance units: false
is: C00009
in compartment: 095758
is: SBO:0000299
boundary condition: false
constant: false
initial concentration: 5.0
name: p_mito
initial amount: NaN

167559
is: SBO:0000011
stoichiometry: 1.0
species: 095806
type: SpeciesReference

095818
has only substance units: false
name: amp
in compartment: 095734
constant: false
is: SBO:0000299
initial amount: NaN
initial concentration: 0.16
boundary condition: false
type: Species
is: C00020

167247
is: SBO:0000015
stoichiometry: 1.0
species: 095830
type: SpeciesReference

168303
product: 168327
reactant: 168315
is: SBO:0000284
fast: false
reversible: true
name: LACT
type: Reaction

096411
constant: false
type: Species
has only substance units: false
name: h20_mito
in compartment: 095758
initial amount: NaN
is: SBO:0000299
boundary condition: false
initial concentration: 55000.0
is: C00080

167931
is: SBO:0000015
stoichiometry: 1.0
species: 096121
type: SpeciesReference

096327
initial amount: NaN
has only substance units: false
in compartment: 095758
is: SBO:0000299
boundary condition: false
constant: false
name: nad_mito
initial concentration: 0.98
type: Species
is: C00003

167859
is: SBO:0000015
stoichiometry: 1.0
species: 095806
type: SpeciesReference

095963
has only substance units: false
in compartment: 095734
boundary condition: false
constant: false
is: SBO:0000299
initial amount: NaN
type: Species
name: glc1p
initial concentration: 0.012
is: C00103

168147
is: SBO:0000011
stoichiometry: 1.0
species: 096327
type: SpeciesReference

167919
is: SBO:0000011
stoichiometry: 1.0
species: 096121
type: SpeciesReference

167775
is: SBO:0000011
stoichiometry: 1.0
species: 096071
type: SpeciesReference

096121
boundary condition: false
is: C00631
constant: false
type: Species
name: pg2
in compartment: 095734
is: SBO:0000299
initial amount: NaN
has only substance units: false
initial concentration: 0.03

168579
is: SBO:0000011
stoichiometry: 1.0
species: 096194
type: SpeciesReference

096687
product: 167991
reactant: 167979
reversible: false
is: SBO:0000014
product: 168003
fast: false
is: P30613
name: PK
reactant: 167967
is: R00200
type: Reaction

167475
is: SBO:0000011
stoichiometry: 1.0
species: 095806
type: SpeciesReference

168603
is: SBO:0000015
stoichiometry: 1.0
species: 096267
type: SpeciesReference

168159
is: SBO:0000011
stoichiometry: 1.0
species: 096339
type: SpeciesReference

096771
product: 168555
reactant: 168519
name: NDK_mito
type: Reaction
reactant: 168531
fast: false
is: R00330
is: SBO:0000014
reversible: true
product: 168543

096591
product: 167667
reactant: 167643
product: 167655
is: P17858
is: SBO:0000014
is: R00756
reversible: false
type: Reaction
name: PFK1
fast: false
reactant: 167631

167331
is: SBO:0000015
stoichiometry: 1.0
species: 095975
type: SpeciesReference

167631
is: SBO:0000015
stoichiometry: 1.0
species: 095794
type: SpeciesReference

096735
is: P07864
reactant: 168243
fast: false
type: Reaction
is: SBO:0000014
reactant: 168267
reactant: 168255
name: LDH
reversible: true
product: 168291
product: 168279
is: P00338
is: P07195

096387
name: glucagon_blood
initial concentration: 4.36E-8
constant: false
type: Species
initial amount: NaN
is: C01501
is: P01275
in compartment: 095746
is: SBO:0000299
has only substance units: false
boundary condition: false

168591
reactant: 168603
is: SBO:0000014
fast: false
reversible: true
name: ACOAFLX
type: Reaction