metformin_ current knowledge

07/05/2015 Metformin:Currentknowledge

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214027/?report=reader 1/10

Metformin: Current knowledge

Hamid Nasri and Mahmoud Rafieian-Kopaei

AbstractDiabetesmellitusisagroupofmetabolicdisordersinwhichthebloodglucoseishigherthannormallevels,duetoinsufficiencyof

insulinreleaseorimproperresponseofcellstoinsulin,resultinginhighbloodpressure.Theresultanthyperglycemiaproducessever

complications.Metformindrughasbeenshowntopreventdiabetesinpeoplewhoareathighriskanddecreasemostofthediabetic

complications.Recentreportsonmetformin,notonlyindicatesomeimplicationssuchasrenoprotectivepropertieshavebeen

suggestedformetformin,butsomereportsindicateitsadverseeffectsaswellthatarenegligiblewhenitsbenefitsarebroughtinto

account.Weaimedheretoreviewthenewimplicationsofmetforminanddiscussabouttheconcernsintheuseofmetformin,

referringtotherecentlypublishedpapers.

Keywords:Diabetes,diabetesmellitus,diabeticnephropathy,glucose,metformin,newapplications,polycysticovarysyndrome,

renoprotection

INTRODUCTIONDiabetesmellitusisagroupofmetabolicdisordersinwhichthebloodglucoseishigherthannormallevels,duetoinsufficiencyof

insulinreleaseorimproperresponseofcellstoinsulin,resultinginhighbloodpressure.Theresultanthyperglycemiaproducesthe

classicalsymptomsofpolyuria,polydipsiaandpolyphagia.Itmayalsocausenerveproblems,kidneyproblems,andblindness,lossof

limbs,andsexualdysfunction,increaseinheartattackorstroke.[1]Metformin(abiguanidederivative),bycontrollingbloodglucose

leveldecreasesthesecomplications.Metforminworksbyhelpingtorestorethebody'sresponsetoinsulin.Itdecreasestheamountof

bloodsugarthattheliverproducesandthattheintestinesorstomachabsorb.[2]Metformin,otherthanhypoglycemicactivity,has

beentakenwithdietandexercisechangestopreventdiabetesinpeoplewhoareathighriskforbecomingdiabetic.Itisalsousedin

womenwithpolycysticovariansyndrome.Metforminmaymakemenstrualcyclesmoreregularandincreasefertility.[3]Metformin

wasfirstsynthesizedandfoundtodecreasethebloodglucoselevelinthe1920showever,itwasnotusedforalongtime.Theuseof

metforminwasrekindledin1957,whentheresultsofaclinicaltrialwerepublishedconfirmingitseffectondiabetes.Metforminis

nowwidelyprescribedasanantidiabeticdrughowever,therehavebeenseriousconcernsaboutitsadverseeffects,especially

ketoacidosis.[4]Recently,notonlysomeimplicationshavebeendiscoveredformetformin,butalsotherearereportsindicatingthat

itsadverseeffectsarenegligiblewhenitsbenefitsarebroughtintoaccount.[3]Theoretically,itsusehasbeenprohibitedinalarge

groupofpatientswithtype2diabetesmellitusduetotheriskoflacticacidosis.However,ithasbeenshownthatseveraldiabetic

patientswhoareconsideredtobeatriskhavereceivedmetforminwithnoincreasedriskoflacticacidosis.[2,3,4,5]Furthermore,

recentlysomepapershavebeenpublishedindicatingrenoprotectivepropertiesformetformin.Weaimedheretoreviewthenew

implicationsofmetforminanddiscussabouttheconcernsintheuseofmetformin,referringtotherecentlypublishedpapers.

NEW AND OLD IMPLICATIONS AND THE MECHANISMS OF ACTION

Diabetes mellitus

Metforminisprimarilyusedforthetreatmentoftype2diabetesmellitus,particularlyinobese.patients.Metforminhasbeenshownto

reducediabetesmortalityandcomplicationsbythirtypercentcomparedtoinsulin,glibenclamideandchlorpropamide.[5]

Metforminreducesserumglucoselevelbyseveraldifferentmechanisms,notablythroughnonpancreaticmechanismswithout

increasinginsulinsecretion.Itincreasestheeffectsofinsulinhence,itistermedinsulinsensitizer.Metforminalsosuppressesthe

endogenousglucoseproductionbytheliver,whichismainlyduetoareductionintherateofgluconeogenesisandasmalleffecton

glycogenolysis.Moreover,metforminactivatestheenzymeadenosinemonophosphatekinase(AMPK)resultingintheinhibitionof

keyenzymesinvolvedingluconeogenesisandglycogensynthesisintheliverwhilestimulatinginsulinsignalingandglucosetransport

inmuscles.AMPKregulatesthecellularandorganmetabolismandanydecreaseinhepaticenergy,leadstotheactivationofAMPK.

Thisstudytoanextenthasputforthtoexplainthemechanismofmetforminactiononlivergluconeogenesis.[6,7]

Furthermore,metforminincreasestheperipheralglucosedisposalthatariseslargelythroughincreasednonoxidativeglucosedisposal



intoskeletalmuscle.Itusuallydoesnotcausehypoglycemiaandthiscausetobeconsideredasauniqueantidiabeticdrug.[8]

Treatmentofdiabeteswithmetforminisassociatedwithlessweightgaincomparedwithinsulinandsulfonylureas.Weightgainhelps

inbetterglucosecontrol.Inastudyitwasshownthat,overa10yeartreatmentperiod,thepatientstreatedwithmetformingained

aboutonekg,thepatientstreatedwithglibenclamidegainedaboutthreekg,andthepatientstreatedwiththeinsulingainedsixkg

weight.[9]

Pre-diabetes

Thechanceofdevelopingtype2diabetesmellitusmaydecreaseinpeopleatriskforthisdiseasehowever,dietingandintensive

physicalexercisemayworksignificantlybetterforthispurpose.InalargestudyintheUnitedStates,participantsweregiven

placebo,lifestyleinterventionormetformin,andfollowedforthreeyears.Thelifestylemodificationsincludeda16lessontraining

onexerciseanddietingfollowedbymonthlysessionsforindividualswiththeaimofdecreasingthebodyweightby7%.These

patientsunderthisgroupwereengagedinaphysicalactivityforabout150minutes/week.Theincidenceofdiabetesmellitusinthis

groupwasby58%,andinmetformingroupby31%.Aftertenyears,theincidenceofthediseasewaslowerby34%inthepatientson

dietandexerciseand18%inthemetformingroup.[10]

Gestational diabetes

Severaltrialshavesuggestedthatmetforminisassafeandeffectiveasinsulinforthetreatmentofgestationaldiabetes,[11]andit

hasbeensuggestedthatthemotherswhohaveusedmetformininsteadofinsulinmightbehealthierintheneonatalperiod.[12]

However,evidenceisstilllackingonthelongtermsafetyofmetforminforbothchildrenandmothers.[13]

Polycystic ovary syndrome

Polycysticovarysyndrome(PCOS)isfrequentlyassociatedwithresistancetoinsulinandsince1994,metforminhasbeenproposedas

atreatmentforPCOS.[14]In2004,NationalInstituteforHealthandClinicalExcellencerecommendedtoprescribemetforminfor

womenwithPCOSandabodymassindexabove25foranovulationandinfertilitywhenothertherapieshavefailedtoproduce

acceptableresults.[15]However,severalsubsequentreviewsdidnotshowpromisingresultsanddidnotrecommenditfurtherorat

leastasafirstlinemedication,[16]exceptforwomenwithglucoseintolerance.[17]Theguidelinesusuallysuggestclomiphenetobe

thefirsttreatmentandrecommendlifestylemodificationindependentfromdrugtherapy.

Asystematicreviewusingcomparativetrialsofclomipheneandmetforminfoundequalresultsforinfertility[18]andABMJ

editorialsuggestedthatmetforminshouldbeusedasasecondchoice,ifclomiphenetreatmentfails.[19]Furthermore,alargereview

using27clinicaltrialsfoundthatmetforminwasnotassociatedwithanyincreaseinthenumberoflivebirthshowever,itimproved

ovulationrates,especiallywhenitwasusedincombinationwithclomiphene.[20]

Further,areviewrecommendedmetforminasafirstchoicebecauseofpositiveeffectsoninsulinresistance,hirsutism,anovulation

andobesity,whichareoftenassociatedwithpolycysticovarysyndrome.[21]

Thedifferenttrialdesignsmightbethereasonsforthecontradictoryresults.Forexample,consideringlivebirthrateinsteadof

pregnancyastheendpointmighthavebiasedafewtrialsagainstmetformin.[22]Anotherexplanationisthatmetforminmayhave

differentefficacyindifferentpopulations.

Cancer protection

Alargecasecontrolstudyhassuggestedthatmetforminmightprotectpatientsagainstpancreaticcancer.Inthisstudy,theriskof

pancreaticcancerinmetformingroupwas62%lowerthaninplacebogroupwhodidnotusemetformin.Theparticipantshaving

sulfonylureasorinsulinwerefoundtohavea2.5foldand5foldhigherriskofpancreaticcancer,respectively,incomparisonto

placebogroup.[23]Severalstudieshavesuggestedthatdiabeticpatientsusingmetforminmightlowertheriskofcancercomparedto

thoseusingotherantidiabeticdrugs.[24,25]However,theresultsneedconfirmationincontrolledtrials.[26]

Metforminhasshownastrongantiproliferativeeffectsoncolon,pancreatic,breast,ovarian,prostateandlungcancercells.

Preclinicalstudieshavealsoshownreliableantitumoraleffectsindifferentanimalmodels.Aclinicaltrialhasdemonstrated

beneficialeffectincolonandbreastcancers.[27]



Themechanismofthisactionisnotclear.Otherantidiabeticdrugshavenotshownthesameanticanceractivitieshence,the

anticancereffectofmetforminshouldnotberelatedtoantidiabeticactivityofthisdrug.Metforminpossessesantioxidantactivity.

[28]Antioxidantshavebeenshowntohavevariousbeneficialeffectssuchasanticancer,[29,30,31,32]antidiabetes[33]and

antiatherosclerosis[34,35]properties.Therefore,somebeneficialeffectsofmetforminmightberelatedtoitsantioxidantactivity.

HIV-associated diabetes

TheuseofsomeofantiretroviraldrugsinHIVinfectionhasbeenassociatedwithglucosetolerance,insulinresistance,

hyperinsulinemiaandtype2diabetesmellitus.LowHDL,Hypertriglyceridemiaandhighriskofcardiovasculardiseaseshavebeen

reportedinthesepatients.Thesemetabolicalterationsarefrequentlyassociatedwithlossofsubcutaneousfatandincreasedvisceral

fat.[36,37]

Antiretroviraltherapieswithproteaseinhibitorsinhibitglucosetransporter(GLUT)4mediatedglucosetransport.[38]Theyare

likelytobe,inpart,responsiblefortheinsulinresistanceandbodycompositionchangesinHIVinfectedpatients.Metforminhas

beenshowntoreducevisceraladiposityandinsulinresistanceafter8weeksofdrugtherapyatdoseof850mg,3timesperday.[39]

Nephrotoxicity prevention

Recentstudieshavesuggestedthatmetforminmayhavetherapeuticorrenoprotectiveeffectsagainstnephrotoxicagents.[40,41]It

hasalsobeenshowntohaveagoodefficacyindiabeticnephropathy.[40,41,42,43,44]Furthermore,itsignificantlydecreases

albuminuriainpatientswithdiabetesmellitus.[41,42,43,44]However,theexactmechanismbeyondtheseeffectsisstillunknown.

Recentstudieshaveshownthattherapeuticeffectofmetforminismediatedthroughitsactiononadenosinemonophosphate(AMP)

activatedkinaseintissues.[43,44,45,46,47,48]Variousstudieshaveshownthatmetforminiscapableofdecreasingintracellular

reactiveoxygenspecies(ROS).[45,46,47,48,49]Itprotectstubularinjurythroughregulationofoxidativestressandrestoringthe

biochemicalalterationsonrenaltubules.Metforminmayalsoprotectthepodocytesindiabeticnephropathy.[47,48,49,50,51]

VariousstudieshaveshownthatAMPKactivationofmetforminissecondarytoitseffectonthemitochondriaastheprimarytarget.

[52]Recentstudieshavedemonstratedadirectormediatedmitochondrialeffectformetformin.[53]Whenmetforminisusedalone,

itsbeneficialeffectisduetothemildinhibitionofthemitochondrialrespiration.[54,55]

Theeffectofmitochondriainprogrammedcelldeathisusuallyassociatedwiththereleaseofapoptoticsignalingmolecules.[56]

Moreover,ROSproductionbymitochondriamayalsoleadtocelldegradation.[57]

MitochondriarepresentsasoneofthemajorcellularsourcesofROSgeneration,[50]andagreatnumberoftissuepathologies,which

induceoxidativestress.[58,59]Thesefindingsmayshowthecriticalroleofmitochondriaintheseconditions.[58,59]

ThenephrotoxicityofaminoglycosidesandmostofotherrenotoxicagentshasbeenattributedtoROS.[60]Incertainconditions,

intracellularROSmayreachatoxiclevel,resultinginoxidativedamageandmalfunctioningoftheorgan.[54]

WeconductedastudyonmaleWistarratstotestthepotentialpropertiesofmetformininprotectingthekidneyfromgentamicin

inducedacuterenalfailure,andtofindoutbypostponingthetreatmentwithmetformininacuterenalfailureexertssimilarbenefits

asongentamicinnephrotoxicityinrats.[61]Metforminnotonlyhadpreventiveeffectbutalsoexertedameliorativeactivityagainst

gentamicinnephrotoxicity.Hence,itmightbebeneficialinpatientsundertreatmentwiththisdrug.[49]

Metforminhasalsoshowntohavebeneficialeffectonrenalfunctionandstructureafterunilateralischemiareperfusioninrats.[62]

Theauthorsinthisstudyhaveconcludedthatmetforminhastissueprotectionwiththeactivationofendothelialnitricoxidesynthase

andAMPK.[61]

VariousstudieshaveshownthatROSoverproductionmightbethekeystartingevents,whichcausedevelopmentofcomplicationsof

diabetes.[63]However,theexactmechanismsthatcausehyperglycemiaanddiabeticnephropathyarenotelucidated.[64]Ithasbeen

shownthatnucleicacidscanbeaffectedbyoxidativestress,therebymodifyingthebasesinDNA.WhenDNAisdamagedthe

affectedcellsstartaresponsesuchascellcycledelay,DNArepairorapoptosisinduction.ROSgenerationbyoxidativestresscauses

celldeath.[65]Apoptosisisimplicatedinthepathogenesisofdiabeticnephropathy.ROSisaninducerofapoptosisinvariouscell

typesincludingpodocytes.[66]

Metforminisabletorestorethepodocytesindiabeticratsanddiabetesinducedpodocytelossindiabeticnephropathyhasbeen

attenuatedtoROS.[67]Podocyteapoptosisisassociatedwithincreasedalbuminuria.PhosphorylationofAMPKisreducedinthe



kidneyofdiabeticrats.Therefore,metforminmayexertsomeofitseffectsbyimprovingtherenaloxidativestress.[67]These

findingsareinagreementwithotherstudiesshowingbeneficialantioxidantpropertiesofmetforminindiabeticrats.[68]

Thesefindingsmayencouragetheclinicaluseofmetforminalongwithnephrotoxicdrugsaswellasforpreventionofdiabetic

nephropathy.

Side effects

Metforminhasnotsignificantadverseeffectshowever,itmaycauseaseriousconditioncalledlacticacidosiswiththefollowing

symptoms:Dizziness,severedrowsiness,musclepain,tiredness,chills,blue/coldskin,fast/difficultbreathing,slow/irregular

heartbeat,stomachpainwithdiarrhea,nauseaorvomiting.[1,41,43,69]

Lacticacidosisusuallyoccursduetodrugoverdoseorinsomecontraindicatedconditions.Itismorelikelytooccurinpatientswith

certainmedicalconditions,includingaseriousinfection,liverorkidneydisease,recentsurgery,anyconditionsthatcausealowlevel

ofoxygeninthebloodorpoorcirculation(suchasrecentstroke,congestiveheartfailure,recentheartattack),heavyalcoholuse,

dehydration,Xrayorscanningproceduresthatrequireaninjectableiodinatedcontrastdrugandthoseolderthan80years.

[1,41,43,70]

Nausea,vomiting,stomachupset,diarrhea,weakness,orametallictasteinthemouthmayoccur.

Metforminusuallydoesnotcausehypoglycemiahowever,lowbloodsugarmayoccurifthisdrugisusedwithotherantidiabetic

drugs.Hypoglycemiaismorelikelytooccurwithheavyexercise,drinkinglargeamountsofalcohol,ornotconsumingenough

caloriesfromfood.

Symptomsofhyperglycemiaincludepolydipsia,polyuria,rapidbreathing,flushing,confusion,drowsiness,andfruitybreathodor.

[1,41,43,71,72]

Seriousallergicreactiontothisdrugisrarehowever,thisproductmaycontaininactiveingredients,whichcancauseallergic

reactionsorotherproblems.Highfever,diarrhea,vomiting,diureticsorexcesssweatingmaycausedehydrationandincreasetherisk

oflacticacidosis.Olderadultsmaybeatgreaterriskforsideeffectssuchaslowbloodsugarorlacticacidosis.[1,41,43,62,71]

Gastrointestinalintoleranceisoneofthemostfrequentlyoccurredandlacticacidosisisarare,butcausesseriousadverseeffects.

[73,74]Incidenceofmyocardialinfarction(MI)isalsoanimportanteventbutseenlessinmetformincomparedwithsulfonylurea

agents.[75]Metformininducedlacticacidosisisararebutimportantandfataladverseevent.

Apopulationbasedstudydemonstratedthataboutonefourthofpatientsprescribedmetforminhadcontraindicationstoitsuse.

However,contraindicationsrarelyresultedindiscontinuationofmetforminusage.[76]Thesedatahavebeenconfirmedbyseveral

otherstudiesindifferentcountries.[77,78]

Furthermore,inarecentreviewarticle,basedon347observationalcohortstudiesandprospectivecomparativetrials,noevidence

indicatingmetformintobeassociatedwithincreasedlevelsoflactateorincreasedriskoflacticacidosisincomparisontoother

antihyperglycaemicdrugshasbeenreported.

[7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,

52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79]Itshouldbenotedthatinthisreport,allclinical

trialsexcludedtheriskpatients.Therefore,thescenariomightberatherdifferent,inrealpopulation.

Inastudysampleof19,691type2diabetesmellitus(DM),patientswithestablishedatherothrombosisparticipatinginstudy,thetwo

yearmortalityratewassignificantlylessinpatientstreatedwithmetformincomparedwiththepatientsnottreatedwithmetformin.

[80,81]

Therefore,itmightbenecessarytoreconsiderthelistofcontraindicationsintheuseofmetformin.

However,consideringthehighprevalenceofstablerenalimpairment,congestiveheartfailureand/orcoronaryarterydiseasein

elderlypatients,thebenefitriskbalanceofmetformintreatmentareofparticularimportantandmorevaluabledataespecially

relevanttotheelderlypopulationarestillrequired.Inthisregard,benefitriskratiosareneededwithoutdeprivationofpatientsat

risk.

METFORMIN DURING PREGNANCY AND LACTATION



Ithasbeenshownthatpregnancymayalterthefunctionofdrugmetabolizingenzymesanddrugtransportersinagestationalstage.

TheactivitiesofseveralhepaticcytochromeP450enzymessuchasCYP2D6andCYP3A4areincreased,whereastheactivityof

someothers,suchasCYP1A2,maybedecreased.Theactivitiesofsomerenaltransporters,includingorganiccationtransporterand

Pglycoproteinincreaseduringpregnancy.However,significantgapsstillexistinourunderstandingofthespectrumofdrug

metabolismandtransportgenesaffected,gestationalagedependentchangesintheactivityofencodeddrugmetabolizingand

transportingprocesses,andthemechanismsofpregnancyinducedalterations.[52,82]

Thepharmacokineticsofmetforminisalsoaffectedbypregnancy,whichisrelatedtothechangesinrenalfiltrationandnettubular

transport,whichcanbeestimatedroughlybytheuseofcreatinineclearance.Atthetimeofdelivery,thefetusisexposedtovariable

concentrationsofmetforminfromnegligibletoashighasmaternalconcentrations.However,infantexposuretometforminthrough

thebreastmilkislow.[83]

Metforminappearstobeeffectiveandsafeforthetreatmentofgestationaldiabetesmellitus,particularlyforoverweightorobese

women.Ithasbeensuggestedthatmetforminissafeduringpregnancy.However,asmetformincrossestheplacenta,itsuseduring

pregnancyraisesconcernsregardingpotentialadverseeffectsonthemotherandfetus.Furthermore,patientswithmultiplerisk

factorsforinsulinresistancemaynotmeettheirtreatmentgoalswithmetforminaloneandmayrequiresupplementarydrugssuchas

insulin.However,therearepotentialadvantagesfortheuseofmetforminoverinsuliningestationaldiabetesmellituswithrespectto

maternalweightgainandneonataloutcomes.Furthermore,theuseofmetforminthroughoutpregnancyinwomenwithpolycystic

ovarysyndromedecreasestheratesofearlypregnancylossandpretermlaborhenceprotectingagainstfetalgrowthrestriction.

Therehavebeennodemonstrableteratogeniceffects,intrauterinedeathsordevelopmentaldelayswiththeuseofmetformin.

Therefore,theevidencesupportstheefficacyandsafetyofmetforminduringpregnancywithrespecttoimmediatepregnancy

outcomes.However,becausetherearenoguidelinesforthecontinuoususeofmetformininpregnancy,thedurationoftreatmentis

basedonclinicaljudgmentandexperienceonacasebycasebasis.[84,85,86,87,88,89]Recently,theEndocrinSocietyhasnotonly

confirmedtheuseofmetforminduringpregnancybutalsohasrecommendeditasafirstlinetreatmentofcutaneousmanifestations,

forpreventionofpregnancycomplications,orforthetreatmentofobesity.[85,86]Itshouldbenotedthatnotallreferencesallowthe

useofmetformininthefirsttrimesterofpregnancy.[90]Therefore,itissuggestedthatmetformintherapybeusedforglycemic

controlonlyforthosewomenwithgestationaldiabeteswhodonothavesatisfactoryglycemiccontroldespitemedicalnutrition

therapyandwhorefuseorcannotuseinsulinorglyburideinthefirsttrimester.

CONCLUSIONMetforminisanoralantidiabeticdruginthebiguanideclassforthetreatmentoftype2diabetesmellitus,inparticular,in

overweightandobesepeopleandthosewithnormalkidneyfunction.

Metforminhasseveralbenefitsinpatientswithtype2diabetesmellitus,includingdecreasedhyperinsulinemia,weightreduction,

augmentedfibrinolysis,improvedlipidprofilesandenhancedendothelialfunction.

Althoughtheuseofmetforminindiabeteshasitssafetyconcerns,itsbenefitsandtherecentresultsindicatethatthenephroprotective

activityagainstnephrotoxicagentsonmetforminanditsrecentgoodsafetyrecordshaveledresearcherstoconsidertheuseofthis

drugmoreandmoreininsulinresistantstatesevenbeforethedevelopmentofhyperglycemia.

AUTHORS CONTRIBUTIONSAllauthorshavecontributedindesigningthestudy.Bothofthemhaveassistedinpreparationofthefirstdraftofthemanuscriptor

revisingitcriticallyforimportantintellectualcontent.Theyhavereadandapprovedthecontentofthemanuscriptandconfirmedthe

accuracyorintegrityofanypartofthework.

FootnotesSource of Support: Nil

Conflict of Interest: None declared.

Article informationJ Res Med Sci. 2014 Jul; 19(7): 658664.



PMCID: PMC4214027

Hamid Nasri and Mahmoud Rafieian-Kopaei

Department of Nephrology, Division of Nephropathology, Isfahan University of Medical Sciences, Isfahan, Iran

Medical Plants Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran

Address for correspondence: Prof. Mahmoud Rafieian-Kopaei, Medical Plants Research Center, Shahrekord University of Medical Sciences, Shahrekord,

Iran. E-mail: [email protected]

Received 2013 Jul 24; Revised 2013 Dec 25; Accepted 2014 Jan 15.

Copyright : Journal of Research in Medical Sciences

This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits

unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Articles from Journal of Research in Medical Sciences : The Official Journal of Isfahan University of Medical Sciences are provided here courtesy of Medknow

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metformin_ current knowledge

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