Dietary program and physical activity impact on biochemical markers in patients with type 2 diabetes: systematic review

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AtenPrimaria.2018;50(10):590---610

www.elsevier.es/ap

Atención

Primaria

ORIGINAL

ARTICLE

Dietary

program

and

physical

activity

impact

on

biochemical

markers

in

patients

with

type

2 diabetes:

A

systematic

review

Eduarda

Barreira

a_,_∗

_,

_André

_Novo

a_,b

_,

_Josiana

_A.

_Vaz

a_,c

_,

_Ana

_M.G.

_Pereira

a

a_Health_School,_Polytechnic_Institute_of_Braganc_¸a,_Braganc_¸a,_Portugal

b_{CINTESIS-Research}_Center_on_Health_Technologies_and_Services,_Porto,_Portugal

c_{CIMO-Mountain}_Research_Centre,_Polytechnic_Institute_of_Braganc_¸a,_Campus_de_Santa_Apolónia,_Braganc_¸a,_Portugal

Received16February2017;accepted13June2017 Availableonline21October2017

KEYWORDS

Nutrition; Physicalexercise; Glycemiccontrol; Dyslipidemia Abstract

Objectives:Evaluatetheeffectivenessoftheimplementation ofindependentlyorcombined dietaryandphysicalactivityprogramsonthebloodglucosevaluesandlipidproﬁleinpatients withtype2diabetes,includingparticipantsaged60yearsandover.

Design:Systematicreview.

Datasource: PubMed/Medlinedatabase,withlanguagerestrictions.Paperspublishedbetween 2010and2016wereincluded.

Studyselection:Atotalof30randomisedcontrolledtrialswereincludedthatfocusedon phys-ical activityanddietaryinterventions inpatients withtype 2diabetes mellitusandinclude participantsaged60yearsandover.

Results:Theselectedarticleshaveshownthattheimplementationofphysicalactivityprograms (aerobic,resistance,ﬂexibilityandcombinedexercises),andprogramsbasedonahigherintake ofvegetables,grains,legumes,fruits,unsaturatedfattyacids,aswellasconsumptionoffoods withlowglycaemicindex,calorierestriction,intakeofprobiotics,vitaminDsupplementation andeducationalsessions aboutdiabetesimproves bloodglucose levels, aswellas thelipid proﬁle,inpatientswithtype2diabetes.

Conclusions:Physical activityand dietary programs arefundamental in the treatment and metaboliccontroloftype2diabetesmellitus.

∗_{Corresponding}_author.

E-mailaddress:[email protected](E.Barreira).

https://doi.org/10.1016/j.aprim.2017.06.012

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PALABRAS

CLAVE

Nutrición;

Ejerciciofísico; Controlglucémico; Dislipidemia

Programadedietaseimpactodelaactividadfísicasobremarcadoresbioquímicosen pacientescondiabetestipo2:unarevisiónsistemática

Resumen

Objetivos: Evaluar la efectividad de la implementación de programas de actividad física y dietéticaindependientementeocombinadosenlosvaloresdeglucosaensangreyperﬁllipídico enpacientescondiabetestipo2,incluyendoparticipantesde60a˜nosymás.

Dise˜no: Revisiónsistemática.

Fuentesdedatos:PubMed/Medline,conrestriccionesdeidioma.Seincluyeronartículos pub-licadosentre2010y2016.

Seleccióndeestudios:Seincluyeron30estudioscontroladosaleatorios,centradosenla activi-dadfísicaeintervencionesdietéticasenpacientescondiabetestipo2queincluíansujetosde 60a˜nosymás.

Resultados: Losartículosseleccionadoshandemostradoquelaimplementacióndeprogramas de actividadfísica (ejerciciosaeróbicos, resistencia,ﬂexibilidad yejercicios combinados)y programasbasadosenunamayoringestadevegetales,granos,legumbres,frutas,ácidosgrasos insaturados,elconsumodealimentosconbajoíndiceglucémico,restriccióncalórica,ingesta deprobióticos,suplementosdevitaminaDysesioneseducativassobreladiabetesmejoranlos nivelesglucémicos,asícomoelperﬁllipídicoenpacientescondiabetestipo2.

Conclusiones:Los programas de actividad física y dietéticos son fundamentales en el tratamientoycontrolmetabólicodeladiabetesmellitustipo2.

Introduction

Diabetesmellitus isametabolicdisordercharacterizedby thepresenceofchronichyperglycemiawithdisturbanceof carbohydrates,proteinandfatmetabolism.Resultsof insuf-ﬁcient secretion of insulin by pancreatic cells and/or an incompleteactionofproducedinsulin,towhicharerelated aserialof macrovascularandmicrovascularcomplications that affect qualityof life.1---7 _It _is _a _chronic _disorder _with majorexpansionworldwide.Itisestimatedthatthenumber ofdiabetessufferersincreaserapidlyinthecomingdecades due to the population ageing, poor diet, lack of physical activityandobesity.8---10_Worldwide,_in_2015,_it_is_estimated thattherewere415millionpeoplewithdiabetes,andthis number is expected to reach642 million by 2040. In the sameyear,thisdiseasewasresponsiblefor5milliondeaths. TheWorldHealthOrganizationprojectsdiabetesasthe7th

leadingcauseofdeathin2030.9,11 _Clinical_{manifestation}_of differentvariantsofthedisease,type2diabeteshasbeen sufferingamajorincreaseworldwiderepresenting90---95% ofallcasesofdiabetesmellitus.1,9_Its_prevalence_increases withage,9,12---16_and_is_directly_related_to_bad_eating_habits, abdominalandvisceralobesity,sedentarylifestyles.1,7,9,16---19 People with diabetes have an increased risk tohave car-diovascular diseasethan non-diabetics, which can be2---4 times greater.6,16,20---22 _Dyslipidemia _and _insulin _resistance are risk factors for cardiovascular disease dyslipidemia and insulin resistance are risk factors for cardiovascular disease.16,21,23---28_This_disease_is_a_major_cause_of_morbidity andreducedlifeexpectancyinpatientswithdiabetes.29,30 It is estimated that at least 68% of diabetic patients over 65 years old diefrom heart disease and 16% due to stroke.31

Abalanced andhealthy dietis an essentialcomponent for the prevention and selfcontrol of type 2 diabetes. It contributestoaharmoniousgrowthanddevelopment,also reflectedinthepatternsofacquireddiseases,thatis,ithas aprofoundimpactontheindividual’shealthinallits dimen-sions(social,physical andmental).Forthis,thedietmust respectthenutritionalrecommendations,namelyhoursand qualityofmeals.32---34 _The_nutrition_intervention emphasiz-ingthepromotionof healthyeatinghasbeenshown tobe animportantpointindiabetesmellitustreatmentsince pro-motesabetterglycemiccontrolandlipidprofile.Dietsrich in whole grains, fruits, vegetables, nuts, whit a moder-atealcohol intake,alowerintakeofred meat,processed refinedfoods,sweets,dairyproductswithhighfatandsoft drinks have been correlated with a reduced risk of dia-betes,betterglycemiccontrolandlipidprofileinpatients withdiabetes.1,35---41 _Physical _activity _can _be _described _as anybodymovement thatwhichrequiresmuscularuseand moreenergyexpenditure than at rest.42 _Is _widely recom-mended as an essential non-pharmacological therapeutic strategy tothe prevention and metabolic control of type 2diabetes.1,9,41

International organizations recommend a weekly accu-mulation of a minimum of 150min of aerobic moderate exercise(50---70%themaximum heartrate),75min of vig-orousintensity,oracombinationofbothtypes,distributed overaminimumof3daysperweek, withnomorethan2 consecutivedayswithoutexercise.1,43

The objectiveof thissystematicreview isevaluatethe effectiveness of the implementation of independently or combined dietary and physical activity programs on the bloodglucosevaluesandlipidproﬁleinpatientswithtype 2diabetes,includingparticipantsaged60andmoreyears.

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592 E.Barreiraetal. Giventhehighagingrateandtheprevalenceoftype2

dia-betesofthepopulation,we choosetoconductananalysis ofseveralpublicationsonthistopic.

Methods

Data

sources

Acomprehensivesearchwasperformedintheinternational scientiﬁcdatabase:

PubMed/Medline, usingthe descriptors‘‘Diabetes AND ((foodhabits) ORBMIORobesityOR(physicalactivity)OR exerciseORglucoseORHbA1cOR(totalcholesterol)ORHDL ORLDLORVLDLORtriglyceridesORapoAORapoBORapoC ORapoDORapoE)’’.

Study

selection,

selection

criteria

and

quality

assessment

Theresearchandstudy selection wasperformed indepen-dentlybytworeviewers.Iftherewereuncertaintyregarding eligibility,theirinclusionornotwasjointlydecidedbythe fourreviewers. Wereconsidered eligible for thepurposes of this review only randomized clinical trials comparing physicalactivityordietaryinterventionswithcontrolgroup in type2 diabetes, that include participants with60 and more years, published between 2010 and 2015, available in full text,with evaluation of theproposed intervention and published in Portuguese, Spanish, English or French. Wereexcludedstudiesthatdidnotrecruitelderlypatients with type 2 diabetes, opinion articles, and with no ﬁnal assessmentoftheproposedintervention.ThefollowingPICO (Population,Intervention,Comparator, Outcome) method-ologywasused:Population:patientswithtype2diabetes, age≥60years;Implementation/Indicator:Dietaryprogram and physical activity; Comparator: control program; Out-come:Impactonthebloodglucosevaluesandlipidproﬁle inpatientswithtype2diabetes.

The includedarticleswereassessedfor theriskofbias usingtherecommendationsforjudgingtheriskofbias, pro-videdin Chapter8oftheCochrane Handbook,44 _since_the selected studies were randomized. Such studies are very prone to bias due to the arbitrariness of researchers in sampleselection,assessmentofthevariablesanalyzedand difﬁcultyincontrolofexternalvariablesthatcaninﬂuence theresults.45

The evaluationconsistsoftwoparts, wherethe riskof biasisassessedin sevenareas:Random sequence genera-tion,allocationconcealment, blinding of participantsand researchers,blinding of outcome assessment, incomplete outcomedata,selectivereportingandothersourcesofbias. Theﬁrstmakesananalysistowhatisdescribedinthatstudy andanalyzedinordertobeabletoclassifytheriskofbias.In thesecondpartismadetheclassiﬁcationoftheriskofbias inoneofthreecategories:lowriskofbias,highriskofbias oruncertainriskofbias,foreachoftheanalyzeddomains.44 Thegeneraldescriptionandanoverallassessmentofriskof biasoftheincludedtrialsinthisreviewareshowninTable1 andFigure1

In Table 2 , are reported the general description of the included trials in this review per intervention and

continent. In this table, taking into account the type of intervention, the articles were grouped in six categories: physical activity; dietary program; physical activity and dietaryprogram;educationalsessions;educationalsessions whit physical activity; and educational sessions, physical activityanddietaryprogram.Each studyhastheyearand place of development, number of participants, descrip-tion of the intervention, its duration and the principal results

Results

and

discussion

Intheinitialsearchwereidentiﬁed230.825studiesthrough the PubMed/Medline database, of which 224.146 studies were excluded due to lack of relevancy and 6.679 were selected. Ofthesepublications, 6.581 wereexcluded and 98 were initiallyselected based ontitle andabstract. Of thesepublications,68 articleswe excludedafter fulltext reading;intheend30mettheinclusioncriteriaandwere consideredforthissystematicreview.Theﬂowchartforthe selectionoftrialsisshowninFigure2.

Results of several studies confirm that physical exer-cise is a key tool in glycemic control and lipid profile in type 2 diabetic patients. The practice of physical activ-ityprogramsiscorrelatedwithbetterglycemiccontroland lipidprofile sinceit decreasesglycated hemoglobinlevels (HbA1c),17,46---52_fasting_glucose17,46,48,50,52,53_and_postprandial levels,48_insulin_resistance48,50,52,53_and_fasting_plasma_insulin levels.50,52---54_It_is_also_observed_a_decrease_in_TG,17,48,50,52,55 TC,17,46,48,50---52 _LDL,17,46,50,52 _Apo_B₄₈55 _an_increase _in HDL-cholesterol.17,46,48,50,51

Regardingthe mode of exercise,it wasfound in three studies47,54,55_that_combined_exercise,_compared_to individ-ual aerobic or resistance exercise, has better benefits to people withdiabetes. The intensity of the exercise influ-encesthe lipidprofile becausea moderatetolowaerobic exercisedoesnotreduceTG.50

Intwostudies48,52 _it _was_found _that_aerobic _resistance andﬂexibilityexercisedecreasesHDLcholesterol.The fas-tingglucoseincreasedinonestudy.54

In summary, with respect to changes caused by exer-cise in thedifferent continents where thevarious studies wereconducteditisdemonstratedreductionofHbA1c, glu-cose, insulin, TG, TC, LDL cholesterol, Apo B 48, lower insulin resistance and HDL cholesterol increase. Accord-ing with studies performed by Nojima et al.,56 _Kasumov etal.,57 _De_Filippis_et_al.,58 _Lazarevic_et_al.59 _and_Hordern et al.,60 _where _it _has _also _found _that _physical _exercise is essential in the metabolic control of type 2 diabetes. The implementation of educational sessions that address the practice of physical activity and healthy eating were addressedin threeofthestudiesanalyzed. Itcanbeseen that educational sessions that address the importance of physical activity and an healthy diet in diabetes control, in conjunction with aerobic exercise of moderate inten-sity,correlateswithlowerHbA1c,61---63_glucose,61,62_TC,_LDL cholesterol, TG and increased HDL cholesterol.62,63 Sim-ilar results were observed in a systematic review with meta-analysis performed by Steinsbekk et al. where the self-managementeducationpromotesbettercontroloftype 2diabetes.64

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Table1 Riskofbiasforeachstudyincludedintheanalysis. Random sequence generation (selection bias) Allocation concealment (selectionbias) Blindingof participants and researchers (performance bias) Blindingof outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Other bias Gavinetal.(2010)55 Okadaetal.(2010)46 Churchetal.(2010)47 Wongetal.(2010)65 DeGreefetal.(2011)61 ArizaCopadoetal.(2011)62 Jorgeetal.(2011)48 Laroseetal.(2011)49 Ferrer-Garcíaetal.(2011)17 CohenandJohnston(2011)37 Sharmaetal.(2011)73 Kahleovaetal.(2011)67 Andrewsetal.(2011)69 Balduccietal.(2012)50 Balduccietal.(2012)51 Swiftetal.(2012)54 Soric(etal.2012)75 Breslavskyetal.(2013)78 Strobeletal.(2014)76 Kampmannetal.(2014)77 Ryuetal.(2014)79 Yuanetal.(2014)63 Asemietal.(2014)93 Lietal.(2014)72 Stenversetal.(2014)70 Vinettietal.(2015)52

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594 E.Barreiraetal. Table1(Continued) Random sequence generation (selection bias) Allocation concealment (selectionbias) Blindingof participants and researchers (performance bias) Blindingof outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Other bias Motahari-Tabarietal.(2015)53 Ostadrahimietal.(2015)94 Hoveetal.(2015)95 Tonuccietal.(2015)96

:lowriskofbias; :highriskofbias; :unclearriskofbias.

230.825 records identified through database searching

6.679 records screened 224.146 recexcluded duordse to lack of relevancy 98 articles selected for

eligibility after reading the abstract

30 full-text articles included in the systematic review

68 full-text articles excluded 6.581 articles excluded after reading the abstract In clu d ed S cree ning E ligib ili ty Id e n ti fi c a ti on

Figure1 Percentageofriskofbiasforeachstudyincludedin

theanalysis.

A healthy and balanced nutrition is an essential com-ponentfor the preventionand selfmanagement of type2 diabetes.1_A_correct_intake_of_the_various_food_components, namely avoiding the excessive consumption of saturated fat andcarbohydratesareimportant for obtaining a good glycemicandlipidcontrol.Adietaryprogramwith empha-sisongreaterconsumptionofpolyunsaturatedfattyacidsis correlatedwithlowerlevelsoffastingglucose,TG,TCand LDLcholesterol.65 _This_is _in_agreement_with_the_results_of thestudyofLeeetal.66

The intake of almonds reduces fasting blood glucose, HbA1candincreasesfastinginsulin.Regardingthelipid pro-ﬁle,thereisan increase ofTCandHDL cholesterolanda reductionofTG.37

The increased consumption of grains, fruit and veg-etables alone (vegetarian diet) or in combination with supervised aerobic exercise correlates with decrease of HbA1c,glucose and fasting insulin, TG, TC and LDL.HDL cholesterolalsodecreases.67 _Given_these_results, _the veg-etarian diets may be beneﬁcial for people with type 2 diabetes,astheyinduceglycemic andlipidcontrol. How-ever,weconsiderthatisneededtobecautiousinthismatter asis alsoneeded tocarryoutfurtherstudiesin thisﬁeld.

AccordingtothestudyofTakahashietal.,theconsumption ofvegetablesiscorrelatedwithimprovedcontrolofHbA1c and TG levels in elderly type 2 diabetes.68 _Modifying _the amountofmacronutrientsmayimproveglycemicandlipid controlinpatientswithtype2diabetes.Low-calorie, low-fat andlow-GIdietscorrelate withlowerlevelsofHbA1c, fastingglucoseandinsulin,insulinresistance,TC,LDLand HDL cholesterol. TG had a slightly increase. When this typeofdietiscombinedwithphysicalactivity,theresults obtained aresimilar.69 _When_uncontrolled _type₂_diabetes ingestalowglycemicindexliquidbreakfast,richin polyun-saturated fatty acids, fiber and fructose, reduces fasting glucose,TC,LDL,HDLcholesterolandincreasethefasting insulin.70_Since_participants_had_uncontrolled_DM2, replace-mentofbreakfastaloneaswellastheinterventionperiod maynothavebeensufficienttoprovidelongtermglycemic control. Thus, further investigationsshould be conducted in this population over alonger periodof time,replacing notonlybreakfastbutothermeals.Theconsumptionoflow glycemicfoodsatbreakfastdecreasedtheHbA1c,glycated serumproteinandinsulin.Therewasanincreaseofglucose, insulinresistance,TG,TC,LDL,HDLcholesterol,ApoA1and ApoB.71_Results_of_the_systematic_review_and_{meta-analysis} ofAjalaetal.72_they_demonstrated_that_{low-carbohydrate,} lowglycemicindex,Mediterranean,andhigh-proteindiets areeffectiveincontrollingtheglycemicandlipidprofileand shouldbepartofthemanagementoftype2diabetes.

Theeffectivenessoftheconsumptionofchromium, vita-minDandprobioticssupplementswerealsostudiedinsome articlesselectedforthisrevision.73---82_The_chromium supple-mentationfor3monthsprovidesareductioninHbA1c.And hasalsobeneﬁcialeffectsondyslipidemia,sincedecrease TC, LDL cholesterol,VLDL cholesterol and TGlevels, and increaseHDLcholesterol.73_The_same_is_veriﬁed_in_a system-atic review withmeta-analysis performed by Suksomboon etal.83

Fiveof the studies analyzed the effectiveness of vita-minDsupplementationinpatientswithtype2diabetes.74---78 The consumption of these supplements decrease the HbA1c,74---76 _glucose, _insulin _resistance75 _and _increased insulinsecretion.76_Glucose_increased_in₃_studies,76---78_such asHbA1c and insulin resistance.77,78 _Given _this, _it _can _be

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and PA impact on biochemical markers in DM2 patients

Table2 Generaldescriptionoftheincludedtrialsinthisreviewperinterventionandcontinent. Physicalactivity:Americancontinent

AuthorReference Year,Country Group,numberofpatients Descriptionofintervention Lengthofprogram Results Gavinetal.55 _2010,_Canada _Aerobic_training_group,₆₀ _Aerobic_training_supervised,_three_times

perweekonatreadmillorcycle ergometer.

6months Triglycerides(TG)werereducedin resistancecombinedandaerobic exercisegroup,

p=0.02/0.001/p>0.05.ApoB48 decreasedinresistanceand combinedexercisegroup, p<0.05/p>0.05.Intheaerobic exercisegroupincreased,p>0.05. Resistanceexercise,64 2---3setstheresistanceexercise

supervisedonweightmachines,2---3 daysperweek

Combinedexercise,64 Fullaerobicplusthefullresistance program.

Control,63 Reverttotheirlevelofactivityat baselineandtomaintainthislevel Churchetal.47 _2010,_USA _Aerobic_exercise,₇₂ _Aerobic_exercise_supervised_at_50%---80%

ofmaximumoxygenconsumptionwith anenergyexpenditureof12kcal/kgper week

9months Comparedwiththecontrolgroup,the HbA1cdecrease0.34%inthe

combinedexercisegroup,0.16%in resistanceexercisegroup,and0.24% inaerobicexercisegroup,

p=0.03/032/0.14.

IndiabetespatientswithHbA1c≥7 andcomparedwiththecontrolgroup, thecombinedexercisereducesHbA1c 0.53%,theaerobicexercise0.50%, and0.33%theresistanceexercise, p=0.008/0.01/0.10.

Resistanceexercise,73 Resistanceexercisesupervised3days perweek

Combinationexercise,76 2resistancetrainingsessionsperweek andaerobicexercisesupervisedwith energyexpenditureof10kcal/kgper week

Control,41 Stretchingandrelaxationclasses supervised.Andwasaskedtomaintain currentactivityduringthestudyperiod Jorgeetal.48 _2011,_Brazil _Aerobic,₁₂ ₆₀_min_of_aerobic_exercise_(cycling)₃

daysperweek

12weeks Ithasbeenfoundin4groupsa reductionoffastingandpostprandial glucose,p<0.05.

TheHbA1candinsulinresistance decreasedintheaerobic,resistance andcombinedexercisegroupand increasedinthecontrolgroup, p>0.05.

Itwasfoundin4groupsdecreasethe TCandTG,p<0.05.

TheHDLcholesterolhadadecreased intheaerobic,resistanceandcontrol group,p<0.05.

Resistance,12 60minofresistanceexercisesupervised 3daysperweek

Combined,12 Aerobicandresistanceexercise interchangedatthesameintensityand halfthevolumeoftheaerobicand resistancegroup

Control,12 Stretchingexercisesdesignedtoprovide participativeinvolvementbutnotto elicitchangesinmusclestrengthor cardiovascularﬁtness

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596 E. Barreira et al. Table2 Continued

Physicalactivity:Americancontinent

AuthorReference Year,Country Group,numberofpatients Descriptionofintervention Lengthofprogram Results Laroseetal.49 _2011,_Canada _Aerobic,₆₀ ₄₅_min_of_aerobic_exercise_supervised

(treadmillorcycleergometer)3days perweek

6months Aerobicexerciseandresistance reducedHbA1c(0.51/0.38%, p=0.007/0.037)comparedwiththe controlgroup.

Inthegroupthatpracticedexercise combinedthereductionwas0.46%, p=0.014comparedtothegroupthat practicedaerobicexerciseand0.59%, p=0.001comparedtothegroupthat performedresistanceexercise. Resistance,64 45minofresistanceexercisesupervised

onweightmachines,2---3daysperweek Combined,64 Aerobicandresistanceexercise

supervised

Control,63 Subsequenttotherun-inphase,were askedtoreverttotheirlevelofactivity atbaselineandtomaintainthislevelfor theremainderofthestudy

Swiftetal.54 _2012,_USA _Aerobic_exercise,₅₀ _Aerobic_training_supervised_by_study

staffinexercisetraininglaboratory.

9months TherewasareductioninHbA1cfrom thegrouppracticedcombined exercise(0.34%,p<0.05)compared withthecontrolgroup(+0.24%).In thegroupaerobicexerciseand resistanceisalsoreduced

(0.15/0.16%,p>0.05).Theincreased fastingglucoseinthe4groups (aerobicexercise:2.96mg/dl; resistance:4.76mg/dl;combined: 0.46mg/dl;control:7.54mg/dl)and fastinginsulindecreased(aerobic exercise:1.53pmol/lresistance: 1.89pmol/l;combined:2.05pmol/l; Control:3.61pmol/l,p>0.05). Resistanceexercise,58 Resistancetrainingsupervisedin

exercisetraininglaboratory3daysper week

Combinationexercise,59 Combinationofresistanceandaerobic traininginexercisetraininglaboratory. Control,37 Stretchingandrelaxationclassesand

wasaskedtomaintaintheircurrent activityduringthestudyperiod.

Physicalactivity:Asiaticcontinent

Authorreference Year,country Group,numberofpatients Descriptionofintervention Lengthofprogram Results Okadaetal.46 _2010,_Japan _Exercise,₂₁ _Aerobic_and_resistance_exercise_program

from3to5daysperweek,supervisedby physiotherapist.

3months TheHbA1cwasdecreasedinthe exerciseandcontrolgroup,p<0.01. Fastingbloodglucoselevelsinplasma intheexercisegroupincreasedand decreasedinthecontrolgroup, p>0.05.Therewasadecreasedin bothgrouptheTC,p>0.05,LDL cholesterol(exercise:p<0.01; control:p<0.05)andTG,p>0.05. TheHDLcholesterolincreased (exercise:p<0.01;control:p<0.05) Control,17 Withoutexercisetraining

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and PA impact on biochemical markers in DM2 patients Table2 Continued

Physicalactivity:Asiaticcontinent Authorreference Year,

country

Group,number ofpatients

Descriptionofintervention Lengthofprogram Results

Motahari-Tabari etal.53

2015, Iran

Exercise,27 Aerobicexercise3timesa week

8weeks Thefastingglucosewasreducedin theexercisegroupandincreasedin thecontrolgroup,p=0.06.These changeswerenotstatistically significantbetweengroups,p=0.06. Plasmainsulinwasreducedinboth groupsthroughoutthestudy p=0.002.Thesechangeswere statisticallysignificantbetween groups,p=0.007.Insulinresistance waslowerintheexercisegroup comparedwiththecontrolgroup. Thesechangeswerestatistically significantthroughoutthestudyand betweengroups,p=0.004/0.007 Control,26 Withoutexercisetraining

Physicalactivity:Europeancontinent Authorreference Year,country Group,number

ofpatients

Ferrer-García etal.17

2011,Spain Intervention, 44

45minofcombinedphysicalexercise program(aerobicandanaerobicexercises) from3to5daysperweek,and

conventionaltreatmentfordiabetes

24weeks HbA1cdecreasedintheexperimental andcontrolgroup,p<0.05.The fastingglucosedecreasedinthe interventiongroup,p=0.002,and increasedinthecontrolgroup, p=0.10.Intheexperimentalgroup TG,TCandLDLdecreasedandHDL increasedafter6months

(p=0.138/0.046/0.217/0.226).Inthe controlgroupTC,LDLandHDLwere reducedandincreasedTG

(p=0.624/0.220/0.460/0.032). Control,40 Conventionaltreatmentfordiabetes

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ofpatients

Descriptionofintervention Lengthofprogram Results Balducci etal.50 2012,Italy Exercise moderate-to-highintensity (HI),152

Aerobicandresistanceexercisesupervised themoderatetohighintensity2daysper weekandrecommendationsonbothtypes ofexerciseevery3months

12months TherewerelowerHbA1c,fasting bloodglucose,plasmainsulin,insulin resistanceintheLIgroup

(p=0.005/0.030/0.009)andtheHI group

(p<0.001/=0.003/=0.03/=0.003).In theLIgroup,TGandHDLcholesterol increased(p=0.010/<0.001),theTC andLDLcholesteroldecreased (p<0.001).

IntheHIgroup,therewasadecrease ofTG,TCandLDL,theHDL cholesterolincreased (p=0.51/<0.001/<0.001/<0.001). Exercise low-to-moderate intensity(LI), 136

Aerobicandresistanceexercisesupervised thelowtomoderateintensity2daysper weekandrecommendationsonbothtypes ofexerciseevery3months

Control,303 Exercisecounseling

Balducci etal.51

2012,Italy Exercisegroup, 36

75mindayofaerobicandresistance exercisesupervisedtwiceweekly.All participantsreceivedstructuredexercise counseling,encouraginganytypeof leisure-timephysicalactivity

12months Intheexercisegrouptherewere lowerHbA1c,TC,andLDLcholesterol (p<0.001/=0.20/=0.04).TGandHDL cholesterolincreased(p=0.80/0.25). InthecontrolgroupHbA1c,TC,HDL andLDLcholesteroldecreased (p=0.16/0.74/0.18/0.75)and increasedTG(p=0.035). Controlgroup,

34

Structuredexercisecounseling,encouraging anytypeofleisure-timephysicalactivity Vinettietal.52 _2015,_Italy _{Intervention,}

10

Aerobic,resistanceandﬂexibilityexercise supervisedbypersonaltrainersand hospital-basedsetting

12months Thefastingplasmaglucosedecreased inintervention/controlgroups (p=0.32/0.26).HbA1cdecreasedin theexperimentalgroupand increasedinthecontrolgroup (p=0.08/0.25,thesechangeswere notstatisticallysignificantbetween groups,p=0.75/0.05).Thesameis observedwiththefastinginsulin (p=0.01/0.42,thesealterationswere statisticallysignificantbetween groups,p=0.02),insulinresistance (p=0.02/p<0.05),TC(p=0.03/0.52, thesechangeswerenotstatistically significantbetweengroups,p=0.05), LDLcholesterol(p=0.04/>0.05)and

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and PA impact on biochemical markers in DM2 patients 599 Table2 Continued

ofpatients

TG(p=0.11/0.33.Thesechanges werestatisticallysigniﬁcantbetween groups,p=0.06).HDLcholesterol decreasedinthe2groups

(p=0.79/0.20).Thisreductionwas notstatisticallysigniﬁcantbetween thegroupsp=0.29.

Control,10 Standardmedicalcareonly

Dietaryprogram:Americancontinent Authorreference Year,country Group,number

ofpatients

Descriptionofintervention Lengthofprogram Results Cohen

and Johnston.37

2011,USA Almond,7 28galmondingestion5day/week 12weeks Theconsumptionofalmond decreasedtheHbA1c,p=0.045, glucoseconcentration,p=0.305and TG,p>0.05.

Thefastinginsulinincreasedin groups2,p=0.610.

TheTCandLDLincreased consumptionalmondgroupand decreasedinthecontrolgroup, p>0.05.

Control,6 2cheesesticksingestion5day/week

Soricetal.75 _2012,_USA _Vitamin_D,₁₉ ₂₀₀₀_IU_vitamin_D3_{(cholecalciferol)}_daily

bymouth

12weeks TheHbA1cdecreasedinVitaminD groupandincreasedincontrolgroup, p=0.16.Inthesubgroupanalysis, diabeticpatientswithbaseline HbA1c>9%whohadreceivedvitamin D,havealargestdeclineinHbA1c (−1.4%,p=0.013)comparedtothose withvaluesbetween8and8.9% (+0.3,p=0.90)andbetween7and 7.9%(+0.1%,p=0.50).

VitaminC (control),18

500mgvitaminCdailybymouth.

Toinucci etal.96

2015,Brazil Probiotic,23 120g/dailyoffermentedmilkfermented milkcontainingLactobacillus

acidophilusLa-5andBiﬁdobacterium animalissubsplactisBB-12

6weeks HbA1cdecreasedintheprobiotic groupandincreasedintheplacebo group,p=0.06/0.82.Thesechanges werestatisticallysigniﬁcantbetween groupsp=0.02.Thefastingglucose

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Dietaryprogram:Americancontinent Authorreference Year,country Group,number

ofpatients

nostatisticallysigniﬁcantdifferences betweengroups,p=0.48.Thesameis observedwithinsulinresistance, p=0.41/0.7;betweengroups: p=0.77,andTG,p=0.16/0.08, betweengroups:p=0.62. Insulindecreasedinthe2groups, p=0.73/0.95,nostatistically signiﬁcantdifferencesbetween groups,p=0.72.

TheTC,LDLandHDLcholesterol werereducedintheprobiotic p=0.52;p=0.31;p=0.50,and increasedintheplacebogroup, p=0.01,p=0.004;p=0.59.These changeswerestatisticallysigniﬁcant differencesbetweengroupsforthe TC/LDLvalues,p=0.04/0.03,butnot HDLcholesterol,p=0.38.

Placebo,22 Conventionalfermentedmilk.

Dietaryprogram:Asiancontinent Authorreference Year,Country Group,number

ofpatients

Wongetal.65 _2010,_China _Fish_oil,₄₉ _Fish-oil₍₄_g/day)_supplements ₁₂_weeks _The_consumption_of_ﬁsh_oil_reduced

theserumTG,p<0.01,TC,p=0.08, LDLcholesterol,p=0.53,HDL cholesterol,p=0.65andfasting glucose,p=0.08.

Control,48 Olive-oil,withequivalentcaloriesof ﬁsh-oilsupplements

Sharmaetal.73 _2011,_India _{Experimental,}

20

9gbrewer’syeast(42_␮gchromium) daily.3capsulesafterbreakfast,lunch anddinnerwitheithermilkorwater

3months Therewasareductioninthe experimentalgroup/controlinthe HbA1c,p<0.001/<0.01,TC, p<0.02/<0.08,LDLcholesterol, p<0.001/<0.04andVLDLcholesterol, p<0.04/<0.02.TheTGdecreasedin theexperimentalgroupandincreased inthecontrolgroup,p<0.05/<0.09. HDLcholesterolincreasedinthe experimentalgroup,anddecreased inthecontrolgroup,p<0.5/<0.06. Control,20 Receivedyeastdevoidofchromium

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ofpatients

Descriptionofintervention Lengthofprogram Results Breslavsky

etal.78

2013,Israel Group1,24 Oraldailysupplementationwithvitamin D(1000U/day)

12months Ingroup1,fastingglucose,HbA1c, insulin,andinsulinresistance increased,p>0.05.Thesamewas foundwithTC,HDLandLDL cholesterol,p>0.05.OnlytheTG decreased,p>0.05.Ingroup2only registeredlowerHbA1c,p>0.05.The fastingglucose,insulin,insulin resistance,TC,HDLcholesterol,LDL cholesterolandTGincreased, p>0.05.

Group2 (control),23

Placebocapsules

Ryuetal.79 _2014,_Korea _Vitamin_D,₄₀ _{Cholecalciferol}₂₀₀₀_IU/day_and_calcium

200mg/day

24weeks HbA1c,insulinresistanceandTG increasedinthevitaminDgroupand decreasedinplacebogroup, p=0.280/0.981/0.682.

Thefastingbloodglucoseincreased 3.2±27.5mg/dlinvitaminDgroup and28.2_±3.9mg/dlintheplacebo group,p=0.891.

TheCT,LDLandHDLcholesterol increasedinthevitaminDgroupand intheplacebogroup,

p=0.248/0.092/0.998. Placebo,41 Calcium200mg/day

Asemietal.93 _2014,_Iran _Synbiotic_food,

31

27×107_UFC_L._sporogenes_and_1.08_g

inulineachday.

6weeks Theconsumptionofprobiotic comparedwiththecontrolresulted inadecreaseinseruminsulinlevels, p=0.03.Thefastingplasmaglucose alsodecreasedintheprobioticgroup andincreasedinthecontrolgroup. Thesameisobservedwithinsulin resistance.TheserumlevelsofTG, TCandLDLcholesterolincreasedin2 groups.TheHDLcholesterol

increasedinthegroupthatconsumed probiotic,anddecreasedinthe controlgroup.Allthesechangeswere notstatisticallysigniﬁcant,p>0.05. Controlfood,

31

Samesubstancewithoutprobiotic bacteriaandinsulin

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ofpatients

Lietal.72 _2014,_China _Breakfast

replacement, 36

75gofthelowglycemicindex multi-nutrientsupplement(provides 346kcalenergy)inplaceofbreakfast

12weeks Inbreakfastreplacementgroup showedadecreaseinHbA1c, glycatedproteinintheserum, p<0.01andinsulin,p>0.05.The fastingglucoseandinsulinresistance increase,p>0.05.Inthecontrol grouptherewasanincreaseinfasting bloodglucose,HbA1c,insulin resistance,p<0.05andinsulin, p>0.05.Glycatedserumprotein decreased,p<0.05.Inthebreakfast replacementgroupTG,TC,HDL cholesterol,ApoA1andApoB increased,p>0.05.Inthecontrol grouptherewasadecreaseofTG,TC andLDLcholesterol,p<0.05)and increasedHDL-cholesterol,ApoA1, p>0.05andApoB,p<0.005. Control,18 Healthybreakfast

Ostadrahimi etal.94

2015,Iran Intervention, 30

600mlfermentedmilk(keﬁr)containing probioticstwiceaday(inlunchand dinner)

8weeks Therewasadecreaseinserum glucoseinbothgroups(intervention: p=0.05;placebo:p>0.05,this decreasewasstatisticallysigniﬁcant betweengroups,p=0.03.HbA1c decreasedintheinterventiongroup andincreasedplacebogroup, p=0.001/p>0.05,thesechanges werestatisticallysigniﬁcantbetween groups,p=0.02.TheTC,LDL cholesterolandTGlevelsdecreased inboth,p>0.05.TheHDLcholesterol decreasedintheinterventiongroup andincreasedintheplacebogroup, p>0.05.

Placebo,30 600mlconventionalfermentedmilk (dough)twiceaday(inlunchanddinner)

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and PA impact on biochemical markers in DM2 patients 603 Table2 Continued

Dietaryprogram:Europeancontinent Authorreference Year,country Group,number

ofpatients

Strobeletal.76 _2014,

Germany

Verum,40 20dropsvigantoloilonceaweek, correspondingtoadailydoseof 1904IU/day

6months ThefastingglucoseandHbA1c decreasedinthe2groups(verum, p=0.282/0.245;control:

p=0.85/0.064).Insulinincreasedin the2groups,p=0.492/0.013.The decreasedinsulinresistanceinverum groupandincreasinginthecontrol group,p=0.954/0.030.TheHbA1c valuewaslowestatbaselineand afterinterventionindiabeticpatients withlevelsof25-hydroxy-vitamin D>20ng/ml,p=0.008/0.009. Placebo,40 Placebooilconsistingofmediumchain

triglycerides

Kampmann etal.77

2014, Denmark

VitaminD,7 Colecalciferol(280␮gdailyfor2weeks, 140␮gdailyfor10weeks)

12week HbA1cdecreasedinvitaminDgroup, andplacebogroup,p=0.79/0.07. Glucoseincreasedin2groups, p=0.78/0.73;noneofthesechanges wasstatisticallysigniﬁcantbetween groups,p=0.13/0.89.Insulinin serumincreasedinthevitaminD groupanddecreasedintheplacebo group,p=0.087/0.95,andinsulin secretionincreasedinthe2groups, p=0.22/0.25.Noneofthesechanges wasstatisticallysigniﬁcantbetween groups,p=0.28/0.34.TheTC (p=0.90/0.61)andLDL

(p=1.00/0.16)increasedinvitaminD andplacebogroup,andHDL

decreasedinthe2groups,

p=0.65/0.92.Noneofthesechanges wasstatisticallysigniﬁcantbetween groups,p=0.71/0.28/0.78. Placebo,8 Identicalplacebotablets

Stenvers etal.70 2014, Nederlands Lowglycaemic response(GR), 9

103mlofGlucernaSR 3months Inthelowglycaemicresponsegroup therewasadecreaseinfasting glucose,TC,LDLandHDL

cholesterol.Fastinginsulinincrease, andHbA1cwasmaintained.

(15)

Dietaryprogram:Europeancontinent Authorreference Year,country Group,number

ofpatients

LDLandHDLcholesterol,anddecreasedTC. Noneofthesechangeswasstatistically signiﬁcant,p>0.05.

Control,11 Free-choicebreakfast Hoveetal.95 _2015,

Denmark

Cardi04yogurt, 23

300mlmilkfermentedwithL. helveticus(Cardi04yogurt)

12weeks HbA1cincreasedintheCardi04yogurtgroup andplacebogroup,p=0.740.Comparedto placebogroup,theplasmaglucoseandinsulin resistancedecreasedintheCardi04yogurt group,p=0.525/0.022.TheC-peptide,insulin, CTandLDLcholesterolincreased,

p=0.616/0.628/0.835/0.851.HDLcholesterol andproinsulindecreased,p=0.092/0.035.The TGshowedthesamevalue.Inthecontrol group,TC,LDL,HDL,TGandproinsulin increased.TheC-peptideandinsulin decreased,p<0.05.

Placebo,18 300mlartiﬁciallyacidiﬁedmilk (placeboyogurt)

Physicalactivityanddietaryprogram:Europeancontinent Kahleova etal.67 2011,Czech Republic Experimental, 37

12weeksofvegetariandiet.Thesecond 12weeksofthedietwerecombined withaerobicexercise.

24weeks TheHbA1candfastingglucosewerereducedin theexperimentalgroupto3/6months, p<0.001.IncontrolgroupHbA1cdecreasedto 3/6months,p<0.001/p=0,370.Thefasting plasmaglucosedecreasedto3/6months, p<0.01/p=0.420.Thefastingplasmainsulin decreasedat3/6monthsintheexperimental group,p<0.05/0.001andexperimentalgroup, p=0.780.

Inexperimentalgroupto3/6monthsdecreased theTC,TG,LDLandHDLcholesterol,

p=0.730/p=0.120/p<0.05/p=0.070. Inthecontrolgroupat3monthsincreasedTC anddecreasedat6months,p=0.730.HDL cholesterolincreased,p=0.70/p<0.05,LDL cholesterolwasreduced,p=0.050and increasedTG,p=0.12.

Control,37 12weeksofconventionaldiabeticdiet. Thesecond12weeksofthedietwere combinedwithaerobicexercise

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Physicalactivityanddietaryprogram:Europeancontinent Andrews etal.69 2011, England Dietary Intervention, 248

Intensivedietinterventiontolose5---10% oftheirinitialbodyweightandto maintainthislossthroughoutthestudy. Plusdietaryconsultationevery3months withmonthlynursesupport.

12moths Comparedwiththecontrolgroup, HbA1cdecreasedindietary interventiongroupandphysical activityanddietaryintervention group,p=0.005/0.027.Thesameis observedwithglucose,

p<0.0001/p=0.01,andfasting insulin,p=0.001/0.022.

Insulinresistancedecreasedinthe dietinterventiongroupanddietary interventionandphysicalactivity, p=0.0001/0.011.Theinsulin secretiondecreasedinthedietary interventiongroupdietanddietary interventionandphysicalactivity group,p>0.05.

TheTCdecreasedinthedietary interventiongroupanddietary interventionandphysicalactivity, p>0.05.TheLDLandHDLcholesterol decreasedinthedietaryintervention groupandincreasedindietary interventionandphysicalactivity group.TGincreasedinthedietary groupanddecreasedindietary interventionandphysicalactivity group,p>0.05.

Dietary intervention andphysical activity,246

Intensivedietinterventionplusa pedometer-basedphysicalactivity program.

Control,99 Initialdietaryconsultationandfollow-up every6months

Educationalsessions:Europeancontinent Authorreference Year,country Group,number

ofpatients

Descriptionofintervention Lengthofprogram Results DeGreef etal.61 2011, Belgium Individual consultation, 22

Physicalactivityindividualcounselingby ageneralpractitioner

12weeks Theparticipantsofindividual, counseling/groupandcontrolgroup hadadecreaseinHbA1cvalue, p≤0.05.Thefastingglucosealso decreased,p<0.05,andincreasedin thecontrolgroup,p>0.05.TheTC increasedinthe3groups,p>0.05. Group

counseling,21

Physicalactivitygroupcounselingbya generalpractitioner

Control,24 Generalcarefromtheirgeneral practitioner

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EducationalsessionsandphysicalactivityEuropeancontinent Authorreference Year,country Group,number

ofpatients

Descriptionofintervention Lengthofprogram Results ArizaCopado

etal.62

2011,Spain 1:diabetes education,27

Educationalsessionswithbasiccontent ondiabetesmellitus

6months Comparedwiththecontrolgroup, HbA1cdecreasedin3groups(Group 1:−1.00;Group2:−1.93,Group3: −1.56%).Thesameistrueofglucose (−1.00,−1.45,−1.48mg/dl),TC (_−1.08;1.48;_−1.20mg/dl),LDL (−1.44,1.82,1,27mg/dl),TG (−1.08;−1.04;−1.04mg/dl).HDL cholesterolincreasedinthe3groups (+1.00,+1.17,+1.11).

2:diabetes educationand physical, exercise,28

Educationalsessionswithbasiccontent ondiabetesmellitusand3---4

sections/weekofaerobicexerciseof moderateintensitywithadurationof 60---90mineach.

3:physical exercise,26

3---4sections/weekofaerobicexercise ofmoderateintensitywithdurationof 60---90mineach.

4:control,27 Itwasfollowedinnormaldiabetes consultations.

Educationalsessions,physicalactivityanddietaryprogram:Asiaticcontinent Authorreference Year,country Group,number

ofpatients

Yuanetal.63 _2014,_Japan _{Intervention,}

44

8-weekeducationonself-management ofdiabetesmellitusandsubsequent4 weeksofpracticeofthe

self-managementguidelines

3-month HbA1clevelsdecreasedinthe interventiongroupandincreasedin thecontrolgroup,p=0.039/0.102, thesamewasfoundwithfasting glucose,p=0.238/0.427andTG, p=0.626/0.850.Inbothgroupsthere wasadecreaseinTC,

p=0.034/<0.001,LDL, p=0.005/<0.001).TheHDL

cholesterolincreasedinintervention groupanddecreasedinthecontrol group,p=0.160/0.303).

Control,44 Standardadviceonmedicalnutrition therapy

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0% 20% 40% 60% 80% 100% Random sequence generation

(selection bias) Allocation concealment (selection

bias)

Blinding of participants and researchers (performance bias) Blinding of outcome assessment

(detection bias) Incomplete outcome data (attrition

bias)

Selective reporting (reporting bias) Other bias

Unclear risk of bias High risk of bias Low risk of bias

Figure2 Flowchartdepictingthestudyselectionprocedure.

seenthatvitaminDsupplementationprovidesablood glu-cosecontrolintheshortandlongtermonlyinstudiesinthe AmericanandEuropeancontinent.InAsiaitwasnotfound relationtobeneﬁts.Thismaybeduetodifferentlifestyles andeatinghabitsofeachregion.

Thelipidlevelresultswerenotfavorablebecausethere was an increase in total cholesterol, LDL, HDL,77,78 _TG increasedin one study78 _in_another _decreased.77 _This dis-crepancymaybeduetothefactthatvitaminDadministered wasnotthesameinallstudies,aswellasthedurationof treatment,ofserumlevelsofvitaminDoftheparticipants could be different, researchers may not have taken into accountthe sun exposureof the participants inthe stud-ies.Somescientific evidencehassuggestedthatvitaminD mayplayacausalroleinthedevelopmentofdiabetesandits complications.Deficiencyofthisvitaminisassociatedwith increasedrisk of cardiovascular disease,obesity,diabetes mellitus, dyslipidemiaand hypertension.High serum vita-min D concentrations have aprotective effect onglucose intolerance, insulin resistance and the risk of developing DM2. The use of supplements of this vitamin in glycemic control,insulinresistanceandlipidprofileisnotyetclear, although some studies have shown beneficial effects.84---96 Fourstudies haveanalyzed theinfluence of the consump-tionofprobioticsinpatientswithtype2diabetes.79,82_It_was foundadecreaseinglucose,79---81_HbA1c,80,82_insulin79,82_and insulin resistance.79,81 _Glucose _and _insulin _resistance _only increasedinonestudy,82 _as_well_as_HbA1c.81_The consump-tionofprobioticsinstudiesconductedinAsiatranslatesinto controloftheshortandlongtermbloodsugar.Onthe Euro-pean continentthere wasonly ablood glucose controlof shorttermandontheAmericancontinentthecontrolwas long-term.

There was a decrease in TC, LDL and TG in two studies,80,82_and_increased_in_two_other_studies.79,81_The_HDL cholesterolincreasedonlyinonestudy79 _and_decreased_in theremaining.80---82_It_may_also_be_noted_that_only_the admin-istrationofprobioticscontainingLactobacillusacidophilus

and Biﬁdobacterium provided lipid control. This discrep-ancyresultsmay beduetoﬁvefacts: theprobiotic used, theamount administered,thetimeof administration, the

thecontinentwherethestudieswereconducted(different dietaryhabitsandlifestyles).

Sincenotallstudiesreplicatepositiveresultsafter tak-ingvitamin Dsupplements andprobiotics,the association betweenthissupplementationandglycemicandlipidprofile intype2diabeticelderlypatients hadasomewhat uncer-taindevelopment.To provide more evidence is necessary toperformfurtherstudiestoconfirmthepotentially bene-ficialrelationshipbetweensupplementationwithvitaminD andprobioticsonglycemicandlipidprofileinpatientswith type2diabetes.

Regardingtheevaluationof thequalityoftheselected studies,ascanbeseenintheFigure1,itwasfoundthatmost ofthearticlesfeatureuncertainselectionbiasbecausethey donotdescribeindetailthemethodusedtogeneratethe randomsequenceandtohidethissequence;halfofthe arti-clesdonotdescribewhatmeasuresusedtoblindoutcome assessorsinrelationtoknowledgeoftheintervention pro-videdtoeachparticipantandtheresultsaccordingtowhat hasbeenproposed.Withregard toattritionandreporting bias,allstudiesareat lowrisksincealldescribethe sam-plesizeatthebeginningandattheendofthestudy.Ifany participantwasdeletedorabandonedthestudythatfactis referencedaswellthereasonsforthat.

Ourstudyshows,however,somelimitationsthatshould be considered when interpreting the results, such as the intensityandtypeofexerciseanddifferentdietplansmay affecttheoutcome;differentdurationoftheprograms,and thepopulationstudiedinthevariousarticlesarealso hetero-geneous.Theexerciseandusualpracticeofphysicalactivity andeatinghabitsmaybeoverunderestimated,lackof mon-itoringofpatientsafterprogramtoevaluatethepersistence ofpotentiallong-termbeneﬁtsandunclearriskofbiasinthe includedstudies.

Anotherofthelimitationsisthefactthat pharmacologi-caltreatmentfordiabetesisnottakenintoaccountaswell astheuseofdietarysupplementsorothertreatments, par-ticularlytoloseweight.Allthismakesitdifﬁculttocompare thestudiesandtheirresults.

Although, some articles do not show favorable results regarding the implementation of dietary programs, and prevails a greater number of articles that highlights the importance of nutrition education, physical activity and healthy eating on glycemic control and lipid proﬁle in patients with type 2 diabetes. We understand therefore thatit is appropriate tocontinue toperform thistype of intervention,sincetheyhavelowercostifcomparedwith pharmacologicaltreatments,butinalongerperiodoftime inordertoprovethelong-termresults.

Conclusions

Giventhehighprevalenceoftype2diabetesinthe popula-tion,particularlyintheelderlypopulation,andconsidering thatthispathologytendstoincreasewithage,itbecomes crucial to change behaviors in activities of daily living, promoting more active and healthy lifestyles throughout life.Physicalactivity,dietaryprogramsand health educa-tionsessionsregardingtheimportanceofchanginglifestyles

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608 E.Barreiraetal. ascomplementarytherapeuticstrategiesintreatmentand

metaboliccontroloftype2diabetes.

Conﬂict

of

interest

statement

Theauthorsstatethattheyhavenoconﬂictsofinterest.

References

1.ADA.Standardsofmedicalcareindiabetes---2016.Diabetes Care.2016;39Suppl.1:S1---112.

2.Goldenberg R, Punthakee Z. Committee CDACPGE. Deﬁni-tion,classiﬁcationanddiagnosisofdiabetes,prediabetesand metabolicsyndrome.CanJDiabetes.2013;37Suppl.1:S8---11. 3.SmushkinG,VellaA.Whatistype2diabetes?Medicine

(Abing-don).2010;38:597---601.

4.VuicaA,FerhatovićHamzićL,VukojevićK,JerićM,PuljakL, GrkovićI,etal.Agingandalong-termdiabetesmellitusincrease expressionof1␣-hydroxylaseandvitaminDreceptorsintherat liver.ExpGerontol.2015;72:167---76.

5.CamenGC,CaraivanO,OlteanuM,CamenA,BungetA,Popescu FC,etal.Inﬂammatoryreactioninchronicperiodontopathies inpatientswithdiabetesmellitus.Histologicaland immunohis-tochemicalstudy.RomJMorpholEmbryol.2012;53:5560. 6.BalasubramaniamK,ViswanathanGN,MarshallSM,ZamanAG.

Increased atherothromboticburdeninpatientswithdiabetes mellitusandacutecoronarysyndrome:areviewofantiplatelet therapy.CardiolResPract.2012;2012:909154.

7.OMS.Globalreportondiabetes.Geneva:WorldHealth Organi-zation;2016.

8.Ena J, Gómez-Huelgas R, Sánchez-Fuentes D, Camafort-BabkowskM,FormigaF,Michán-Do˜naA,etal.Managementof patientswithtype2diabetesandmultiplechronicconditions: aDelphiconsensusoftheSpanishSocietyofInternalMedicine. EurJInternMed.2016;27:31---6.

9.IDF.Diabetesatlas.7thed.Karakas:InternationalDiabetes Fed-eration;2015.

10.WildS,RoglicG,GreenA,SicreeR,KingH.Globalprevalenceof diabetes:estimatesfortheyear2000andprojectionsfor2030. DiabetesCare.2004;27:104753.

11.MathersCD,LoncarD.Projectionsofglobalmortalityand bur-denofdiseasefrom2002to2030.PLoSMed.2006;3:e442. 12.Basanta-AlarioML,FerriJ,CiveraM,Martínez-HervásS,Ascaso

JF,RealJT.Diferenciasenlascaracterísticasclínico-biológicasy prevalenciadecomplicacionescrónicasenrelaciónconel enve-jecimientodepacientescondiabetestipo2.EndocrinolNutr. 2016;63:79---86.

13.FernándezMA.Tratamientodelancianocondiabetes. SEMER-GEN.2014;40Suppl.1:10---6.

14.FormigaF,Gómez-HuelgasR,RodríguezMa˜nasL. Característi-casdiferencialesdeladiabetesmellitustipo2enelpaciente anciano.Papeldelosinhibidoresdeladipeptidilpeptidasa4. RevEspa˜nolaGeriatrGerontol.2016;51:44---51.

15.GómezHuelgasR,Díez-EspinoJ,FormigaF,LaﬁtaTejedorJ, RodríguezMa˜nasL,González-SarmientoE,etal.Tratamientode ladiabetestipo2enelpacienteanciano.MedClín.2013;140, 134.e1---e12.

16.HalterJB,Musi N, McFarlandHorneF,CrandallJP, Goldberg A, Harkless L, et al. Diabetes and cardiovascular disease in older adults:current statusand future directions. Diabetes. 2014;63:2578---89.

17.Ferrer-García JC, SánchezLópez P,Pablos-Abella C, Albalat-GaleraR,ElviraMacagnoL,Sánchez-JuanC,etal.[Beneﬁtsofa home-basedphysicalexerciseprograminelderlysubjectswith type2diabetesmellitus].EndocrinolNutr.2011;58:387---94.

18.GanzML,WintfeldN,LiQ,AlasV,LangerJ,HammerM.The association ofbody mass index withthe risk oftype 2 dia-betes: a case-control study nested in an electronic health records system in the United States. Diabetol Metab Syndr. 2014;6:50.

19.HofeCR,FengL,ZephyrD,StrombergAJ,HennigB,GaetkeLM. Fruitand vegetableintake,asreﬂectedbyserumcarotenoid concentrations, predicts reduced probability of polychlori-natedbiphenyl-associated risk for type 2 diabetes: National HealthandNutritionExaminationSurvey2003---2004.NutrRes. 2014;34:285---93.

20.Alvarez MM. Plano alimentar em algumas complicações metabólicasdodiabetesmellitus:hiperglicémia.nefropatiase dislipidemias.In:SBD,editor.Manualdenutrição---profissional daSaúde.SãoPaulo:DepartamentodeNutriçãoeMetabologia daSBD;2009.p.42---7.

21.Miselli MA, Nora ED, Passaro A, Tomasi F, Zuliani G. Plasmatriglycerides predict ten-years all-cause mortality in outpatientswithtype2diabetesmellitus:alongitudinal obser-vationalstudy.CardiovascDiabetol.2014;13:135.

22.Hormigo-PozoA,Mancera-RomeroJ,Perez-UnanuaMP, Alonso-Fernandez M, Lopez-Simarro F, Mediavilla-Bravo JJ, et al. [Consensusdocumentonthetreatmentofdyslipidemiain dia-betes].SEMERGEN.2015;41:89---98.

23.Luksiene D, Tamosiunas A, Baceviciene M, Radisauskas R, Malinauskiene V, Peasey A, et al. Trends in prevalence of dyslipidaemias and therisk ofmortality inLithuanian urban populationaged45---64inrelationtothepresenceofthe dyslip-idaemiasandtheothercardiovascularriskfactors.PLOSONE. 2014;9:e100158.

24.PikhartH,HubáˇcekJA,PeaseyA,KubínováR,BobákM. Asso-ciation between fasting plasma triglycerides, all-cause and cardiovascularmortalityinCzechpopulation.Resultsfromthe HAPIEEstudy.PhysiolRes.2015;64Suppl.3:S355---61.

25.MillerM,StoneNJ,BallantyneC,BittnerV,CriquiMH,Ginsberg HN,etal.Triglyceridesandcardiovasculardisease:ascientiﬁc statementfromthe AmericanHeartAssociation. Circulation. 2011;123:2292---333.

26.HirakawaY,LamTH,WelbornT,KimHC,HoS,FangX,etal. Theimpactofbodymassindexontheassociationsoflipidswith theriskofcoronaryheartdiseaseintheAsiaPaciﬁcregion.Prev MedRep.2016;3:79---82.

27.RamasamyI.Updateonthemolecularbiologyofdyslipidemias. ClinChimActa.2016;454:143---85.

28.Cortez-DiasN,RobaloMartinsS,BeloA,FiúzaM.VALSIMendIdE [Characterizationoflipidproﬁleinprimaryhealthcareusersin Portugal].RevPortCardiol.2013;32:987---96.

29.Hippisley-CoxJ,CouplandC.Developmentandvalidationofrisk predictionequationstoestimatefutureriskofheartfailurein patientswithdiabetes:aprospectivecohortstudy.BMJOpen. 2015;5:e008503.

30.IDF.Global guidelinefor managing olderpeople withtype 2 diabetes.Bélgica:InternationalDiabetesFederation;2013. 31.MozaffarianD,BenjaminEJ,GoAS,ArnettDK,BlahaMJ,

Cush-manM,etal.Heartdiseaseandstrokestatistics---2015update: a report from the American Heart Association. Circulation. 2015;131:e29---322.

32.CalhauC,FariaA,KeatingE,MartelF,AzevedoI,MartinsMJ, etal.Guiasdesaúdenutrição.Porto:QUIDNOVI;2011. 33.Graça P, Gregório MJ. Estratégias para a Promoção da

Alimentac¸ão Saudável em Portugal. Portugal Saúde Núm. 2015;4:37---41.

34.AbellánBG, HidalgoJDLT, SotosJR, López JLT,Jiménez CLV. Alimentación saludabley autopercepción de salud. Atención Primaria.2016.

35.Ley SH,HamdyO,Mohan V,Hu FB.Prevention and manage-mentoftype2diabetes:dietarycomponents andnutritional strategies.Lancet.2014;383:19992007.

(20)

36.Salas-SalvadóJ,Martinez-GonzálezM,BullóM,RosE.Theroleof dietinthepreventionoftype2diabetes.NutrMetabCardiovasc Dis.2011;Suppl.2:B32---48.

37.Cohen AE, Johnston CS. Almond ingestion at mealtime reducespostprandialglycemiaand chronic ingestion reduces hemoglobinA(1c)inindividualswithwellcontrolledtype2 dia-betesmellitus.Metabolism.2011;60:1312---7.

38.JenkinsDJ, Kendall CW,Banach MS, Srichaikul K, Vidgen E, MitchellS,etal.Nutsasareplacementfor carbohydratesin thediabeticdiet.DiabetesCare.2011;34:1706---11.

39.Nishi SK, Kendall CW, Bazinet RP, Bashyam B, Ireland CA, AugustinLS,etal.Nutconsumption,serumfattyacidproﬁle andestimatedcoronaryheartdiseaseriskintype2diabetes. NutrMetabCardiovascDis.2014;24:845---52.

40.ShidfarF, Froghifar N, Vafa M, RajabA, Hosseini S, Shidfar S, et al. The effects of tomato consumption on serum glu-cose,apolipoprotein B,apolipoproteinA-I,homocysteineand bloodpressureintype2diabeticpatients.IntJFoodSciNutr. 2011;62:289---94.

41.InzucchiSE, Bergenstal RM, BuseJB, Diamant M, Ferrannini E,Nauck M,et al. Managementof hyperglycemia in type2 diabetes:apatient-centeredapproach:positionstatementof the American Diabetes Association (ADA) and the European Associationforthe StudyofDiabetes (EASD).Diabetes Care. 2012;35:1364---79.

42.WorldHealth Organization. Global strategyondiet, physical

activityandhealth;2017.Availablefrom:http://www.who.int/

dietphysicalactivity/pa/en/

43.OMS.Globalrecommendationsonphysicalactivityforhealth. Geneva:WorldHealthOrganization;2010.

44.Higgins J, Altman D, The Cochrane Collaboration. Assessing riskofbiasin includedstudies.In:Higgins J,GreenS, edit-ors.Cochranehandbookforsystematicreviewsofintervention version510(updateMarch2011).2011.

45.CarvalhoAPV,SilvaV,GrandeAJ.Avaliac¸ãodoRiscodeViésde EnsaiosClínicosRandomizadospelaFerramentadaColaborac¸ão Cochrane.DiagnTratamento.2013;18:33---44.

46.OkadaS,HiugeA,MakinoH,NagumoA, TakakiH,KonishiH, etal.Effectofexercise interventiononendothelialfunction andincidenceofcardiovasculardiseaseinpatientswithtype2 diabetes.JAtherosclerThromb.2010;17:828---33.

47.Church TS, BlairSN, Cocreham S, JohannsenN, Johnson W, KramerK,etal.Effectsofaerobicandresistancetrainingon hemoglobinA1clevelsinpatientswithtype2diabetes:a ran-domizedcontrolledtrial.JAMA.2010;304:2253---62.

48.JorgeML,deOliveiraVN,ResendeNM,ParaisoLF,CalixtoA, DinizAL,etal.Theeffectsofaerobic,resistance,andcombined exerciseonmetaboliccontrol,inﬂammatorymarkers, adipocy-tokines,and muscleinsulin signalinginpatientswithtype2 diabetesmellitus.Metabolism.2011;60:1244---52.

49.LaroseJ, Sigal RJ, Khandwala F,Prud’homme D, BouléNG, Kenny GP, et al. Associations between physical ﬁtness and HbA1c in type 2 diabetes mellitus. Diabetologia. 2011;54: 93---102.

50.BalducciS,ZanusoS,CardelliP,SalviL,BazuroA,PuglieseL, etal.Effectofhigh-versuslow-intensitysupervisedaerobicand resistancetrainingonmodiﬁablecardiovascularriskfactorsin type2diabetes;theItalianDiabetesandExerciseStudy(IDES). PLOSONE.2012;7:e49297.

51.Balducci S, Zanuso S, Cardelli P, Salerno G, Fallucca S, NicolucciA,etal.Supervisedexercisetrainingcounterbalances the adverse effects of insulin therapy in overweight/obese subjects with type 2 diabetes. Diabetes Care. 2012;35: 39---41.

52.VinettiG,MozziniC,DesenzaniP,BoniE,BullaL,LorenzettiI, etal.Supervisedexercisetrainingreducesoxidativestressand cardiometabolicriskinadultswithtype2diabetes:a

random-53.Motahari-Tabari N, Ahmad Shirvani M, Shirzad-E-Ahoodashty M, YouseﬁAbdolmaleki E, Teimourzadeh M. The effect of 8 weeks aerobic exercise on insulin resistance in type 2 dia-betes:arandomizedclinicaltrial.GlobJHealth Sci.2015;7: 115---21.

54.SwiftDL,JohannsenNM,EarnestCP,BlairSN,ChurchTS.Effect ofexercise trainingmodalityonC-reactive proteinintype2 diabetes.MedSciSportsExerc.2012;44:1028---34.

55.GavinC,SigalRJ,CousinsM,MenardML,AtkinsonM,Khandwala F,et al.Resistanceexercise butnotaerobic exerciselowers remnant-likelipoproteinparticlecholesterolintype2diabetes: arandomizedcontrolledtrial.Atherosclerosis.2010;213:552---7. 56.Nojima H, WatanabeH, Yamane K, Kitahara Y, Sekikawa K, YamamotoH,etal.Effectofaerobicexercisetrainingon oxida-tivestressinpatientswithtype2diabetesmellitus.Metabolism. 2008;57:170---6.

57.KasumovT, SolomonTP,HwangC,HuangH, HausJM,Zhang R,etal.Improvedinsulinsensitivityafterexercisetrainingis linkedtoreducedplasmaC14:0ceramideinobesityandtype2 diabetes.Obesity(SilverSpring).2015;23:1414---21.

58.DeFilippisE,CusiK,OcampoG,BerriaR,BuckS,ConsoliA, et al. Exerciseinduced improvement in vasodilatory function accompaniesincreasedinsulinsensitivity inobesity andtype 2diabetesmellitus.JClinEndocrinolMetab.2006;91:4903---10. 59.LazarevicG,AnticS,CvetkovicT,VlahovicP,TasicI,Stefanovic V.Aphysicalactivityprogrammeanditseffectsoninsulin resis-tanceandoxidativedefenseinobesemalepatientswithtype2 diabetesmellitus.DiabetesMetab.2006;32:58390.

60.Hordern MD, Cooney LM, Beller EM, Prins JB, Marwick TH, CoombesJS.Determinantsofchangesinbloodglucoseresponse toshort-termexercisetraininginpatientswithType2diabetes. ClinSci(Lond).2008;115:273---81.

61.DeGreefK, DeforcheB, Tudor-LockeC,DeBourdeaudhuijI. IncreasingphysicalactivityinBelgiantype2diabetespatients: a three-arm randomized controlled trial. Int J Behav Med. 2011;18:188---98.

62.Ariza Copado C, Gavara Palomar V, Mu˜noz Ure˜na A, Aguera MengualF,Soto Martínez M,LorcaSerralta JR. Mejoraenel controldelosdiabéticostipo2trasunaintervenciónconjunta: educacióndiabetológicayejerciciofísico.AtenciónPrimaria. 2011;43:398---406.

63.YuanC,LaiCW,ChanLW,ChowM,LawHK,YingM.Theeffectof diabetesself-managementeducationonbodyweight,glycemic control,and othermetabolicmarkersinpatientswithtype2 diabetesmellitus.JDiabetesRes.2014;2014:789761.

64.Steinsbekk A, RyggL, Lisulo M,RiseMB, FretheimA. Group baseddiabetesself-managementeducationcomparedto rou-tine treatment for people with type 2 diabetes mellitus. A systematic reviewwith meta-analysis.BMC Health Serv Res. 2012;12:213.

65.WongCY,YiuKH,LiSW,LeeS,TamS,LauCP,etal.Fish-oil sup-plementhasneutraleffectsonvascularandmetabolicfunction butimprovesrenal functioninpatientswithType2 diabetes mellitus.DiabetMed.2010;27:54---60.

66.Lee TC, Ivester P, Hester AG, Sergeant S, Case LD, Mor-ganT,et al.Theimpactofpolyunsaturatedfatty acid-based dietary supplements on disease biomarkers in a metabolic syndrome/diabetes population. Lipids Health Dis. 2014;13: 196.

67.KahleovaH,MatoulekM,MalinskaH,OliyarnikO,KazdovaL, NeskudlaT,etal.Vegetariandietimprovesinsulinresistance and oxidative stress markersmorethanconventionaldiet in subjectswithType2diabetes.DiabetMed.2011;28:549---59. 68.TakahashiK, Kamada C,Yoshimura H, OkumuraR, Iimuro S,

OhashiY,et al.Effects oftotaland greenvegetableintakes onglycatedhemoglobinA1candtriglyceridesinelderlypatients withtype2diabetesmellitus:theJapaneseElderlyIntervention

(21)

610 E.Barreiraetal.

69.AndrewsRC,CooperAR,MontgomeryAA,NorcrossAJ,Peters TJ,SharpDJ,et al.Dietordietplusphysicalactivityversus usual care in patients with newly diagnosed type 2 dia-betes: the early ACTID randomised controlled trial. Lancet. 2011;378:129---39.

70.StenversDJ,SchoutenLJ,JurgensJ,EndertE,KalsbeekA,Fliers E,etal.Breakfastreplacementwithalow-glycaemicresponse liquidformulainpatientswithtype2diabetes:arandomised clinicaltrial.BrJNutr.2014;112:504---12.

71.LiD,ZhangP,GuoH,LingW.Takingalowglycemicindex multi-nutrientsupplementasbreakfastimprovesglycemiccontrolin patientswithtype2diabetesmellitus:arandomizedcontrolled trial.Nutrients.2014;6:5740---55.

72.Ajala O, English P,Pinkney J. Systematic review and meta-analysisofdifferentdietaryapproachestothemanagementof type2diabetes.AmJClinNutr.2013;97:505---16.

73.SharmaS,AgrawalRP,ChoudharyM,JainS,GoyalS,Agarwal V.Beneﬁcialeffectofchromiumsupplementationonglucose, HbA1Candlipidvariablesinindividualswithnewlyonsettype-2 diabetes.JTraceElemMedBiol.2011;25:14953.

74.Soric MM, Renner ET, Smith SR. Effect of daily vitamin D supplementationonHbA1cinpatientswithuncontrolledtype2 diabetesmellitus:apilotstudy.JDiabetes.2012;4:104---5. 75.StrobelF,ReuschJ,Penna-MartinezM,Ramos-LopezE,Klahold

E,KlepzigC,etal.Effectofarandomisedcontrolledvitamin Dtrialoninsulinresistanceandglucosemetabolisminpatients withtype2diabetesmellitus.HormMetabRes.2014;46:54---8. 76.Kampmann U, Mosekilde L, Juhl C, Moller N, Christensen B, Rejnmark L, et al. Effects of 12 weeks high dose vita-min D3 treatment on insulin sensitivity, beta cell function, and metabolic markersin patientswithtype2 diabetesand vitaminDinsufﬁciency---adouble-blind,randomized, placebo-controlledtrial.Metabolism.2014;63:1115---24.

77.BreslavskyA,FrandJ,MatasZ,BoazM,BarneaZ, Shargorod-skyM.EffectofhighdosesofvitaminDonarterialproperties, adiponectin,leptinandglucosehomeostasisintype2diabetic patients.ClinNutr.2013;32:970---5.

78.RyuOH,ChungW,LeeS,HongKS,ChoiMG,YooHJ.Theeffect of highdosevitamin D supplementation on insulinresistance andarterialstiffnessinpatientswithtype2diabetes.KoreanJ InternMed.2014;29:620---9.

79.AsemiZ,Khorrami-RadA,AlizadehSA,ShakeriH,Esmaillzadeh A.Effectsofsynbioticfoodconsumptiononmetabolicstatusof diabeticpatients:a double-blindrandomizedcross-over con-trolledclinicaltrial.ClinNutr.2014;33:198---203.

80.Ostadrahimi A, Taghizadeh A, Mobasseri M, Farrin N, Paya-hooL, BeyramalipoorGheshlaghiZ,etal.Effectofprobiotic fermented milk (keﬁr) on glycemic control and lipid pro-ﬁle in type 2 diabetic patients: a randomized double-blind placebo-controlledclinicaltrial.IranJPublicHealth.2015;44: 228---37.

81.Hove KD, Brøns C, Færch K, Lund SS, Rossing P, Vaag A. Effectsof12weeksoftreatmentwithfermentedmilkonblood pressure, glucosemetabolism and markersof cardiovascular risk in patientswithtype 2 diabetes: a randomised double-blind placebocontrolled study. Eur J Endocrinol. 2015;172: 11---20.

82.Tonucci LB, Olbrich Dos Santos KM, Licursi de Oliveira L, RochaRibeiroSM,Duarte Martino HS.Clinical applicationof probioticsintype2diabetesmellitus:arandomized, double-blind,placebo-controlledstudy.ClinNutr.2015.

83.SuksomboonN,PoolsupN,Yuwanakorn A. Systematicreview and metaanalysis of the efﬁcacy and safety of chromium supplementation in diabetes. J Clin Pharm Ther. 2014;39: 292---306.

84.Forouhi NG, Ye Z, Rickard AP, Khaw KT, Luben R, Langen-bergC,etal. Circulating25-hydroxyvitamin Dconcentration and the risk of type 2 diabetes: resultsfrom the European ProspectiveInvestigationintoCancer(EPIC)-Norfolkcohortand updated meta-analysis of prospective studies. Diabetologia. 2012;55:2173---82.

85.NielsenNO,BjerregaardP,RønnPF,FriisH,AndersenS,Melbye M,etal.AssociationsbetweenVitaminDstatusandtype2 dia-betesmeasuresamongInuitinGreenlandmaybeaffectedby otherfactors.PLOSONE.2016;11:e0152763.

86.KnektP,LaaksonenM,MattilaC,HärkänenT,MarniemiJ, Heliö-vaaraM,etal.SerumvitaminDandsubsequentoccurrenceof type2diabetes.Epidemiology.2008;19:666---71.

87.PittasAG,LauJ,HuFB,Dawson-HughesB.TheroleofvitaminD andcalciumintype2diabetes.Asystematicreviewand meta-analysis.JClinEndocrinolMetab.2007;92:2017---29.

88.AljabriKS,BokhariSA,KhanMJ.Glycemicchangesaftervitamin Dsupplementationinpatientswithtype1diabetesmellitusand vitaminDdeﬁciency.AnnSaudiMed.2010;30:454---8.

89.MuscogiuriG, SoriceGP,AjjanR,MezzaT,PilzS,PriolettaA, etal.CanvitaminDdeﬁciencycausediabetesand cardiovas-culardiseases?Presentevidenceandfutureperspectives.Nutr MetabCardiovascDis.2012;22:81---7.

90.DavidsonMB,DuranP,LeeML,FriedmanTC.High-dosevitamin Dsupplementationin peoplewithprediabetes and hypovita-minosisD.DiabetesCare.2013;36:260---6.

91.Oosterwerff MM, Eekhoff EM, Van Schoor NM, Boeke AJ, Nanayakkara P, Meijnen R, et al. Effect of moderate-dose vitamin D supplementation on insulin sensitivity in vita-minD-deﬁcient non-Western immigrants inthe Netherlands: a randomized placebo-controlled trial. Am J Clin Nutr. 2014;100:152---60.

92.BarengoltsE,ManickamB,EisenbergY,AkbarA,KukrejaS, Ciub-otaruI.Effect ofhigh-dose vitamin D repletionon glycemic controlinAfrican-Americanmaleswithprediabetesand hypovi-taminosisD.EndocrPract.2015;21:604---12.

93.DalgårdC,PetersenMS,WeiheP,GrandjeanP.VitaminD sta-tusinrelationtoglucosemetabolismand type2diabetesin septuagenarians.DiabetesCare.2011;34:1284---8.

94.TalaeiA,MohamadiM,AdgiZ.TheeffectofvitaminDoninsulin resistance in patients withtype 2 diabetes. Diabetol Metab Syndr.2013;5:8.

95.ZhangJ,YeJ,GuoG,LanZ,LiX,PanZ,etal.VitaminDstatus isnegativelycorrelatedwithinsulinresistanceinChinesetype 2diabetes.IntJEndocrinol.2016;2016:1794894.

96.González-Molero I, Rojo-Martínez G, Morcillo S, Gutiérrez-Repiso C, RubioMartínE, Almaraz MC, et al. Vitamin D and incidence ofdiabetes:a prospectivecohortstudy.ClinNutr. 2012;31:571---3.