ATP_ADP_CHANGE

ATP+ADP change

∅ > atp

ATPconsumption

ATP consumption

atp + h2o > adp + phos + h

ATPformation

ATP formation

adp + phos + h > atp + h2o

ENO

Enolase (ENO)

pg2 = pep + h2o

FBA

Fructose-Bisphosphate Aldolase (FBA)

fbp = dhap + grap

FBP

Fructose-Bisphosphatase (FBP)

fbp + h2o > f6p + phos

FBP26

Fructose-2, 6-Bisphosphate 2-Phosphatase (FBP26)

f26bp + h2o > f6p + phos

GAPD

Glyceraldehyde-3-Phosphate Dehydrogenase (GAPD)

grap + phos + nad = bpg13 + nadh + h

GLCt1r

Glucose Import (GLUT)

glc_ext = glc

HEX1

Hexokinase (D-Glucose:ATP) (HEX1)

glc + atp = g6p + adp + h

IRS

IRS insulin secretion

∅ > ins_ext + cpep_ext

LDH_L

L-Lactate Dehydrogenase (LDH_L)

pyr + nadh + h = lac + nad

L_LACt2r

L-Lactate Transport (L_LACt2r)

lac > lac_ext

PFK

Phosphofructokinase (PFK)

f6p + atp > adp + fbp + h

PFK26

6-Phosphofructo-2-Kinase (PFK26)

atp + f6p > adp + f26bp + h

PGI

Glucose-6-Phosphate Isomerase (PGI)

g6p = f6p

PGK

Phosphoglycerate Kinase (PGK)

adp + bpg13 = atp + pg3

PGM

Phosphoglycerate Mutase (PGM)

pg3 = pg2

PYK

Pyruvate Kinase (PYK)

pep + adp + h = pyr + atp

PYRt2r

Transport of Pyruvate (PYRt2r)

pyr > pyr_mito

TPI

Triose-Phosphate Isomerase (TPI)

dhap = grap

cpep_ext*

glc_ext*

h*

h2o*

ins_ext*

lac_ext*

pyr_mito*

adp*

atp*

bpg13*

dhap*

f26bp*

f6p*

fbp*

g6p*

glc*

grap*

lac*

pep*

pg2*

pg3*

pyr*

Assignment rules

ext = 1000.0 * cell

cyto = 0.95 * cell

mito = 0.05 * cell

atp_adp = atp + adp

atp_ratio = atp / (adp + 1e-8)

nadh_nad = nadh + nad

nadh_ratio = nadh / (nad + 1e-8)

fbp_grap = fbp + grap

fbp_dhap_grap = fbp + dhap + grap

fbp_dhap = fbp + dhap

lac_pyr_ratio = lac / pyr

phos = piecewise(10.1746465657385, lt(glc_ext, 2.4), 10.1746465657385 + -0.184822580052604 * (glc_ext - 2.4), and(geq(glc_ext, 2.4), lt(glc_ext, 4.0)), 9.87893043765431 + -0.184822580052604 * (glc_ext - 4.0), and(geq(glc_ext, 4.0), lt(glc_ext, 8.6)), 9.02874656941233 + -0.184822580052604 * (glc_ext - 8.6), and(geq(glc_ext, 8.6), lt(glc_ext, 14.5)), 7.93829334710197 + -0.184822580052604 * (glc_ext - 14.5), and(geq(glc_ext, 14.5), lt(glc_ext, 16.0)), 7.66105947702306, geq(glc_ext, 16.0), 0.0)

nad = 0.3 * (pow(glc_ext, 1.39) / (pow(glc_ext, 1.39) + pow(5.32, 1.39))) + 0.59

nadh = 0.23 * (pow(glc_ext, 1.53) / (pow(glc_ext, 1.53) + pow(9.13, 1.53))) + 0.13

datp_dt = ATPformation - ATPconsumption + PGK + PYK - PFK26 - HEX1 - PFK + ATP_ADP_CHANGE

IRS_per_vol = IRS / cell

atp_adp_ss = 1.87 * (pow(glc_ext, 2.03) / (pow(glc_ext, 2.03) + pow(4.01, 2.03))) + 4.66

IRS_ss = IRSss_Vm * (pow(atp / adp, IRSss_hillatp_ratio) / (pow(atp / adp, IRSss_hillatp_ratio) + pow(IRSss_Katp_ratio, IRSss_hillatp_ratio)))

IRS_fp = piecewise(IRSfp_Vm * datp_dt / (datp_dt + IRSfp_Kdatp_dt), gt(datp_dt, 0.0), 0.0)

Function definitions

event_simulation

Trigger: geq(time, presim_duration)

Delay:

Assignments:

• glc_ext = sim_glc_ext

event_presimulation

Trigger: and(gt(presim_duration, 0), lt(time, presim_duration))

Delay:

Assignments:

• glc_ext = presim_glc_ext

Note that constraints are not enforced in simulations. It remains the responsibility of the user to verify that simulation results satisfy these constraints.