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AWebBasedEducationalSimulation
PackageforGlucoseInsulinLevelsin
theHumanBody

Warning:
"Thesimulatordoesnotdifferentiatebetweenpeopleregarding
theirsex,age,race,orBMI(bodymassindex)insteadit
representsanaverageperson.Also,GlucoSimdoesnottakeinto
accountintraandinterpersonalvariationsanditshouldnotbe
usedformakingmedicaldecisions."
TheGlucoSimshouldonlybeusedforeducationalpurposes.

ModelEquations
OverallModel:
Modeling the glucoseinsulin interaction requires an understanding of the physiological and metabolic
processesthatdeterminetheobservablebehavior.Chemicalreactionsandtransportprocessesforman
integrated network when modeling the glucoseinsulin interaction in human body. A number of
mathematicalmodelsoftheinsulindependent(typeI)diabetesmellitushavebeenpreviouslyreported
in the literature (Puckett, 1992 Cobelli 1983 Bergman, 1973 Leaning 1991). We have extended and
utilized two mathematical models (Puckett, 1992) based on pharmacokinetic diagrams of glucose and
insulin(Figures12),whichrepresentthetransportofglucoseandinsulinthroughthemajorvesselsto
thecapillaries.
Theglucosediagram(Figure1)containstissuesincludingheart,brain,liver,kidneyandmusclewhere
the glucose is used for energy. Glucose excretion by kidney and gastrointestinal tract where the
exogenous glucose enters the blood, are also included. The diagram for insulin (Figure 2) includes
subcutaneoustissueasasourceforinsulin.Itisassumedthatpancreascompletelylackingtheinsulin
production. Removal and degradation of insulin occurs mostly in liver, kidney and peripheral tissue,
they degrade onehalf, onethird and onesixth, respectively, of the insulin presented to them,
regardlessoftheplasmaconcentrationofinsulin.

Figure1.PharmacokineticDiagramoftheGlucoseModel

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Figure2.PharmacokineticDiagramoftheInsulinModel
Changesinbloodflowwouldchangethesefractions,butthemodelflowsareconstant(Hillman,1976).
Mass balances for the glucose model, which is coupled to the insulin model, result in a set of
simultaneousordinarydifferentialequations.
The model to be presented here is a flowlimited model for diabetes mellitus based on the work of
Puckett (1992). A mass balance equation is written for each compartment in the model. The
compartments here represent actual body regions. The advantage of this type of modeling is that the
modeldesignisbasedonanunderstandingofthephysiologyandsimulationsthatcanyieldinsightinto
the physiological processes (Hillman, 1976). The main disadvantage of these models is that the
personal variations in physiological parameters are not taken into account. Therefore, the outputs are
averagevalues.Foratypicalorgan(e.g.liver),massbalanceiswrittenasfollows:

Glucose:

(1)

Insulin:

(2)

PleaseseetheMassBalanceNomenclaturefordetails:
Whentheperfusiontimescalesofthevarioustissuesareconsidered,theyarefoundtobeverysmall.
Therefore, it is assumed that within the individual tissues, changes in the blood glucose and insulin
concentrationsarefast.Thebalancesforeachtissueareinquasisteadystate(i.e.dG/dt@0)shortly
afteraperturbation.SettingdG/dt=0inmassbalanceequations:

(3)
Similarly,settingdI/dt=0intheinsulinequations:

(4)
DetailedModel:
Thequasisteadystateassumptionisremovedandresultingordinarydifferentialequations(seebellow)
forthemassbalancesofglucoseandinsulinaresolvedsimultaneously.

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Glucose:
Circulating
Blood:

(5)

Kidney:

(6)

Nervous
System:

(7)

Periphery:

(8)

Pancreas
&Spleen:

(9)

Gastro
intestinal
Tract:

(10)

Heart:

(11)

Liver:

(12)

Insulin:
Circulating
Blood:

(13)

Kidney:

(14)

Subcutaneous
Tissue:

(15)

Periphery:

(16)

Pancreas
&Spleen:

(17)

Gastro
intestinal
Tract:

(18)

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(19)

Liver:

RepresentationoftheFunctionsforBloodGlucose
Majortissues,includingliver,muscle,adipose,heart,kidneyandbrain,removeglucosefromtheblood
and store or oxidize it for energy. To formulate tissue glucose uptake models, the tissues have been
groupedintothreecategories:(1)Insulinandglucoseindependentuptake:Centralnervoussystemand
red blood cells, (2) Glucose dependent uptake: Kidneys, (3) Insulin and glucose dependent uptake.
Remainingmajortissues:

GlucoseandInsulinIndependentUptake
Theglucoseuptakeratebytheglucoseandinsulinindependenttissuesisconstant.Itwillbe
representedas:

(20)
The brain is the major consumer of this category and is almost totally dependent on glucose as an
energy source. The brain contains only 0.1 weight percent glycogen (Fenn and Rahn, 1965) and thus
must rely on a minutetominute supply of glucose from the blood. Brain glucose uptake rate remains
constant with respect to changes in blood glucose concentration except in the case of severe
hypoglycemia and is not affected by exercise or by elevated metabolite levels following a meal. The
usage by the red blood cells is also constant and relatively small metabolic sink for glucose in the
model.

GlucoseDependentUptake
The only glucose dependent uptake occurs in kidneys where the rate of glucose excretion is equal to
itsrateofglomerularfiltrationminusitsrateoftubularreabsorption(Robinson,1967).Urinaryexcretion
of glucose begins when the blood glucose levels exceed a limit of approximately 176 mg/dl. The
removalrateofglucoseismodeledas:

(21)
where:

GE

glucoseexcretingrate

GB

circulatingplasmaglucoseconcentration(mg/dl)
stepfunctionthatsignifiesthatglucoseexcretiondoesnotoccur
until

Since the glomerular membrane is very permeable and allows everything to pass through except the
red blood cells and most proteins, the filtrate concentration of different species such as glucose is
approximately that of the plasma (Puckett, 1992). The rate at which glucose is filtered can be
calculated by multiplying the plasma glucose concentration by glomerular filtration rate which is 125
ml/min (Guyton, 1976). When the glucose load through the tubules reaches 220 mg/min, the transport
mechanismsforthereabsorptionprocessstartsaturatingandsomeoftheglucoseleavesintheurine.
Inthemodel,thisthresholdisthefactor1.25dl/min*176mg/dl.

InsulinandGlucoseDependentUptake
ThefollowingmodelbyPuckett(1992)fortotalglucoseuptake(TGU)ratewhichincludestheinsulinand
glucosedependentuptakeandinsulinandglucoseindependentuptakeisvalidatedbyusingtheisotope
datefromPehlingetal.Thedelayininsulinactioninthismodelhasbeenapproximatedasafirstorder
systemwithatimedelay.

(22)
(23)
where:

IA

effectiveinsulinconcentrationoractivity

IBD

circulatingbloodinsulinconcentrationdelayedbyTD,TGU

TD,TGU

puretimedelayforthetotalglucoseuptake

TIA

firstordertimeconstantforinsulinactionactivation

rateconstantforthetotalglucoseuptake

CNU

glucoseandinsulinindependentuptakerate

IB0

initialbloodinsulinconcentration

ThismodelproposedbyPuckett(1992)issimilartoanothermodelavailableintheliterature(Radziuket
al.,1974),andtheparameterestimatesshowsimilarresults.

GlucoseInputForcingFunctions
Glucose enters the blood either through the small intestine of from the liver. Therefore, first

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ModelEquations
carbohydrate ingestion must be supplied to the model as a given input. Secondly, liver glucose
production (LGP) needs to be modeled. The model has been adapted from Biermann and Mehnert
(1990)torepresentglucoseabsorptionratefromthesmallintestine.Thisisanempiricalrepresentation
of the absorption process and instead of using the parameter estimates obtained by Biermann and
Mehnert(1990),thedategiveninPehlingetal.(1984)hasbeenfittothemodelbyPuckett(1992).
Therateofabsorbtionfromthesmallintestineis:

(24)
where:

TA

timeconstantforabsorbtionratetoequilibratewithgastricemptying

fractionofmealcarbohydratesthatactuallyabsorbintotheblood

Thetotalamountofglucoseinthestomachis:

(25)
where:

TGE

timeconstantforgastricemptying(min)

Thecumulativeamountofglucose(i.e.hydrolyzedcarbohydrates)fromthemealthatappearsinthe
stomachis:

(26)

where:

CHOG

rateofhydrolyzedmealcarbohydratesthatentersthestomach(mg/kgmin)

CHOM

carbohydratecontentofthemeal(mg/kg)

tM

timeofthemeal(min)

time(min)

LiverGlucoseProduction
The following submodel has been proposed by Puckett (1992) for the rate of liver glucose production
(LGP).TheparametershavebeenobtainedbyusingtheexperimentaldataofLGPfromPehlingetal.
(1984).
Therateofliverglucoseproductionis:

(27)

(28)

where:

GID

GLDxIBDdelayedinafirstordermannerwithatimeconstantk A1ork D1

a1a4

constantsforthequasisteadystaterelationshipsthatlinkthehormoneand
theratelimitingsteps

GLD

averageglucoseconcentrationenteringtheliverdelayedbyTD,LGP(mg/dl)

IBD

circulatingbloodinsulinconcentrationdelayedbyTD,LGP(U/dl)

k A1

timeconstantfortheactivationofprocessesthatcausesuppressionof
liver
glucoseproduction(min)

k D1

timeconstantfortheactivationofprocesses(min)

ThismodelproposedbyPuckett(1992)issimilartoanothermodelavailableintheliterature(Radziuket
al.,1974),andtheparameterestimatesshowsimilarresults.

SubcutaneousInsulinTransportModels
Puckett and Lightfoot (1995) have determined that a threepool model similar to the model of Kraegen
and Chisholm (1984) is necessary to describe patients data. The following threepool model has been

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foundtoproduceanadequatefittopatientdataanddescribestheabsorptionfromaninjectionofshort
actinginsulinatt=0(Puckett,1992).

(29)

(30)

(31)
where:

IP

totalamountofinsulinpocket(U/dl)

IS

insulinconcentrationininterstitialfluid(U/dl)

IB

insulinconcentrationinthecapillaryblood(U/dl)

kP

rateconstantforthetransportofinsulinfromthepocketintothe
surrounding
interstitialfluid(min1)

kS

rateconstantforthetransportofinsulinfromtheinterstitialregiontothe
capillaryblood(min1)

kB

rateconstantfortheremovalofinsulinintheliverandkidney(min1)

VS,VB

correspondingpoolvolumes(ml)

,and

ThismodelproposedbyPuckett(1992)issimilartoanothermodelavailableintheliterature(Radziuket
al.,1974),andtheparameterestimatesshowsimilarresults.

ModelDevelopmentforHealthyPeople
The only difference from the insulin model of diabetic patients is that injection from subcutaneous
tissueisomittedandpancreaticinsulinreleaseisincludedinstead.Thediagramfortheglucosemodel
remains the same. In this work, two pancreatic insulin release (PIR) models have been used for
simulatingtheinsulinreleasebypancreas.ThefirstmodelistheonedevelopedbyCarsonandCramp
(1976).Intheirwork,theinsulinreleasehasbeendefinedas:

(32)
where:

BPIR

basalinsulinreleaserate=4U/min

glucoseconcentration

GB

basalglucoseconcentration=90mg/dl

c1

constant(U/min)(mg/dl)1

c2

constant(U/min)(mg/dl)1

andthesuperscript0+indicatesthattheargumentsinbracketsassumeavalueofzerounlesstheyare
greaterthanzero.
ThesecondmodelistheisletinsulinresponsemodeldevelopedbyNomuraetal.(1984)forratislets.
When islets are used in place of insulin injections, a model is needed to describe the insulin release
rate from an islet and its dependence on plasma glucose levels. This model treats the islet insulin
release rate as a proportionalderivative control system. This response is represented by the following
generalequation:

(33)

NomenclatureforMassBalances
Variables:
G
I
Q
V
t
r

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GlucoseConcentration(mg/dl)
InsulinConcentration(U/dl)
BloodFlowRate(dl/min)
Volume(dl)
Time(min)
MetabolicSourceorSinkRate(mg/min)

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Subscripts:

PhysiologicalCompartments

B
HA
K
NS
PR
PN
PV
GT
H
L
SC

Blood
HepaticArtery
Kidney
NervousSystem
Periphery
PancreasandSpleen
PortalVein
GastrointestinalTract
Heart
Liver
SubcutaneousTissue

Subscripts:

MetabolicRates

KGU
NSGU
HGU
LGU
PRGU
LGP
GA
GE
KIR
PRIR
LIR
IA

KidneyGlucoseUtilization
NervousSystemGlucoseUtilization
HeartGlucoseUtilization
LiverGlucoseUtilization
PeripheryGlucoseUtilization
LiverGlucoseProduction
GlucoseAbsorbtion
GlucoseExcretion
KidneyInsulinRemoval
PeripheryInsulinRemoval
LiverInsulinRemoval
InsulinAbsorbtion

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