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European Journal of Endocrinology 10.1530/EJE-17-0724 The termdiabeticcardiomyopathy isappliedwhencardiac myocardial structural,functional andmetabolicchanges. a variety of mechanisms, including disease-specific HF development( percentage pointofHbA1c)isanimportantpredictor ( ratesof with pooroutcomesandfive-yearsurvival particularly commoncomplicationofdiabetes( , despiteadvancesintreatment( disease istheleadingcauseofmortalityinpatientswith disease ( artery absence ofcoronary (HF)andcardiovascularmortalityeveninthe diabetes (T2D)isassociatedwithanincreasedriskofboth among thetop10causesofdeathworldwide( Diabetes hasreachedepidemicproportionsandisnow Introduction modulation strategiesandcardiovascularoutcomeswithnewclassesofglucose-loweringtherapies. cardiac energymetabolismandenergeticdeficiency, ectopicandvisceraladiposity, diabeticliverdisease,metabolic invasive technologiestoourunderstandingofdiabeticcardiomyopathy, includingdataoncardiacdiseasephenotype, functional andmetabolicchanges.Thisreviewwillfocusonthecontemporarycontributionsofstateart non- development ofheartfailurethroughavarietymechanisms,includingdisease-specificmyocardialstructural, Heart failureisamajorcauseofmorbidityandmortalityintype2diabetes.Type 2diabetescontributestothe Abstract Metabolic Medicine,UniversityofLeeds,UK) Cardiovascular ResearchCentreandBiomedicalImagingScienceDepartment,LeedsInstituteof Cardiovascular Medicine,Radcliffe DepartmentofMedicine,Oxford,UK, 2 1 Eylem Levelt of theartreview and potentialmetabolicinterventionsstate Diabetic : pathophysiology MECHANISMS INENDOCRINOLOGY University ofOxfordCentreforClinicalMagneticResonanceResearch,Oxford,Division British HeartFoundationCardiovascularResearchCentre,UniversityofLeicester, GlenfieldHospital,Leicester, UK, 5 https://doi.org/10.1530/EJE-17-0724 www.ej Review ). Poorerglycemiccontrol(hazardratio(HR)1.32per T2D contributestothedevelopment ofHFthrough e-online.org 1, † , Gaurav Gulsin 3 ). 4 1 E Leveltandothers ,Stefan Neubauer 2 Published byBioscientifica Ltd. , 3 ). Cardiovascular Printed inGreat Britain 4 , © 2018Theauthors 5 ). HFisa 1 ). Type 2 6 , < 7 25% , 2 and 8 ), † (E LeveltisnowatMultidisciplinary Gerry P McCann other vasculardiseases( myocardial damage exists in diabetes independently of not until 1972 when Rubler described the evidence that been suggested by Leyden as early as 1881 ( Although thelinkbetween HFanddiabeteshadfirst Myocardial structural changes indiabetes cardiovascular mortality. the robust association of diabetes with HF and increased but isclearlyofsignificantclinicalimportance,given ( diseaseandhypertension,inpatients withdiabetes artery attributable to other confounding factors such as coronary structural andhaemodynamicchangesarenotdirectly Diabetic heartdisease 9 ). This clinicalentity is currentlypoorly understood, 1 Attribution 4.0International License. This workislicensed under a Downloaded fromBioscientifica.com at10/01/202103:53:21AM 11 ). They observed ventricular ). Theyobserved (2018) Endocrinology European Journal of [email protected] Email to ELevelt should beaddressed Correspondence 178 178 :4 , R127–R139 Creative Commons

R127 10 ), it was –R139 via freeaccess European Journal of Endocrinology www.eje-online.org samples obtainedfrompatients withHF( closely withcollagenproportionate areaonhistology expansion, anditwasdemonstrated thattheECVcorrelates quantification ofmyocardial extracellularmatrix volume (ECV)quantification allowsfornon-invasive native andpost-contrastT1mappingforextracellular Cardiovascular magneticresonance(CMR)imaging appearsto predominate inthe earlystages ( clear, asabnormal myocytehypertrophyratherthan in stable/earlydiabeticcardiomyopathyismuchless role ofinterstitialfibrosisinthepathogenesis LVH advanced stages of diabetic cardiomyopathy ( pathogenesis ofLVH andhasbeenidentifiedinthemore remodelling ( predictive ofcardiovascularmortalitythaneccentric concentric remodellingwasshowntobemorestrongly absence ofCAD,obesityorhypertension( ventricular dilatationandeccentricremodellinginthe There islessevidencethatdiabetesitselfcancauseleft strong predictorofadversecardiovascularevents( the developmentofclinicalHFandwasshowntobea structural characteristic of diabetic heart disease, precedes ( diabetes, often this increase was shown to be modest an increasedLV massisindependentlyassociatedwith 3.0 reported a1%riseinHbA1clevelwasassociatedwith demonstrated inpatientswithdiabetes.Onestudyhas changes reportedbymanystudies. from that of on the myocardial structural making it difficult todistinguish the impactof diabetes the complicationsofdiabetesandhypertension( accepted, withasignificantamountofoverlapbetween among hypertension,anddiabetes( blood pressure( response oftheleftventricle(LV) independentlyofarterial technologies, demonstratingthepresenceofhypertrophic with anuanceddescriptionofdiseaseburdenusingthese Patients with diabetes have been extensivelyphenotyped about thestructureofheartinhealthanddisease. technologies capableofprovidingdetailedinformation in the armamentarium of non-invasive imaging cardiomyopathy’. studies offourdiabeticcasesandcoinedtheterm‘diabetic onhistopathologyinaseriesofpost-mortem between bundlesofmusclefibresandmyofibrillar hypertrophy with diffuse fibrotic strands extending 16 Review , g increaseinLV massinelderlysubjects( Interstitial fibrosishasbeenimplicated inthe Several alterationsinLV havebeen geometry In thelast2decades,therehasbeenanexpansion 17 ). LV concentricremodellingrepresentsthemain 18 ). 12 ). However, thestrongassociation E Leveltandothers 13 ) isuniversally 19 21 15 ). Further, LV ). Usingthis ). Although 11 ). The 14 20 18 ); ). ). stimulation and then increased collagen formation ( myocardium duetocardiomyocytehypertrophy, fibroblast stiffness andafterload,leadingtoremodellingofthe hypertensionresultsinincreasingarterial in summary overlap with the diabetic cardiomyopathy phenotype, of thisreviewarticle.However, giventhesignificant in hypertensiveheartdiseasedetailisbeyondthescope hypertension, whichconfoundstheresults. study, 85%ofthepatientswithdiabeteshaddiagnosed those withoutdiabetes( median ECV in patients with diabetes ( CMR withoutamyloidosis,investigatorsshowedhigher 23 LV concentricremodellinganddiastolicdysfunction( extra cellular matrix expansion, even in the presence of well-controlled T2D, suggestingtheabsence of significant increase in ECV and native T1 mapping in patients with technique, tworecentstudiesdemonstratednosignificant reliable index of left ventricular filling pressure. E/e transmitral inflowvelocity (E)hasbeenvalidatedasa of the medial mitral annulus (e HbA1c level( diastolic dysfunctionwasdirectlyproportionaltothe Study demonstratedthattheextentandfrequency of Despite thelinkwithHFonapopulationlevel( Myocardial functionalchangesindiabetes patients ( prevalent thaneccentricremodellinginhypertensive study hasshownconcentricLV hypertrophytobemore in patientswithsignificant LV hypertrophy( with smallincreasesinT1valueswhichwereonlydetected mapping revealedincreaseddiffusemyocardialfibrosis, a cohortofwell-controlledhypertensivepatients,CMRT1 has beenshowntobeauseful prognosticbiomarkerin from 15toashigh75percent( asymptomatic, normotensivepatientswithT2Dvarying cardiomyopathy, withreportedprevalencerates in suggested astheearliestfunctionaleffectofdiabetic Consequently, diastolicabnormalitieshave been diastolic dysfunctionmainlybasedonechocardiography. ( demonstrated thepresenceofamildreductioninLVEF the exception of the Strong Heart Study, which has or noeffectonglobalLV ejectionfraction(LVEF), with the majorityofstudiesreportthatdiabeteshaslittle Diabetic heartdisease 16 ). Inalargerstudyofconsecutivepatientsreferredfor ). However, diabetestraditionallyhasbeenlinkedto Describing themyocardialstructuralchangesdetected The combinationofpulsed tissueDopplervelocity 26 ). 16 ). Downloaded fromBioscientifica.com at10/01/202103:53:21AM n 4) ( =945) 24 ′ 27 ) with early passive 178 ). However, inthis ). TheStrongHeart :4 n 3) hn in than =231) 25 ). Another R128 ′ 3 ratio ). In 12 22 via freeaccess ), , European Journal of Endocrinology -mediated transport ( to theattenuationofinsulin signals,therebyinhibiting metabolism in the heart by activating pathways that lead energy generation ( utilisation, impairedcardiac efficiencyanddecreased the heart,culminatinginabnormalcardiacsubstrate metabolic changes in diabetes modify metabolism in transporter 4(GLUT4)( FA uptakeandmetabolismwhiledecreasingglucose receptor- This, inturnactivatesperoxisomeproliferatoractivated secretion intheliverleadingtohighcirculating FAs. low-density lipoprotein lipase inadiposetissueandvery In diabetes, insulin fails to suppresshormone-sensitive (FA), withalesserproportion(10–40%)fromglucose( 60–90% ofATP synthesisisgeneratedfromfattyacids leading todiabeticheartdisease.Inthenormalheart, widely consideredamongthepotentialmechanisms heart function.Alteredmyocardialmetabolismhasbeen storage compound,areofvitalimportancefornormal contraction and phosphocreatine (PCr), the major energy phosphate metabolites,ATP, theenergysource for Maintenance of adequatelevelscardiac high-energy Myocardial energymetabolismindiabetes Myocardial metabolicchangesindiabetes define thespectrumofdiabeticheartdisease. longitudinal studieswillneedtoassessthisandbetter the useofstrainmeasuresindiabetesislackingandlarge the onsetofclinicalHFindiabetes,prognosticdataon in contractilityarewidelyconsideredtobeaprecursor in diabetics( impaired systoliccircumferential strainhavebeenshown patients. Bothreducedlongitudinalcontractilityand as amarkerofsubclinicalheartdiseaseindiabetic the presenceofsubtle systolic dysfunction to be frequent imaging byechocardiographyandCMRhasdemonstrated sensitive measuresofmyocardialfunctionwithstrain or otherechocardiographicparameters( disease mortality independent of hypertension, coronary with thesubsequentdevelopmentofHFandincreased that abnormalitiesinE/e’diabeticpatientsisassociated a tissueDopplerechocardiographicassessmentshowed and coworkersinlargestudyof1760diabeticpatientswith shown to be associated with ( diabetic patients.Importantly, abnormalityinE/e Review The recentuseofrelativelylessloaddependent, α (PPAR 30 ). Althoughthesesubclinicalabnormalities α 19 ), whichupregulates myocardial , 34 32 , 35 , , 33 36 ). Hence,thesesystemic , E Leveltandothers 37 ). FA regulate glucose 38 29 , ). 39 , 28 40 ). From ). Due ′ was 31 ). ( sensitive indexoftheenergeticstatemyocardium The relativeconcentrationofPCrtoATP (PCr/ATP) isa with type 2diabetes Myocardial energeticimpairmentinpatients mitochondrial inefficiencyandlower ATP yield. are used compared to glucose ( substrate oxidized( free energyyieldedbyhydrolysisofATP isaffectedbythe use andATP productioninthediabeticheart( loss ofmetabolicflexibility, efficiencybetweensubstrate usage ( in FA availability, andconsequently, increasedcardiac PPAR gene expressionofFA oxidationenzymesviaperoxisome to increasedFA availabilityasasubstrateandincreased MRS) allowsnon-invasiveassessmentofthemyocardial pharmacological agentstoimprove thecardiacfunction. substrate metabolismhasbecome apotentialtargetof and incidenceofHFinpatients withT2D.Assuch alternative therapeuticstrategies toreducetheprevalence ( increased theriskofHFcomparedwithstandardcare Paradoxically, overall,glucose-loweringdrugsor strategies has beenplaced on thecarbohydrate mechanism. risk of T2D ( glycaemia andincidentHFeventsinpatientswithor at Epidemiological datahaveshownanassociationbetween Manipulation ofsubstrateutilisation patients withT2D. energetics inthedevelopmentofcardiacdysfunction to delineate the role of myocardial is therefore necessary in diabeticheartsremainsunclear, andadditionalresearch causal roleofalteredenergeticsincontractiledysfunction systolic strainandPCr/ATP weredemonstrated( increased workload( derangement of cardiac energetics under conditions of microvasculardysfunctionexacerbates coronary perfusion andoxygenation,suggestingthat,indiabetes, ATP wasshowntocorrelatewithimpairedmyocardial exacerbated by exercise ( existing energetic deficit in diabetic cardiomyopathy is well-recognized complicationofdiabetes( ( PCr/ATP. DecreasedPCr/ATP isapredictorofmortality Diabetic heartdisease 56 31 31 ). There is therefore a need for new and effective ). Phosphorusmagneticresonancespectroscopy( ), linkedto contractile dysfunction( Although significant correlations between myocardial α activation,the 36 , 41 , 52 42 , , 53 43 , 47 , 54 30 44 ) andthisislowerwhenexcessFA β -oxidation increases.Thisincrease , ). , Downloaded fromBioscientifica.com at10/01/202103:53:21AM 55 45 30 ); as a result, major emphasis , ). Additionally, exercise PCr/ 46 ), isthoughttoresultina 48 , 49 178 , www.eje-online.org :4 50 ), resulting in 30 51 ). Thispre- ) andisa 46 30 R129 ). The ), the 31 via freeaccess P- European Journal of Endocrinology www.eje-online.org glucose transporter, PCrphosphocreatine, Crfreecreatine. lesser extentamiodarone.Group (B)includestrimetazidineandranolazine.Group(C) dichloroacetate.GLUTdenotes the lattertworepresentclinically pertinenttherapeutictargets.Group(A)includesperhexiline, etomoxir, oxfenicineandtoa carnitine shuttle(CPTinhibitors) and(B) Cardiac energymetabolismand thesitesofactiondifferent metabolicmodulators. Theserangefrom(A)mitochondrial Figure 1 activity, therebymodifyingenergymetabolismbypartial A thiolase(thelastenzymeinvolvedin which selectivelyinhibitslong-chain3-ketoacylcoenzyme reported) ( antioxidant andevenanti-apoptoticroleshavebeen pleiotropic beneficialproperties(e.g.anti-ischaemic, ( diabetic cardiomyopathyandreverseinsulinresistance T2D, trimetazidinewasshowntoamelioratefeaturesof influences ofreduced FA oxidationinanimalmodelsof restore thebalanceoffuelutilisation. Table 1 uptake orcellularsubstratehavebeendeveloped. ( ( mitochondria andalsoatthesiteofcellularentry by substrateavailability, competitionatthelevelof Myocardial utilization of theglucose and FAs are regulated 58 Fig. 1 Trimetazidine Review Amiodarone ). Trimetazidine isapiperazinederivativewith Ranolazine Perhexiline Meldonium Supporting the hypothetical cardiovascular beneficial Oxfenicine L-carnitine Etomoxir ). Thus,agentsthataffectmitochondrialsubstrate includesalistofpotentialtherapeuticstrategiesto 59 Triglycerides ). Itislicensedasananti-anginalagent, + Free FattyAcids Fatty-acyl-CoA CD36 E Leveltandothers β -fatty acidoxidationinhibitors (C)pyruvatedehydrogenase(PDH)activators.Inpractice,

Fatty-acyl-CoA Mitochondria CPT-1 CPT- 2 B oxidation β -oxidation) Glucose-6-Phosphate Glucose Acetyl-CoA Pyruvate GLUT 57 MPC Krebs cycle PDH ) ischaemic heartdisease( on clinicalprognosisofdiabeticpatientswithadvanced While studies reported beneficial effects of trimetazidine chain FA. Perhexiline was also shown to improve LVEF, the enzyme responsible for mitochondrial uptake of long- through the inhibition of carnitine palmitoyltransferase, is anothermetabolicagentreducingFA metabolism in clinicalstudies. patients withT2Datanearlystagehasnotbeenexplored beneficial effectscanpreventthedevelopmentofHFin and plasmaB-typenatriureticpeptide(BNP)levels( cause mortality, improveLVEF, reducesymptomsofHF trimetazidine. Trimetazidine wasshowntoreduceall- of patientswithchronicHFsuggestingtheefficacy there havebeen16randomisedcontrolledclinicaltrials large-scale clinicaltrialswithmetabolicmodulators, inhibition ofFA oxidation.Althoughthereisalackof PDK Diabetic heartdisease Lactate Perhexiline, 2-(2,2-dicyclohexylethyl)piperidine CO FADH NADH 2 2 ETS Dichloroacetate ATP ADP ATP Downloaded fromBioscientifica.com at10/01/202103:53:21AM Creatine kinaseshuttleforATPtransfer 60 ), whetherornotthese PCr Cr 178 :4 ADP ATP Contraction R130 59 via freeaccess ). European Journal of Endocrinology a statistically non-significant trend towards a reduction a statisticallynon-significant trendtowardsareduction PPAR- andEventLoweringinDiabetes(FIELD)study,Intervention health inpatientswithT2D ( ‘paradoxically’ have beneficialeffects oncardiovascular increased cardiacandhepaticPPAR- meldonium reducedplasmainsulinconcentrationand animal modelsofobesityandimpairedglucosetolerance, away from FA metabolism towards glucose metabolism. In biosynthesis anduptakeconsequentlyleadingtoashift γ is alsoanantianginaldrug,whichpartiallyinhibits long-chain FA intothemitochondrialmatrix.Meldonium carbohydrate metabolism.Itisresponsiblefortransferof towards theuseofglucoseandlactate( related toinhibitionofFA uptakeandametabolicshift beneficial cardiovascular effectsareconsidered tobe effect toreducethecardiacworkload,consequently, their metabolic modulatorsshowedanynegativeinotropic compared toplacebo( to dobutaminestressand adverse effect on strain rate was showntohavenoeffectonwallmotionresponse In patientswithischaemiccardiomyopathy, perhexiline energetics, diastolicfunctionandexercise capacity( cardiomyopathy (HCM),withimprovedmyocardial also showninpatientswithsymptomatichypertrophic myocardial energetics( HF ( (VO muscle energetics,peakexercise oxygenconsumption resting andpeakstressmyocardialfunctionskeletal Carnitine acylcarnitinetransferaseactivation Meldonium γ Long-chain 3-ketoacyl-CoAthiolaseinhibitors CPT-1 inhibition Dichloroacetate Pyruvate dehydrogenasekinase1–4inhibition Strategy/Agent Table 1 -butyrobetaine hydroxylasepartialinhibition -butyrobetaine hydroxylase, reducing L-carnitine -butyrobetaine hydroxylase, reducing L-carnitine Review l Trimetazidine, Ranolazine Perhexiline, Amiodarone,Etomoxir, Oxfenicine -propionylcarnitine 2 There isevidencethatincreasedFA utilisationmay L-carnitine playsapivotalroleinbothFA and 61 max) reduceHFsymptomsinpatientswithchronic α agonist fenofibrate treatment was associated with agonistfenofibratetreatment wasassociatedwith ), andinaseparatestudy, perhexilineimproved Potential therapeuticstrategiestorestorethebalanceoffuelutilisationintype2diabetes. l -carnitine 64 62 ). Neitheroftheseantianginal ). Efficacyofperhexilinewas

E Leveltandothers 66 ). In the Fenofibrate ). IntheFenofibrate α activity( 61 , 62 ). 65 ). 63 ). Increased glucoseoxidation Increased fattyacidtransportacrossmitochondrialmembrane Increased glucoseoxidation Decreased Increased glucoseoxidation Decreased fattyacidoxidation Increased glucoseoxidation Decreased fattyacidoxidation Pyruvate dehydrogenaseactivation Increased oxidativemetabolism Increased Krebscycleflux Increased fluxthroughPDH Effect CI 0–21%), proportional riskreductionof11%(adjustedHR0.89(95% in the5-yearCVDriskof14.5to13.1%,representinga been showntoactivatesignalling pathwaysaffectingATP such asceramideanddiacyl-glycerol ( processes with the production of lipotoxic intermediates fatty acyl-CoAisthendiverted towardsnon-oxidative for impairedcardiacfunction ( the conceptof‘lipotoxicity’asapotentialmechanism deleterious effectandcellularlipidoverloadingunderlies not specialised to store lipid, this finding suggests a CoA concentrations( results inincreasedintracellularlong-chainfattyacyl- FA availabilityand/oruptakewiththatofFA oxidation remodelling ( diabetic cardiomyopathy, particularlyconcentric LV as animportantcontributortothedevelopment of Excess myocyteaccumulationoflipidshasemerged Myocardial steatosisinpatientswithtype2diabetes responsible forthesebeneficialeffects( Additionally, pleiotropicbenefitsoftheseagentsmaybe that couldbeharmfultothecardiomyocyte( needs and(ii)avoidingaccumulationoflipidbyproducts providing continuedsupporttothemuscle’s metabolic may bebeneficialwithtwosignificantadvantages:(i) ( the diabetichearttoinjury rather thanspecificsubstratepreferencethatpredisposes this mayindicatethatitisthelackofmetabolicflexibility, patients withT2D.Ratherthanrepresentingaparadox, delineate theprecisemetabolicchangesthatoccurin outcomesmakeitevenmorepertinentto contradictory Diabetic heartdisease l -carnitine synthesis P

= 23 0.052; absolute risk reduction 1.4%). These 0.052; absoluteriskreduction1.4%).These ). Thediscordancebetweentheratesof 19 Downloaded fromBioscientifica.com at10/01/202103:53:21AM ). Sincecardiomyocytesare 67 ). Further, PPAR- 32 ). Theexcesslong-chain 178 67 www.eje-online.org :4 32 ). ). Thesehave α activation activation R131 68 via freeaccess ). ). European Journal of Endocrinology www.eje-online.org by cardiacstructuralandfunctional changes( a formofectopicfat,hasbeen showntobeaccompanied was demonstrated( correlation of EAT volumes with cardiac systolic strain diabetic heartdisease.Supporting thistheory, aninverse signalling pathways,EAT mayplayasignificantrolein adipokines andcytokinesthroughparacrine/autocrine myocardium, and,bysecretingproinflammatory of visceralfat,hasnoanatomicalbarrierswiththe liver diseasethanleanT2Dpatients( cardiac contractiledysfunctionandfibroinflammatory propensity forectopicfatdepositionthatisassociatedwith ( function, energeticsandcardiachepaticsteatosis diabetes isrelatedtosignificantabnormalitiesincardiac it wasdemonstratedthat,irrespectiveofbodymassindex, ( with bothsystemicandlocalmanifestationsofdisease organ andtoexaminetheassociationofvariousfatdepots quantify adiposetissueamountorlipidcontentwithinan MRI, ultrasonography and diabetes andobesity( pathogenesis ofcardiomyopathyprocessassociatedwith distribution ofexcessfatmayalsoplayaroleinthe risk than subcutaneous adiposity ( risk; (ii)ectopicandvisceraladiposityconferamuchhigher of excessfatisanimportantdeterminantcardiovascular Accumulating evidencesuggeststhat:(i)thedistribution resistance inpatientswithtype2diabetes Ectopic andvisceraladiposityinsulin needed toconfirmtheseobservations. larger studiestargetingmyocardiallipidaccumulationare shown toreverseconcentricLV remodelling.However, mineralocorticoid receptor blockers ( of myocardialsteatosiswithGLP-1agonists( been showntobemodifiable( fold in T2D ( content hasbeenshowntobeincreasedby1.5-2.3- diseases ofupregulatedFA metabolismsuchasdiabetes. steatosis, lipotoxicityandconcentricLV remodellingin another potentialmechanisticlinkbetweencardiac show aphenotypesimilartodiabetes( metabolising pathway, andPPAR- cardiac PPAR- and apoptosis( production, insulinsensitivity, myo-cellularcontractility 81 70 Review ). However, obesepatientswithT2Dshowedagreater , Epicardial adiposetissue(EAT), whichisaform Using proton( 76 , 77 , 78 23 α , , , resultinginupregulationofthelipid 79 70 32 , ). Importantly, myocardial steatosis has , 81 80 69 1 ). Similarly, excessliver fat,whichis ). Recently, usingthesetechniques, H)-MRS, myocardialtriglyceride 75 ). IncreasedFA levelsstimulate ). Computed tomography (CT), ). Computedtomography(CT), 1 H-MRS have all been used to H-MRS have all been used to 71 , 73 E Leveltandothers 72 α , ). Successfulreduction -overexpressing mice 81 74 72 ) ( ) and (iii) abnormal ) and (iii) abnormal 32 ) have both been Fig. 2 ). Thisprovides 82 ). ). 71 ) and College ofCardiology. (%) and(D)hepaticcorrectedT1map(ms).Thedotsindicate strain; (B)diastolicstrainrate;(C)hepatictriglyceridecontent cT1 amongthestudycohorts.(A)Peakcircumferentialsystolic Differences incardiacfunction,hepaticsteatosis,and Figure 2 permission fromLevelt values outsidetheinterquartilerange.Reproducedwith paradigm shiftintheconsensus regardingthenature Consequently, lately, therehasbeensomethingofa resistance isan antioxidant defence mechanism ( induced damage ( protects critical tissues, such as the heart, from nutrient- and coworkersrecentlyarguedthatinsulinresistance with anevengreatercardiovascularrisk( that insulinresistanceandectopicadiposityareassociated nature ( whether thisrelationshipisofprotectiveorpathological ( geometry myocardium leading tochanges of leftventricular ( metabolic inefficiency ( and non-ischaemiccardiomyopathy( contribute to the association between insulin resistance HF ( association betweeninsulinresistanceandnon-ischaemic adiposity. Additionally, thereisevidenceforastrong cardiovascular risk that is linked to ectopic and visceral insulin resistancemayberesponsiblefortheincreased dysregulated fattissue( that insulinresistanceisprompted,andsustainedby, diabetes ( lipodystrophy’ islinkedtoinsulinresistanceand Diabetic heartdisease 88 ), inflammation,mitogenicactionsofinsulinon Ectopic and visceral adiposity or ‘acquired 87 ). Therearemanymolecularmechanismsthatmay 90 83 , 89 91 ). Multiplestudies support theconcept ). However, there aredifferingopinions , 92 92 ). Although it has been demonstrated ). It has been proposed that insulin et al 84 Downloaded fromBioscientifica.com at10/01/202103:53:21AM 19 . ( , ), impaired vascular function 83 85 ). Copyright©TheAmerican , 86 ). Itispossiblethatthe 178 87 :4 ). Theseinclude 93 , 94 ), Nolan R132 90 via freeaccess ). European Journal of Endocrinology exogenously administered GLP-1 regulate blood glucose intake (the‘incretineffect’). Thepredominantactionsof dependent insulin secretion in responsetonutrient GLP-1, whichispartlyresponsible foraugmentingglucose- specifically targetingthereceptor fortheincretinhormone analogues exert their effect via the incretin system, 4 (DPP-4)inhibitorsandGLP-1analogues.The clearance ( peptidase 4(DPP-4)andneutralendopeptidaserenal GLP-1 includeenzymaticinactivationbydipeptidyl The principaldeterminants of the levels of active plasma inhibitory, antiobesityand antidiabeteseffects( metabolic effectsafterbariatricsurgery, withitseating- mediator ofbeneficial investigation asapotentialprimary surprisingly therefore GLP-1 iscurrently under intensive is implicatedinthecontrolofappetiteandsatiety, not substrates ( intake, absorption,retentionanddisposalofenergy-rich invasive imagingtechniques. health willbereflectedbythechangesmeasuredwithnon- beneficial effectsofthesenoveltherapiesoncardiovascular are speculative.Itwouldbeinterestingtoseeifthepotential cardiovascularbenefits mechanisms behindtheobserved of these novel drugs on clinical outcomes, and therefore, the these recenttrialsweredesignedtoassessthespecificeffects cardiovascular mortalityinpatientswithT2D.However, results withimprovedglycaemiccontrolaswellreduced of sodium–glucosecotransporter2( glucagon-like peptide-1 (GLP-1) analogues ( Recently newclassesofglucose-loweringtherapies,suchas improved cardiovascular outcomes Novel glucose-loweringtherapiesand the developmentofHFinpatientswithdiabetes( resulted indeleteriouseffectssuchasPPARs, including therapeutically targetingimpairedinsulinsensitivity might offeranswerstowhysomepreviousresearch reverses insulinresistance( ( (ROS) productioninmusclesofdiet-induceddiabeticmice capacity, whichfollowsincreasedreactiveoxygenspecies the evidence that impairment of mitochondrial oxidative in thedevelopmentofnon-ischaemicHF. Thisisbasedon etiologicalfactor regarded insulinresistanceasaprimary cardiovascular risk,whenthetraditionalthinkinghad of theroleinsulinresistanceindiabetesassociated 95 Review ) andinhibitionofmitochondrialROSproduction The incretin-baseddrugsincludedipeptidylpeptidase The biologicactionofGLP-1isfocusedonthe 102 100 ). ). Innormalphysiology, endogenousGLP-1 96 , 97 E Leveltandothers ). Thisnovelperspective 7 ) have shown exciting ) haveshownexciting 99 ) and inhibitors ) and inhibitors 90 , 101 98 ). ). is anexendin-4-basedGLP-1receptoragonistwhicha through controlofbloodglucose,insulinandFas( indirectly byimprovementofthemetabolicenvironment through generationofcAMPincardiomyocytesand/or ( function inthesettingofexperimentalcardiac injury and administrationofGLP-1improvescardiovascular emptying andstimulationofinsulinsecretion( via inhibition of appetite, glucagon secretion and gastric who hadawiderangeofcardiovascularrisk( safety andefficacyofexenatide,inpatientswithT2D Lowering (EXSCEL)assessedthelong-termcardiovascular drug. The Exenatide Studyof Cardiovascular Event once-weekly, injectable,extended-releaseformulation lower forsemaglutidethanplacebo( ornonfatal stroke was significantly T2D patients,therateofcardiovasculardeath,nonfatal T2D andhighcardiovascularrisk.Similarly, inhigh-risk group comparedtotheplaceboinpatientswith in fewerpatientstheGLP-1analogueliraglutide showed thatdeathfromcardiovascular causes occurred of CardiovascularOutcomeResults(LEADER)trial The LiraglutideEffectandActioninDiabetes:Evaluation induced damage( protects critical tissues, such as the heart, from nutrient- recently byNolanandcoworkers thatinsulinresistance also providingextrasupport fortheargumentputforward dependent insulinsecretion withGLP1agonists.Thisis potentially associated with the promotionofglucose- negative outcomeinthisstudywasspeculatedtobe walk distanceorqualityoflifescoreswereshown.The points basedonechocardiographicmeasures,6-minute end No favourableeffectsofliraglutideonsecondary reported inpatientswithseverecardiomyopathies( ameliorate mechanismsofmyocardialinsulinresistance despite priorstudiesindicatingthatGLP-1therapymight stability inpatientswithadvancedHFandreducedLVEF liraglutide doesnotimprovepost-hospitalizationclinical established HFandreducedLVEF hasdemonstratedthat controlled randomizedclinicaltrialofpatientswith study whichwasamulticentre,double-blind,placebo- Impact ofGLP-1forHeartFailureTreatment (FIGHT) not statisticallysignificant.Furthermore,theFunctional (hazard ratio,0.86;95%CI,0.77–0.97);thisdifferencewas in theexenatidegroupand7.9%placebo to efficacy. Theriskofdeathfromanycausewas6.9% safety, but it was not superior to placebo with respect non-inferior toplacebowithrespectcardiovascular The resultsofthisstudyshowedthatexenatidewas Diabetic heartdisease 104 GLP-1 receptorsarealsoexpressedintheheart, ). TheactionsofGLP-1ontheheartmaybedirectly 92 ) thatenhancingendogenous insulin Downloaded fromBioscientifica.com at10/01/202103:53:21AM 178 www.eje-online.org :4 106 ). Exenatide 103 R133 ). 108 107 105 via freeaccess ). ). ). European Journal of Endocrinology www.eje-online.org than those who received placebo, but they were at a than thosewhoreceivedplacebo, buttheywereata causes, nonfatalmyocardial infarction ornonfatal stroke a significantlylowerrisk of deathfromcardiovascular of cardiovasculardiseasetreated withcanagliflozinhad trial programshowedthat T2D patientswithhighrisk the cardiovascularsafetyandefficacyofcanagliflozin. The Program, comprising two sistertrials,wasdesigned to assess Canagliflozin CardiovascularAssessmentStudy(CANVAS) ( 0.4% reduction in glycated haemoglobin of over 94 weeks improvement inglycaemiccontrol,withapproximately with almostimmediatebeneficialeffectdespiteamodest group whenthestudydrugswereaddedtostandardcare and ofdeathfromanycausethandidthoseintheplacebo composite cardiovascular outcome rates of the primary sodium–glucose cotransporter2,hadsignificantlylower events whoreceivedempagliflozin,aselectiveinhibitorof showed thatpatientswithT2Dathighriskforcardiovascular glucose excretion ( urinary decreasing renalglucosereabsorption,therebyincreasing 2 reduceratesofhyperglycemiainpatientswithT2Dby patients withnonalcoholicsteatohepatitis( and alsoinasmallclinicalphase2studyoverweight their actiononbodyweightinanexperimentalstudy( occurrence anddegreeofhepaticsteatosisindependent increased riskofhospitalizationforHF( of oralantidiabeticdrugs,wasnotassociatedwithan incretin-based drugs,ascomparedwithcombinations of several large cohorts of patients with T2D, the use of sitagliptin, vs standard care respectively. Meta-analysis among patients randomly assigned to alogliptin and no increase in the overall risk of hospitalization for HF care andTECOStrial( studies EXAMINEtrial( any cardioprotectivebenefit;(ii)cardiovascularoutcomes those whoreceivedplacebo,andthedrugdidnotprovide in patientswithT2Dassignedtosaxagliptincompared showed 27%increaseintheriskofhospitalizationforHF effect on HF admissions: (i) SAVOR–TIMI 53 trial ( of DPP4inhibitorsshowednobeneficialresultsontheir studies system. Theresultsofmulticentreobservational beneficial effectsofDPP-4inhibitorsonthecardiovascular has beenconsiderablespeculationaboutthepotential endogenous GLP-1. UnlikewithGLP-1 analogues, there adaptive mechanisminpatientswithadvancedHF. myocardial insulinresistanceinHFmodelsmightbean secretion isdisadvantageousinthesettingofHF, and 7 ). CanagliflozinisanotherSGLT2 inhibitor. The Review Finally, inhibitorsofsodium–glucosecotransporter The incretin-based drugs were also shown to reduce the Inhibitors ofDPP-4reducethebreakdown 111 115 110 ) ofsitagliptinbothshowed ). EMPA-REG OUTCOME trial ) ofalogliptinvsstandard E Leveltandothers 112 114 ). ). 109 113 ) ) been reportedfordifferent animal modelsofT1D( retinopathy comparedtothose withoutHF. pressure, andhigherprevalence ofalbuminuriaand duration ofdiabetes(35 who developed HF were reported to be older with a longer during a12-yearfollow-upperiod( 17 patientsoutof462(3.7%)wereshowntodevelopHF of heart disease only patients without a previous history study of a relatively large cohort of T1D observational type ofdiabetescomparedtoT2D( (T1D), clinicalpresentationsofHFisrelativelyrareinthis has beenreportedintheearlystageoftype1diabetes high prevalenceofsubclinicalmyocardialdysfunction cardiomyopathy intype1vs2diabetes.Although underlying mechanisms and clinical features of diabetic Relatively little research has taken place comparing the Diabetic cardiomyopathy intype1diabetes therefore, beingmore‘energy-efficient’( yields moreATP peroxygenconsumptionthanpalmitate, and function,giventhattheketonebodyoxidation This mayimprovemyocardial/renalmetabolicefficiency effects arenotyetclear, howeverrecentlysuggested associated cardiovascularbenefits( the mechanismslinkinguseofSGLT-2 inhibitorsand risk. However, thisstudysimilartoothersdidnotaddress benefits withSGLT-2 inhibitors,asthosewithhigher suggesting thatlowerriskpatientsmayderivesimilar of patientsincludedinthestudyhadnoestablishedCVD, class related.Importantly, majority(87%) overwhelming particularly relevanttoHFadmissions,appearedbe reduction inall-causemortality. Thesebeneficialeffects, 39% relative risk reduction in HF hospitalization, a 51% treatment withSGLT-2 inhibitorswasassociatedwith with theEMPA-REG OUTCOME,CVD-REALStudyshowed inhibitors vsotherglucose-loweringdrugs.Consistent all-cause deathinpatientswith T2D treated withSGLT-2 the associationofoutcomeshospitalizationforHFand studydesignedtoevaluate was aretrospectiveregistry greater riskofamputation( 120 cellular energyhomeostasisbyactivationofAMPK( admission for HF on empaliflozin arm) ( conjunction with a 35%relative risk reduction in hospital volume contraction(5%increaseinhaematocrit theories include:(i)SGLT2 inhibitorinducedplasma Diabetic heartdisease ); (iii) SGLT2 inhibitor induced mild ketosis ( Similar toT2D( As aresult,thereasonsforbeneficialcardiovascular 125 ), cardiomyocytehypertrophy has Downloaded fromBioscientifica.com at10/01/202103:53:21AM ±

9 years), andhadhigherblood 9 years), 116 ). The CVD-REAL Study ). TheCVD-REALStudy 117 123 124 178 ). ). Inalongitudinal 118 :4 ). Thosepatients 49 ). ); (ii) Restoring 121 R134 , 126 122 119 via freeaccess ), ). , European Journal of Endocrinology N andGMeachcontributedtodrafting ofmanuscriptandrevisions. integrity oftheworkareappropriately investigatedandresolved.EL,GS,S agree tobeaccountableinensuringthat questionsrelatedtotheaccuracyor public responsibilityforappropriateportions ofthemanuscriptcontent;and and assuchhavereadapproved thefinalmanuscript.Allauthorstake All authorsmadeappropriatecontributions accordingtotheICMJEguidance, Authors contributionstatement 207726/Z/17/Z). This workwassupportedbytheWellcome Trust (grantnumber Funding interests. policy ondeclarationofinterestsanddeclarethatwehavenocompeting All authorshavereadandunderstood Declaration ofinterest still appearslong,butpromisessignificantadvances. and preventionofdiabetes-associatedHF, theroadahead therapies alsoremaintobeshown.Insearch oftreatment mortality benefitsofnewclassesglucose-lowering cardiovascular The mechanismsbehindtheobserved therapeutic targetwhichmayshedlightonthisquestion. to manipulatecardiacmetabolismisapromising for cardiac dysfunction remains uncertain. The ability alteration insubstrateutilisationdiabetesisresponsible the fundamentalquestionofwhetherornotaprimary remodelling, structuralandfunctionalchanges.However, the relationshipamongmyocardialmetabolic phenotype inthediabeticheartanddefining advances havebeenmadeincharacterizingthemetabolic of diseasemechanismsintype2diabetes,andsignificant Science hasprogressedsignificantlyinitsunderstanding Conclusions the roleofmyocardialsteatosisinT1D. ( changes, similarly to T2D of myocardial perfusion reserve reduction inmyocardialenergeticsatrestindependently scarce in T1D. A single study demonstrated a significant ( tracking echocardiographytechniquesinT1Dpatients has alsobeendetectedbytissueDopplerandspeckle investigated in most studies. Significant LV dysfunction and lowerincidenceofhypertensioninT1Dpatients compared to T2D.This may be due to the younger age Fewer studies of T1D have shown an increase in LV mass inamodelofT1D( sectional areawasalsoobserved however significantreductioninthecardiomyocytecross 129 128 Review ). To ourknowledgenostudiestodatehaveevaluated ). Myocardialmetabolicremodellingstudieshavebeen European JournalofEndocrinology E Leveltandothers 127 ).

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