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modelo matematico insulina

modelo matematico insulina

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01/29/2015

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Please
 
cite
 
thisarticle
 
inpressas:R.Burattini,M.Morettini,Identificationofanintegratedmathematicalmodelofstandardoralglucose
 
tolerancetestfor
 
characterizationofinsulinpotentiationinhealth,Comput.MethodsProgramsBiomed.(2011),doi:10.1016/j.cmpb.2011.07.002
ARTICLE IN PRESS
COMM-3248;No.ofPages14
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 journalhomepa
 
ge:www.intl.elsevierhealth.com/journals/cmpb
Identification
 
of 
 
an
 
integratedmathematicalmodelof standardoralglucosetolerancetestfor
 
characterization
 
of insulin
 
potentiation
 
in
 
health
Roberto
 
Burattini
,
 
MicaelaMorettini
Department
 
ofInformationEngineering,PolytechnicUniversityofMarche,Via
 
BrecceBianche,60131
 
 Ancona,Italy
art
 
ic
 
le
 
in
 
fo
 Articlehistory:
Received10
 
December2010Receivedinrevisedform14
 
May2011Accepted4
 
 July2011
Keywords:
Glucose-insulinsystemGastric
 
emptyingOralglucose
 
absorptionGIPGLP-1IncretineffectParameterestimation
ab
 
s
 
t
 
rac
 
t
Two
 
newformulations,respectivelydenominatedINT M1
 
and
 
INT M2,ofanintegratedmathematicalmodelto
 
describe
 
the
 
glycemic
 
and
 
insulinemic
 
responsesto
 
a75
 
g
 
oralglucose
 
tolerance
 
test
 
(OGTT)are
 
proposedand
 
compared.The
 
INTM1
 
assumesasin-gle
 
compartmentfor
 
the
 
intestine
 
and
 
the
 
derivative
 
ofapower
 
exponentialfunctionfor
 
the
 
gastric
 
emptying
 
rate,while,inthe
 
INTM2,anonlinearthree-compartmentsys-tem
 
modelisadoptedto
 
produce
 
amore
 
realistic,multiphase
 
gastric
 
emptying
 
rate.Bothmodelswere
 
implementedina
Matlab
-based,two-stepprocedure
 
for
 
estimationofsevenadjustable
 
coefficientscharacterizingthe
 
gastric
 
emptying
 
rate
 
and
 
the
 
incretin,insulinandglucose
 
kinetics.Modelbehaviourwastestedvs.meanplasmaglucagon-like
 
peptide
 
1
 
(GLP-1),glucose-dependentinsulinotropic
 
polypeptide
 
(GIP),glucose
 
and
 
insulinmeasurementsfromtwo
 
different
 
laboratories,where
 
glycemic
 
profilesobservedduring
 
a75
 
g
 
OGTTwerematched
 
inhealthysubjects(HC1-and
 
HC2-group,respectively)bymeansofanisoglycemicintravenousglucose
 
(I-IVG)infusion.Under
 
the
 
hypothesisofanadditive
 
effect
 
ofGLP-1and
 
GIPoninsulinpotentiation,our
 
resultsdemonstratedasubstantialequivalence
 
ofthetwo
 
modelsinmatching
 
the
 
data.Modelparameterestimatesshowedto
 
be
 
suitable
 
mark-ers
 
ofdifferencesobservedinthe
 
OGTTand
 
matchedI-IVG
 
responsesfromthe
 
HC1-groupcomparedto
 
the
 
HC2-group.Modelimplementationinour
 
two-stepparameterestimationprocedure
 
enhancesthe
 
possibilityofaprospective
 
applicationfor
 
individualizationoftheincretineffect
 
inasingle
 
subject,whenhis/her
 
dataare
 
pluggedin.©
 
2011
 
Elsevier
 
IrelandLtd.Allrightsreserved.
1.
 
Introduction
Mathematicalmodelling
 
inthe
 
assessment
 
ofinsulin–glucoseinteractionshasalongstandingtradition,and
 
reportedmod-elsshowawide
 
degree
 
ofcomplexitydepending
 
ontheirpurpose.Besidesmodelsofminimalcomplexity,some
 
of whichare
 
referredto
 
as“minimalmodels”,after
 
Bergmanet
 
al.[1],increasing
 
relevance
 
isbeing
 
assumedbyintegratedsimu-
Correspondingauthor
.Tel.:+39
 
071
 
2204458;fax:+39
 
071
 
2204224.E-mailaddress:r.burattini@univpm.it(R.Burattini).
lationmodelsofthe
 
glucose-insulincontrolsystemduring
 
anoralglucose
 
tolerance
 
test
 
(OGTT)or
 
mealglucose
 
tolerancetest
 
(MGTT)to
 
improve
 
knowledge
 
ofdiabetespathophys-iologyand
 
assessthe
 
efficacyofhypoglycemic
 
agentsinclinicaldrug
 
development[2–6].Inthiscontext,akeyissue concernsthe
 
modelling
 
ofglucose
 
transit
 
throughthe
 
gastro-intestinaltract,to
 
describe
 
glucose
 
absorption[7–9]and
 
therelated“incretineffect”[8,10–19],mostlydue
 
to
 
the
 
contribu-tionofglucagon-likepeptide-1
 
(GLP-1)and
 
glucose-dependent
0169-2607/$
 
see
 
front
 
matter
 
©
 
2011
 
Elsevier
 
IrelandLtd.Allrightsreserved.doi:10.1016/j.cmpb.2011.07.002
 
Please
 
cite
 
thisarticle
 
inpressas:R.Burattini,M.Morettini,Identificationofanintegratedmathematicalmodelofstandardoralglucose
 
tolerancetestfor
 
characterizationofinsulinpotentiationinhealth,Comput.MethodsProgramsBiomed.(2011),doi:10.1016/j.cmpb.2011.07.002
ARTICLE IN PRESS
COMM-3248;No.ofPages14
2
 
c
e
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insulinotropic
 
polypeptide
 
(GIP)releasedinresponse
 
to
 
nutri-ent
 
ingestion,whichstimulate
 
oralglucose
 
dependent
 
insulinsecretion.Apromising
 
simulationmodelofthe
 
oralglucose
 
tolerancetest,primarilyintendedto
 
illustrate
 
the
 
importance
 
ofincretinwithinthe
 
normalrangesobservedclinicallyinhumans,hasrecentlybeenproposedbyBrubakeret
 
al.[4].Unfortunately, asimple
 
empiric
 
descriptionofthe
 
rate
 
ofgastric
 
emptyingofingestedglucose
 
into
 
the
 
gut,
G
empt
,constrainsthe
 
modelto
 
the
 
reproductionofglycemiaand
 
insulinemiaresponsesto
 
50
 
and
 
100
 
g
 
oralglucose
 
loads,and
 
doesnot
 
allowaneffective
 
modeltesting
 
versusexperimentaldatameasuredduring
 
clinicalOGTTprotocols,whichgenerallyconsist
 
oftheadministrationofastandard75
 
g
 
glucose
 
dose.Initsorig-inalformulation[4]the
 
modelwascharacterizedbyfifteenparameters,tenofwhichwere
 
givennumericalvaluesknown
a
 
 priori
frompreviouslyreportedmeasurements,thusleavingfive
 
“adjustableparameters.However,the
 
lack
 
ofavalidationagainst
 
standardOGTTdatalimitsthe
 
reliabilityofthe
 
valuesassumedfor
 
these
 
“adjustable”parameters,thusaffecting
 
thepredictivecapabilitiesofthe
 
model.Basedonthese
 
consider-ations,the
 
aimofthe
 
present
 
studywasto
 
improve
 
the
 
modelformulationbyincorporatingamathematicaldescriptionof oralglucose
 
absorptionthat
 
allowsmodelapplicationto
 
stan-dardOGTTdata,suchthat
 
“adjustable”modelparameterscanbe
 
better
 
assessedbyfitting
 
to
 
clinicaldata.Two
 
competing
 
integratedmathematicalmodelsoforalglucose
 
tolerance
 
test,denominatedINTM1
 
and
 
INTM2,respectively,were
 
obtainedbyincorporatingtwo
 
alterna-tive
 
representationsofglucose
 
absorption.The
 
former
 
modelincorporatesasingle
 
compartmentfor
 
the
 
intestine
 
andthe
 
derivative
 
ofapower
 
exponentialfunctionfor
 
thegastric
 
emptying
 
rate
 
[7].Inthe
 
latter,anonlinearthree-compartmentsystemmodelisadoptedto
 
produce
 
amorerealistic
 
multiphase
 
gastric
 
emptying
 
rate
 
[9].AcomparativeanalysisofINTM1
 
and
 
INTM2
 
behaviourwasperformedintermsoftheir
 
abilityto
 
reproduce
 
the
 
augmentedglucose-dependent
 
plasmainsulinconcentration(generallyreferredto
 
asincretin-inducedinsulinpotentiation)observedafter
 
anOGTT,asit
 
compareswiththe
 
insulinresponse
 
to
 
anintra-venousglucose
 
infusiongiveninamount
 
sufficient
 
to
 
matchthe
 
profile
 
ofglucose
 
concentrationobservedduring
 
OGTT(isoglycemic
 
intravenousglucose,I-IVG,infusion)[15,18,19].Especially,meandataofOGTTand
 
I-IVG
 
responsesfromtwogroupsofmetabolicallyhealthysubjects(here
 
denominatedHC1-and
 
HC2-group),respectivelyreportedbyMuscelliet
 
al.[18]andNauck
 
et
 
al.[15],were
 
usedto
 
test
 
our
 
modelscapabil-ityto
 
reproduce
 
and
 
interpret
 
differencesinessentialaspectsofinsulinpotentiationinhealthobservedinthe
 
datasetsfromthe
 
two
 
different
 
laboratories.
2.
 
Methods
2.1.
 
Modelformulation
The
 
modelpreviouslyproposedbyBrubakeret
 
al.[4]to
 
sim-ulate
 
the
 
glycemic
 
and
 
insulinemic
 
responsesto
 
a50
 
and
 
a100
 
g
 
oralglucose
 
load,withexplicit
 
incorporationofincretinaction,wasusedasabasisto
 
build-upanintegratedmodeluponanOGTTprotocolconsisting
 
oforaladministrationof astandard75
 
g
 
oralglucose
 
load
 
(i.e.1
 
g
 
ofglucose
 
per
 
kgbodyweight,BW,administeredat
 
time
 
t
 
=
 
0
 
min,and
 
stan-dardizedto
 
a75
 
kg
 
individual).To
 
thisaimthe
 
descriptionofthe
 
oralglucose
 
absorptionwasmodifiedbyincorporat-ing
 
either
 
aone-compartmentmodel[7],denotedasM1,or athree-compartmentmodel[9],denotedasM2.The
 
two
 
ver-sionsofour
 
integratedmodel,the
 
flowdiagramofwhichisdepictedinFig.1,were
 
denotedasINTM1
 
whenincorporatingthe
 
M1,and
 
INTM2
 
whenincorporatingthe
 
M2,respectively.The
 
overallmathematicaldescriptionisgiveninthe
 
AppendixA.Description,basalvaluesand
 
unitsfor
 
boththe
 
INTM1andthe
 
INT M2
 
variablesare
 
giveninTable
1.Intheabsence
 
ofmeasurementsofbasalhepatic
 
glucose
 
bal-ance,HGB
b
,the
 
value
 
of0.77
 
mmolmin
1
wasdeducedfromthe
 
literature
 
bymultiplying
 
the
 
BWof75
 
kg
 
times10.25
 
×
10
3
mmolmin
1
kg
1
determinedasthe
 
meanoftwohepatic
 
glucose
 
balance
 
valuesper
 
unit
 
BWreportedbyBellet
 
al.[20](andsummarizedat
 
points3
 
and
 
4
 
ofTable
 
A.1in[21])for
 
humanswithmeanglycemiaof5.28
 
mmolL
1
and
 
meaninsulinemiaof10
 
mU
 
L
1
,whichare
 
consistentwiththe
 
meanfasting
 
valuesofglycemiaand
 
insulinemiacharacterizingour
 
HC1-group(5.4
 
mmolL
1
and
 
10.2
 
mU
 
L
1
,respectively)and
 
HC2-group(5.5
 
mmolL
1
and
 
7.6
 
mU
 
L
1
,respectively).Besidesthe
 
basalvaluesofvariablesasgiveninTable
1,andconsideredthat
 
HGB
b
istreatedasafixedparameter,the
 
INTM1
 
formulationconsistsoffifteenfurther
 
indepen-dent
 
parameters;namely,
k
3
,
k
4
,
k
5
,
k
6
,
k
7
,
k
8
,
k
9
,
 p
,
V
,
M
,
 
,
k
abs
,
 f 
,
k
e
and
 
ˇ
.Instead,the
 
INTM2
 
ischaracterizedbyseventeenparameters,because
 
inthismodelthe
 
k
e
and
 
ˇ
characteristicparametersofthe
 
monophase
 
waveshape
 
forthe
 
rate
 
ofgastric
 
emptying
 
(
G
empt
;Eq.(A1))are
 
replacedbythe
 
c
,
b
,
k
min
,and
 
k
max
coefficientsofthe
 
emptying
 
function
k
empt
(
q
sto
)ofEq.(A10).Quantificationofallthese
 
parameterswasaccomplishedasfollows.The
 
k
3
,
k
4
,
k
6
,
k
9
,
 p
 
and
 
V
wereassumedasfixedand
 
were
 
givennumericalvalues(Table
2)known
a
 
 priori
fromobservationsreportedinthe
 
literature,asdiscussedbyBrubakeret
 
al.[4].The
 
k
abs
,
 f 
,
b
 
and
 
c
 
parame-terspertaining
 
to
 
glucose
 
absorptionwere
 
also
 
assumedasxed(Table
2).Inaccordance
 
withthe
 
validationstudiesonglucose-absorptionmodelsreportedbyDallaMan
 
et
 
al.[9,22],the
 
value
 
of0.22
 
min
1
wasassumedfor
 
the
 
rate
 
constant,
k
abs
,ofintestinalglucose
 
absorption,while
 
the
 
value
 
of0.90wasassumedfor
 
the
 
fraction,
 f 
,ofthe
 
ingestedglucose
 
dose,
D
,that
 
isactuallyabsorbed.Eventually,the
 
b
 
and
 
c
 
dimen-sionlesscoefficientswere
 
giventhe
 
valuesof0.85
 
and
 
0.25,respectively,thusfixing
 
the
 
percentage
 
ofthe
 
glucose
 
dose,
D
,for
 
whichthe
 
emptying
 
function
k
empt
(Eq.(A10))decreases (
b
)and
 
subsequentlyincreases(
c
)at
 
(
k
max
k
min
)/2
 
[9].Theremaining
 
independentmodelparameters,denotedas
k
5
,
k
7
,
k
8
,
M
and
 
 
,whichwere
 
assumedas“adjustable”inthe
 
orig-inalmodelofBrubakeret
 
al.[4]and
 
presumablymanuallyadjusted,were
 
consideredasfree
 
parametersinadditiontothe
 
k
e
and
 
ˇ
inthe
 
INTM1
 
modelformulation,and
 
inadditionto
 
k
min
and
 
k
max
inthe
 
INTM2
 
modelformulation.One
 
novelaspect
 
ofthe
 
present
 
work
 
isthat
 
these
 
free
 
parameterswereautomaticallyestimatedbyatwo
 
step
 
procedure
 
asdescribedinSection2.3.
 
Please
 
cite
 
thisarticle
 
inpressas:R.Burattini,M.Morettini,Identificationofanintegratedmathematicalmodelofstandardoralglucose
 
tolerancetestfor
 
characterizationofinsulinpotentiationinhealth,Comput.MethodsProgramsBiomed.(2011),doi:10.1016/j.cmpb.2011.07.002
ARTICLE IN PRESS
COMM-3248;No.ofPages14
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Fig.
 
1
 
Flow
 
diagram
 
of 
 
our
 
integratedmodelincorporatingeither
 
oneof 
 
twoalternativeformulationsof 
 
glucoseabsorption,denotedasM1
 
andM2.
 
TheM1
 
representation
 
assumesthederivativeof 
 
a
 
power
 
exponentialfunction
 
for
 
thegastricemptyingrate
G
empt 
 )
 
of 
 
theoralglucosedose
D
 ),
 
anda
 
singlecompartmentfor
 
thegut
q
gut 
 ).
 
In
 
theM2configuration,theoralglucosedoseentersa
 
twocompartmentmodel
q
sto1
and
q
sto2
 )
 
of 
 
thestomach,whilea
 
gastricemptyingfunction
 
k
empt 
 ),
 
dependenton
 
thetotalamountof 
 
glucosein
 
thestomach
 
q
sto
,
 
equaltothesum
 
of 
 
q
sto1
and
q
sto2
 ),
 
playsa
 
keyrolein
 
determiningthetimecourseof 
 
 both
 
therateof 
 
emptyingof 
 
oralglucoseloadintothegut
G
empt 
 )andtheglucosequantityin
 
thegutcompartment
q
gut 
 ).
 
In
 
 both
 
our
 
integratedmodelformulations(denominatedINT
 
M1andINT
 
M2,
 
respectively),the
G
empt 
istransmutedbythe
k
5
coefficientintoa
 
signalthatentersthecompartmentof 
 
plasmaincretin
 
(INC).Similarly,
q
gut 
ismultipliedbythe
k
abs
rateconstantof 
 
intestinalabsorption
 
andthef 
 
fraction
 
of 
 
theintestinalabsorption
 
thatactuallyappearsintoplasma,topredicttheRa
G
rateof 
 
glucoseabsorption
 
from
 
thegutintothemesentericcirculation.Thisfeedstheglucosecompartment
G
 ).
 
Solidlineswith
 
arrowsindicatedirectionalflows.Dashedlineswitharrowsindicatecontrolactionsof 
 
incretin
 
(INC)andglucose
G
 )
 
on
 
post-hepaticinsulin
 
secretion,aswellascontrolactionsof 
 
insulin
 
I
 )
 
on
 
hepaticglucosebalance(HGB)andglucosedeliverytotheperipheraltissues.

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