Impact of Positive Family History and Genetic Risk Variants on the Incidence of Diabetes: The Finnish Diabetes Prevention Study.

0.13 MB·English

by  Uusitupa, Matti I.

Pathophysiology/Complications
O R I G I N A L A R T I C L E
Impact of Positive Family History and
Genetic Risk Variants on the Incidence
of Diabetes
The Finnish Diabetes Prevention Study
B
MATTI I. UUSITUPA, MD, PHD1,2 PIRJO ILANNE-PARIKKA, MD10,11 oth genetic and environmental fac-
ALENA STANC(cid:1)ÁKOVÁ, MD, PHD3 SIRKKA KEINÄNEN-KIUKAANNIEMI, MD, torsplaymajorrolesinthedevelop-
MARKKU PELTONEN, PHD4 PHD12,13 mentoftype2diabetesmellitus.In
JOHAN G. ERIKSSON, MD, PHD5,6,7,8 JAAKKO TUOMILEHTO, MD, PHD4,5,14 recent years, the research aiming to ex-
JAANA LINDSTRÖM, PHD4 MARKKU LAAKSO, MD, PHD3
SIRKKA AUNOLA, PHD9 phlaosreptrhoegrgeesnseedticsbigansiifiscoafnttylyp.eC2udriraebnettleys,
.30geneticvariantshavebeenidentified
OBJECTIVE—Weaimedtoinvestigatetheinfluenceofpositivefamilyhistory(FH+)ofdi- in large multicenter studies with suffi-
cient power to be associated with an in-
abetesand19knowngeneticrisklociontheeffectivenessoflifestylechangesandtheirpredictive
valueontheincidenceoftype2diabetesintheFinnishDiabetesPreventionStudy(DPS). creased risk of type 2 diabetes (1–3).
Typically,eachvarianthasonlyalimited
RESEARCHDESIGNANDMETHODS—Atotalof522subjectswithimpairedglucose effect on the risk, i.e., the risk may in-
tolerance(IGT)wererandomizedintothecontrol(n=257)andintervention(n=265)groups. crease by 10 to 15% per copy of each
The mean follow-up was 6.2 years (median 7 years), and the lifestyle intervention, aimed at riskalleleexceptforTCF7L2,whichisso
weight reduction, healthy diet, and increased physical activity, lasted for 4 years (range 1–6
far the most convincing type 2 diabetes
years). An oral glucose tolerance test (OGTT) and assessment of basic clinical variables were
risk gene, increasing the risk 1.4-fold
performedannually.
(2). The known risk variants explain
RESULTS—Theeffectofinterventionontheincidenceofdiabeteswasalmostsimilarinsub- only;10%ofthegeneticbasisoftype2
jectswithFH+comparedwithsubjectswithanegativefamilyhistory(FH2)ofdiabetesduring diabetes(2).Onthebasisoffindingsina
theentirefollow-up.IntheCoxmodel,includingFH,geneticriskSNPs,and randomization limited number of longitudinal studies,
group,andadjustedfortheeffectsofage,sex,BMI,andstudycenter,onlylifestyleintervention the risk variants have only a small effect
hadasignificanteffect(hazardratio0.55,95%CI0.41–0.75,P,0.001)ontheincidenceof
ontheabilitytopredictthedevelopment
d1-iaybeeatrecsh.aFnugretsheinr2an-halgylsuecsossheoawnedd2t-hhaitnisnulainddacithioienvetodbthyelibfeassteyllieneingtelurvceonsetioanndhaindsausliingnviafilcuaenst, of type2 diabetes (4–6). In two lifestyle-
baseddiabetespreventiontrialsinpersons
effectontheincidenceofdiabetes.
with impaired glucose tolerance (IGT),
CONCLUSIONS—Theseresultsemphasizetheeffectivenessoflifestyleinterventioninre- the Diabetes Prevention Program (DPP)
ducingtheriskofdiabetesinhigh-riskindividualsindependentlyofgeneticorfamilialriskof and the Finnish Diabetes Prevention
type2diabetes. Study(DPS),ithasbeenpossibletoexam-
ine the interaction between genetic and
DiabetesCare34:418–423,2011
lifestyle factors regarding the future risk
of diabetes. In these studies, lifestyle
changesmodifiedtheriskofdiabetesde-
pending on the genetic variation (2,7,8).
Specifically, the increased risk of type 2
c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c
diabetes was completely abolished by
Fromthe1InstituteofPublicHealthandClinicalNutrition,ClinicalNutrition,UniversityofEasternFinland,
lifestyles in both DPP and DPS among
Kuopio,Finland;the2ResearchUnit,KuopioUniversityHospital,Kuopio,Finland;the3Departmentof
the persons with the risk allele for
Medicine,InstituteofClinicalMedicine,UniversityofEasternFinlandandKuopioUniversityHospital,
Kuopio,Finland;the4DepartmentofHealthPromotionandChronicDiseasePrevention,NationalInstitute TCF7L2 (9,10). It is commonly believed
for Health and Welfare, Helsinki, Finland; the 5Department of Public Health, University of Helsinki, that type 2 diabetes is highly heritable
Helsinki,Finland;the6FolkhälsanResearchCenter,Helsinki,Finland;the7DepartmentofGeneralPractice (11), and a positive family history (FH+)
and Primary Health Care, University of Helsinki, Helsinki, Finland; the 8Vasa Central Hospital, Vasa,
Finland;the9DepartmentofHealth,FunctionalCapacityandWelfare,NationalInstituteforHealthand predictsthedevelopmentoftype2diabe-
Welfare, Turku, Finland; the 10Diabetes Centre, Finnish Diabetes Association, Tampere, Finland; the tesevenafteradjustmentforcommonrisk
11ScienceCentre,PirkanmaaHospitalDistrict,TampereUniversityHospital,Tampere,Finland;the12In- factorsfortype2diabetes(4–6,12–14).In
stituteofHealthSciences,UniversityofOulu,Oulu,Finland;the13UnitofGeneralPractice,OuluUniversity the DPP, the known genetic risk variants
Hospital,Oulu,Finland;andthe14SouthOstrobothniaCentralHospital,Seinäjoki,Finland.
Correspondingauthor:MattiI.Uusitupa,matti.uusitupa@uef.fi. were not associated with an increased
Received28May2010andaccepted18October2010. risk of diabetes, and only one potential
DOI:10.2337/dc10-1013.Clinicaltrialreg.no.NCT00518167,clinicaltrials.gov. genotype-intervention interaction for
This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10. CDKN2A/B was reported previously
2337/dc10-1013/-/DC1.
(15). However, the responses to lifestyle
©2011bytheAmericanDiabetesAssociation.Readersmayusethisarticleaslongastheworkisproperly
cited,theuseiseducationalandnotforprofit,andtheworkisnotaltered.Seehttp://creativecommons.org/ according to FH of diabetes were not
licenses/by-nc-nd/3.0/fordetails. documented.
418 DIABETESCARE,VOLUME34,FEBRUARY2011 care.diabetesjournals.org
UusitupaandAssociates
The aim of the current study was (midwaybetweenthelowestribandiliac negativefamilyhistory(FH2)ofdiabetes
toinvestigatewhether an FH+ ofdiabetes crest), and systolic and diastolic blood weretestedwiththettestforcontinuous
orgeneticvariantsoftype2diabetescould pressure. Serum total cholesterol, HDL variablesandtheFisherexactorx2testfor
modulate the effect of lifestyle changes cholesterol,andtriglyceridesweredeter- dichotomous variables. Changes during
achieved in the Finnish DPS (16,17) on mined from fasting samples using an follow-up(Dvaluesbetweenthevalueat
the incidence of type 2 diabetes. Further- enzymaticassaymethod. 1yearoffollow-upandthebaselinevalue)
more,weaimedtoassesstheabilityofFH The diagnosis of diabetes was based in body weight, glucose, and other vari-
andgeneticriskvariants,inadditiontolife- ontherepeatedOGTT(16,17).FHofdi- ableswereanalyzedwiththegenerallinear
stylechangesandbasicclinicalvariables,to abetes was based on a questionnaire ap- model,adjustingforage,sex,studycenter,
predicttheincidenceoftype2diabetesin pliedintheDPS.Ifoneofthefirst-degree BMI,andfastingglucoseatbaseline.Inter-
individualsathighriskoftype2diabetes. relatives (father, mother, sister, brother) actionbetweenFHandtherandomization
haddiabetes,FHwasregardedaspositive groupwastestedforeachmodel,modeled
RESEARCH DESIGN AND (FH+).Thesedataarebasedonthefollow- asfixedfactor.Variableswithnon-normal
METHODS—The DPS is a clinical trial upof4yearswhenactiveinterventionwas distribution were log-transformed before
with five participating centers (Helsinki, finished and on the 3 years of follow-up analyses.Kaplan–Meiermethodwasused
Kuopio, Turku, Tampere, and Oulu) in afteractiveinterventionwithatotalfollow- toestimatetheincidenceofdiabetesinthe
Finland (NCT00518167). Details of the up of an average of 6.2 years (median two groups. The difference in incidence
DPS study design, methods, and proce- 7 years).Altogether,75persons(28%)in between the groups was tested with the
dures have been published (16–19). the intervention group and 110 persons log-rank test. The Cox proportional haz-
Briefly, study participants were recruited (43%) inthecontrol groupdeveloped di- ardsmodelwasusedtoestimatethehaz-
mainly by screening of high-risk groups abetesduringtheentirefollow-up.During ard ratio for the development ofdiabetes
whovoluntarilyrespondedtolocaladver- the entire study period, the incidence of betweenthegroups.Hazardratiosforcon-
tisements. The inclusion criteria were 1) diabeteswassubstantiallylowerinthein- tinuoustraitsareexpressedasunitchange
age 40–64 years at screening, 2) BMI tervention group compared withthecon- per 1 SD. If not stated otherwise, the
.25 kg/m2 at screening, and 3) the trol group (HR0.57, 95% CI0.4320.76, modelswereadjustedforage,sex,BMIat
meanvalueoftwo75-goralglucosetoler- P,0.001)(18).Nosignificantdifference baseline, fasting glucose at baseline, and
ance tests (OGTTs) in the IGT range was found in mortality rates between the study center. No multicollinearity prob-
based on World Health Organization groups(19). lemswerefoundforanymodel.Interaction
1985 criteria. Exclusion criteria included between FH (or GRS) and randomization
recent (within 6 months) cardiovascular Genotyping group was modeled as a covariate in Cox
disease event. The randomization of par- Nineteen type 2 diabetes-susceptibility regression. All comparisons of the end
ticipants started in 1993 and continued SNPs (PPARG rs1801282, KCNJ11 points were based on the intention-to-
until1998. rs5219, TCF7L2 rs7903146, SLC30A8 treatprinciple.Theresultsforcontinuous
A total of 522 overweight men and rs13266634,HHEXrs1111875,CDKN2B variables are given as means 6 SD. P ,
womenwererandomlyallocatedtooneof rs10811661, IGF2BP2 rs4402960, 0.05 was considered statistically signifi-
the two treatment modalities, the inten- CDKAL1 rs7754840, FTO rs9939609, cant.Analysesweredonewiththestatistics
sive diet-exercise counseling group (n = HNF1B rs757210, WFS1 rs10010131, package Stata version 10.1 (StataCorp.,
265, 66% were women) or the control JAZF1 rs864745, CDC123 rs12779790, CollegeStation,TX)andSPSS14.0(SPSS
group(n=257,69%were women).The TSPAN8 rs7961581, THADA rs7578597, Inc.,Chicago,IL).
participantsrandomizedtointensivelife- ADAMTS9 rs4607103, NOTCH2
style intervention were given individual- rs10923931,KCNQ1rs2283228,MTNR1B RESULTS
izedcounselingbythestudynutritionists rs10830963) were genotyped using the
to achieve the lifestyle goals. They were TaqManAllelicDiscriminationAssay(Ap- Baseline characteristics and 1-year
also advised to increase their level of plied Biosystems, Foster City, CA). The changes in clinical variables by
physical activity, and voluntary physical genotypingcallratewas99.22100%.Ge- family history
activity sessions were offered. The life- notype distributions of all SNPs were in Nosignificantdifferenceintheprevalence
style goals were 1) weight reduction of Hardy–Weinbergequilibrium(P.0.05). of FH of diabetes was observed between
$5%,2),30%ofthedailyenergyintake theinterventionandcontrolgroups(66%
fromfat,3),10%ofthedailyenergyin- Calculations vs.61%).Table1showsbaselinecharac-
take from saturated fat, 4) fiber intake Genetic risk score (GRS) for type 2 di- teristicsoftheDPSparticipantsaccording
$15gper1,000kcal,and5)moderately abetes was calculated as a sum of type 2 totheFHofdiabetes.Withtheexception
intense physical activity $30 min per diabetes-riskallelesin19confirmedtype ofthe1-yeardifferenceinage(P=0.012),
day. The control participants were given 2 diabetes-susceptibility SNPs. Further- the two groups (FH+ vs. FH2) did not
general health behavior information at more,GRS basedoneightSNPsinflu- differ significantly from each other. Fur-
SECR
randomization. The median length of encing insulin secretion (at loci KCNJ11, thermore, persons with FH+ and FH2
theactiveinterventionperiodwas4years TCF7L2, SLC30A8, HHEX, CDKN2B, weresimilarregardingtheirdietatbaseline,
(range126years). IGF2BP2, CDKAL1, MTNR1B) (20) was but the total leisure time physical activity
All participants had an annual calculated. wasgreaterinpersonswithFH2.
OGTT, a medical history, anda physical The1-yearchangesinthemainclin-
examination with measurements of Statistical analysis icalandmetaboliccharacteristicsaccord-
height (without shoes), weight (in light Baseline differences in characteristics of ing to FH and randomization group
indoor clothes), waist circumference the FH+ group and the group with a (intervention vs. control group) are
care.diabetesjournals.org DIABETESCARE,VOLUME34,FEBRUARY2011 419
TheFinnishDiabetesPreventionStudy
Table1—Baselinecharacteristics, diet,andphysicalactivity oftheDPSparticipantsby differintheGRS(17.562.7vs.17.66
familyhistoryoftype2diabetes 2.8,P=0.726).Nostatisticalevidencefor
aninteractionbetweenGRS(orGRS )
SECR
FH+ FH2 Pvalue and randomization group on the inci-
dence of type 2 diabetes was found (P =
N,men/women 327,95/231 195,76/119 0.656or0.340fortheinteraction).
Age,years 55(7) 56(7) 0.012
Men,BMIkg/m2 30.1(3.8) 29.6(3.3) 0.365 Predictors of the incidence of type 2
Women,BMIkg/m2 32.1(5.0) 31.4(4.3) 0.185 diabetes
Fastingglucose,mmol/L 6.1(0.7) 6.2(0.8) 0.737 IntheCoxregressionanalysis,including
2-hglucose,mmol/L 8.9(1.4) 8.9(1.6) 0.897 GRS (19 SNPs), FH, and randomization
Fastinginsulin,mU/L 15(7) 14(8) 0.381 group, adjusted for age, BMI, sex, and
2-hinsulin,mU/L 96(60) 94(73) 0.282 center,onlytheinterventiongrouphada
HOMA-IR 4.2(2.3) 4.0(2.3) 0.250 significant effect on the incidence of di-
HOMA-B 120(67) 115(67) 0.217 abetes(Table2).AfurtherCoxregression
Drugtreatmentforhypertension,% 28.8 30.4 0.692 analysis including age, sex, BMI, fasting
CVDatbaseline 7.9 8.6 0.866 and 2-h glucose and fasting and 2-h in-
Energyintake,kcal/day 1,788(529) 1,705(511) 0.079 sulin at baseline, GRS (as a continuous
Fat,E% 36.6(6.6) 36.4(6.6) 0.724 variable), FH,randomizationgroup,and
Saturatedfats,E% 16.6(4.2) 16.5(4.2) 0.784 studycenterinthemodelwasperformed
Carbohydrates,E% 43.5(6.9) 43.2(7.4) 0.664 to determine the predictors of the inci-
Protein,E% 17.5(3.5) 17.8(3.3) 0.364 denceoftype2diabetesduringtheentire
Dietaryfiber,g/1,000kcal 11.6(3.7) 11.9(4.4) 0.305 follow-upperiod(Table2).Itshowedthat
TotalLTPA,h/week 6.6(5.6) 8.1(6.5) 0.007 fastingand2-hplasmaglucose,fastingin-
Moderate-vigorousLTPA,h/week 2.6(3.0) 2.9(3.2) 0.279 sulin, and the randomization group sig-
Means(SD)areshownforcontinuousvariables.BoldfacedataindicatethesignificanceofPvalue(P,0.05or nificantly predicted the development of
less).CVD,cardiovasculardisease;LTPA,leisuretimephysicalactivity. diabetes. Fasting glucose was the stron-
gest predictor (P = 2.2 3 10210). This
couldbeexplainedbytheinclusioncrite-
riaofthestudy,comprisingonlysubjects
shown in Supplementary Table 1. As (P=0.61).Afteradjustmentforage,sex, with IGT. However, when the 1-year
shown previously, weight reduction was baseline BMI, fasting glucose, and study changes of metabolic variables were
greater and glycemic control improved center, the HR for diabetes in the inter- addedinthe model baseline, fasting and
more in the intervention group than in ventiongroupcomparedwiththecontrol 2-hglucose,baselinefastinginsulin,and
the control group (17,18). In the inter- groupwas0.42(95%CI0.2620.70,P= changes in 2-h glucose and insulin pre-
vention group, persons with FH+ ach- 0.0008)inpersonswithFH+,whereasit dictedtheincidenceofdiabetes(Table2).
ieved significantly greater reduction in was 0.61 (95% CI 0.3321.12, P = 0.11) Neither FH nor GRS was a significant
2-h plasma glucose than did persons in persons with FH2. During the entire predictor of the development of type 2
with FH2. However, no significant in- follow-up, in the adjusted model, the diabetes,andtheeffectoftheintervention
teractions between FH and control/ effect of intervention was, however, sig- became nonsignificant (HR 0.74, P =
intervention groups were found in the nificantinbothFH+(P=0.002)andFH2 0.106) because the effect of lifestyles
changes in body weight, fasting plasma (P = 0.006) groups, and there was no surely was mediated through glucose
glucose,2-hplasmaglucose,homeosta- significant interaction between the FH andinsulinmetabolism.
sismodelassessment(HOMA)ofinsulin and randomization group (P = 0.19 for
resistance,HOMAofinsulinsensitivity, the follow-up during intervention, P = CONCLUSIONS—The current study
or energy intake. In addition, no major 0.97fortheentirefollow-up). aimedtoinvestigatewhethertheFH+per
differences werefound inthe distribution se, or the genetic risk variants and GRS
of macronutrients or physical activity be- Effect of gene variants and genetic based on 19 known type 2 diabetes-risk
tweenFH+andFH2groupsafter1year risk score on the incidence of SNPs, modulated the effects of lifestyle
ofintervention(datanotshown). type 2 diabetes intervention in the DPS participants. FH
Wedidnotfindanysignificanteffectsof did not affect the result of lifestyle in-
Incidence of type 2 diabetes by the 19 risk variants on the incidence of tervention during the entire follow-up.
family history type 2 diabetes (data not shown). Simi- We did not observe any aggregation of
Incidence of type 2 diabetes in the in- larly,combinedtype2diabetesriskalleles known genetic risk variants in persons
tervention and control group by FH of of 19 SNPs (presented as GRS) did not with FH+, nor did genetic risk variants
diabetes is shown in Fig. 1 (data in haveasignificanteffect on theincidence modifytheincidenceofdiabetes.Onthe
SupplementaryTable2).Duringtheorig- of diabetes during the entire follow-up basis of different analyses, in addition to
inalrandomizedtrialperiodof4yearson period(P=0.784intheadjustedmodel). the intervention, fasting and 2-h plasma
average,theincidenceofdiabetesseemed GRSbasedoneightSNPsinfluencingin- glucose and fasting insulin at baseline,
tobelowerintheinterventiongroupthan sulin secretion (20) (GRS ) also did and the 1-year changes of 2-h plasma
SECR
inthecontrolgroupinpersonswithFH+ not have a significant effect (P = 0.459). glucose and 2-h insulin were the main
(P=0.0002),butnotinthosewithFH2 ThepersonswithFH+andFH2didnot determinantsofthedevelopmentofdiabetes
420 DIABETESCARE,VOLUME34,FEBRUARY2011 care.diabetesjournals.org
UusitupaandAssociates
during the follow-up, independently of
the effects of genetic risk variants and
FH.
Although the participants with FH+
seemed to have a lower incidence of
diabetes than those with FH2 during
the first 4 years of follow-up when the
active intervention was carried out, this
early difference disappeared during the
entire follow-up. The seemingly better
earlyresponsecouldbeexplainedbythe
fact that individuals with FH+ may be
more aware of the risk of diabetes than
others (21) and thus more motivated, as
suggestedbytheirgreaterdecreaseintotal
caloric intake during the first year of in-
tervention (P = 0.012). In addition, the
mean 1-year change in the 2-h plasma
glucosevalueswasgreateramongthepar-
ticipants with FH+ in the lifestyle inter-
ventiongroup.Itshouldbenoticedthatat
baselinenodifferenceswerefoundinany
clinical or biochemical measurements,
whichcouldexplainthepresentfindings
ofthedifferencesduringtheintervention
phase in the incidence of diabetes be-
tweenindividualswithFH+andFH2.
Theknowngeneticriskvariantswere
not associated with the FH of diabetes.
However,thismaynotbeanunexpected
findingbecauseitisknownthatriskloci
confer only 10% of the risk of type 2
diabetes (2,22). Furthermore, all partici-
pantsintheDPShadscreenedIGTbased
on two OGTTs and .60% had an FH+,
whichalsomightindicateanaggregation
of genetic risk variants. In the general
population, FH+ varies from 25% to
40% depending on selection of popula-
tions in different studies (4,12–14). It
could beargued thata small samplesize
couldexplainwhynosignificantassocia-
tionbetweengeneticriskvariantsandFH
or the type 2 diabetes risk was found.
However, this may not be the case, be-
cause in regression analyses not even a
trend to an association with the diabetes
riskwasfound.Itisofnotethatthetotal
numberofdiabetescaseswas185during
theentire follow-up. Thisfigureisalmost
comparableto255casesintheFramingham
OffspringStudy(5),including2,377par-
ticipants with 28 years of follow-up. In
that study, the adjusted C-statistic was
Figure1—Incidenceoftype2diabetesduringtheinterventionperiodof4years(A)(endin- 0.595 without the genotype score and
dicatedbyaverticalline)andduringtheentirefollow-upperiod(B)byFHandrandomization 0.615withthescore(P=0.11).Inalarger
group(interventionvs.control)intheDPS.Solidlineisforthecontrolgroup.Duringthein- studyonSwedishandFinnishcohorts,in-
terventionfollow-upof4yearsonaverage,interventionhadsignificanteffectontheincidenceof
cluding 18,831 individuals (4), of whom
type2diabetesintheFH+group(P=0.0002,*P=0.0008)butnotintheFH-group(P=0.61,*P=
2,201developeddiabetesduringamedian
0.11).Duringtheentirefollow-up,interventionhadaneffectinbothFH+(P=0.0004,*P=0.002)
andFH2(P=0.13,*P=0.006)groups.PisfromKaplan–Meieranalysis,*Pafteradjustmentfor follow-up of 23.5 years, the addition of
specificgeneticinformationtoclinicalfac-
age,sex,baselineBMI,baselinefastingglucose,andstudycenterinCoxregressionmodel.
torsslightlyimprovedthepredictionof
care.diabetesjournals.org DIABETESCARE,VOLUME34,FEBRUARY2011 421
TheFinnishDiabetesPreventionStudy
Table2—Effectoffamilyhistoryofdiabetes, geneticrisk score,intervention,andclinical among known risk factors for type 2 di-
variablesontheincidenceoftype2diabetes abetes.Wecannotexcludethepossibility
thattheknowngeneticriskvariantscould
HR 95%CI Pvalue havebeenoperativeinanearlierphaseof
development of diabetes, but along with
A this line, the changes in lifestyle also
FamilyhistoryofT2DM 0.78 (0.57–1.06) 0.118 might be more effective in earlier phases
GRS(19SNPs) 1.04 (0.90–1.20) 0.617 ofthisdisease.
Interventionvs.controlgroup 0.55 (0.41–0.75) 1.231024 Becauseinsulinsecretionandinsulin
B sensitivity are not independent of each
FamilyhistoryofT2DM 0.80 (0.57–1.11) 0.180 other,both mechanisms couldbeopera-
GRS(19SNPs) 1.02 (0.87–1.18) 0.840 tive when searching biological explana-
Interventionvs.controlgroup 0.52 (0.38–0.72) 5.931025 tions for the markedly decreased risk of
Fastingglucose(baseline) 1.69 (1.44–1.99) 2.2310210 diabetes in prevention trials such as the
2-hglucose(baseline) 1.35 (1.14–1.60) 0.0005 DPS. It has been hypothesized that life-
Fastinginsulin(baseline) 1.25 (1.03–1.53) 0.025 style intervention may have beneficial
2-hinsulin(baseline) 0.81 (0.63–1.02) 0.076 effects on insulin secretion avoiding the
BMI(baseline) 1.17 (0.98–1.39) 0.077 exhaustion of b-cells and thus delaying
C the progression of disturbed insulin se-
FamilyhistoryofT2DM 0.92 (0.65–1.29) 0.609 cretion capacity. Because the decrease in
GRS(19SNPs) 1.02 (0.88–1.18) 0.797 the2-hglucoseandinsulinhadamarked
Interventionvs.controlgroup 0.74 (0.52–1.06) 0.106 impactontheriskreductionofdiabetes,
Fastingglucose(baseline) 1.93 (1.57–2.38) 3.5310210 webelievethatanimprovementininsulin
DFastingglucose(1-yearchange) 1.15 (0.96–1.38) 0.129 sensitivity and perhaps concomitant re-
2-hglucose(baseline) 1.69 (1.39–2.05) 9.131028 covery of b-cell sensitivity to glucose
D2-hglucose(1-yearchange) 1.62 (1.32–1.98) 3.431026 (24) could mainly explain the observed
Fastinginsulin(baseline) 1.35 (1.06–1.73) 0.015 beneficial effects of changing lifestyles
DFastinginsulin(1-yearchange) 1.18 (0.97–1.44) 0.103 onthediabetesrisk.
2-hinsulin(baseline) 1.05 (0.79–1.39) 0.755 To conclude, conventional risk fac-
D2-hinsulin(1-yearchange) 1.36 (1.05–1.75) 0.018 tors and lifestyle changes known to de-
BMI(baseline) 1.18 (0.99–1.40) 0.061 crease the risk of diabetes are the most
DBMI(1-yearchange) 1.19 (0.98–1.44) 0.084 importantpredictorsoftype2diabetesin
Fordichotomousvariables,HRsareshownfortheinterventiongroup,FH+ofT2DM,andmalesubjects.For persons with IGT, and lifestyle changes
continuousvariables,HRsareexpressedasunitchangeper1SD.A,B,Crepresentalternativemodels:A= overcome the impact of the known ge-
effectsofFH,GRS,andinterventionwithoutclinicalvariables.B=includingclinicalvariablesatbaseline.C= neticandfamilialrisk.Thisinformationis
including1-yearchangesinthesevariables(Coxregression,allmodelsareadjustedforage,sex,baselineBMI,
andstudycenter).BoldfacedataindicatethesignificanceofPvalue(P,0.005orless).T2DM,type2diabetes important both for health professionals
mellitus. andforpersonsatincreasedriskfortype2
diabetes.Ourresultsinconjunctionwith
future diabetes, from 0.74 to 0.75 (the Themainpredictorsoftheincidence some former population-based studies
area under the receiver operating char- of type 2 diabetes in our study were the andtheDPPgeneticstudiesindicatethat
acteristic curve); however, the P value lifestyleintervention,fastingand2-hglu- genetic risk testing at this point may not
wassignificant(P=1.031024).These cose, fasting insulin at baseline, and offermuchadditionalinformationappli-
results are in line with the Health Pro- 1-year change in 2-h glucose and 2-h cable to prevention strategies of type 2
fessionalsFollow-upStudyandNurses’ insulin. The finding that the 1-year diabetes to that obtained from patients’
HealthStudy(6)applyingacase-control changes in the 2-h glucose and insulin FH and the well-known clinical risk
studydesign,inwhichGRSbasedon10 levelswerepowerfulpredictorsofdiabe- markers.
polymorphisms in nine loci increased tes, whereas the 1-year change in fasting
the predictive value from 0.78 to 0.79 glucose level, which primarily reflects
(P , 0.001). In the latter study, how- insulin secretion, did not contribute to Acknowledgments—This study has been fi-
ever, glucose values were not included thesuccessrateofprevention,suggestsa nanciallysupportedbygrantsfromtheAcad-
intheanalyses(6).InboththeDPPand significant role of an improvement of emyofFinland(117844and40758,211497,
DPS, in which gene–lifestyle interac- insulin sensitivity along with weight re- and118590[toM.I.U.];38387and46558[to
tions have been examined, lifestyle duction. Indeed, in a substudy of DPS, J.T.];206310and73566[toS.K.-K.]);128315
changes abolished the increased risk of there was a marked improvement of in- and 129330 [to J.L.]; the Juho Vainio Foun-
type2diabetesinthecarriersoftherisk sulin sensitivity based on intravenous dation[toJ.L.];theNovoNordiskFoundation
allele at TCF7L2 locus (9,10). No other glucose tolerance test along with weight [toJ.L.];TheEVO-fundofKuopioUniversity
Hospital(5106,5168,and5254[toM.I.U.]);
studies have used a similar approach. loss,butonlysmallchangeswerefoundin
The Ministry of Education of Finland; The
Thus, lifestyle intervention per se, at insulin secretion (23). Overall, these re-
FinnishDiabetesResearchFoundation;Sigrid
leastinpart,seemstoabolishthegenetic sultsshowthatanelevationoffastingglu-
JuseliusFoundation;TheGraduateSchoolof
risk associations observed in observa- cosewithpoorinsulinsecretioncapacity MolecularMedicine;NordicCentreofExcel-
tional cross-sectional and longitudinal and the degree of insulin resistance and lenceon“Systemsbiologyincontrolleddietary
studies. obesityremainthemainpredictivefactors interventions and cohort studies” (SYSDIET;
422 DIABETESCARE,VOLUME34,FEBRUARY2011 care.diabetesjournals.org
UusitupaandAssociates
project number 070014); TEKES 70103/06 8. WeyrichP,StefanN,HäringHU,Laakso programme. Diabetologia 1999;42:793–
and40058/07;andINTERACT. M,FritscheA.Effectofgenotypeonsuc- 801
Nootherpotentialconflictsofinterestrel- cessoflifestyleinterventioninsubjectsat 17. Tuomilehto J, Lindström J, Eriksson JG,
evanttothisarticlewerereported. riskfortype2diabetes.JMolMed2007; etal.;FinnishDiabetesPreventionStudy
M.I.U. and J.T. are the principal inves- 85:107–117 Group. Prevention of type 2 diabetes
tigatorsoftheDPS.M.I.U.andA.S.wrotethe 9. FlorezJC,JablonskiKA,BayleyN,etal.; mellitus by changes in lifestyle among
article.A.S.and M.P.analyzedthedata.J.T., Diabetes Prevention Program Research subjectswithimpairedglucosetolerance.
J.L., M.I.U., S.K.-K., S.A., P.I.-P., and J.G.E. Group.TCF7L2polymorphismsandpro- NEnglJMed2001;344:1343–1350
participated in the data collection and inter- gression to diabetes in the Diabetes Pre- 18. Lindström J, Ilanne-Parikka P, Peltonen
pretationoftheresults.M.L.wasresponsible ventionProgram.NEnglJMed2006;355: M, et al.; Finnish Diabetes Prevention
for genetic analyses and contributed to the 241–250 StudyGroup.Sustainedreductioninthe
interpretationoftheresults.Allauthorshave 10. Wang J, Kuusisto J, Vänttinen M, et al. incidence of type 2 diabetes by lifestyle
seen the final version of the article and have Variants of transcription factor 7-like 2 intervention: follow-up of the Finnish
commentedonitbeforetheacceptanceofthe (TCF7L2)genepredictconversiontotype DiabetesPreventionStudy.Lancet2006;
article. 2 diabetes in the Finnish Diabetes Pre- 368:1673–1679
Part of these results were presented at the vention Study and are associated with 19. Uusitupa M, Peltonen M, Lindström J,
28th International Symposium on Diabetes impairedglucoseregulationandimpaired etal.;FinnishDiabetes PreventionStudy
andNutrition,Oslo,Norway,1–4July2010. insulin secretion. Diabetologia 2007;50: Group. Ten-year mortality and cardiovas-
1192–1200 cular morbidity in the Finnish Diabetes
11. KaprioJ,TuomilehtoJ,KoskenvuoM,etal. Prevention Study—secondary analysis of
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