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DiabeticPeripheralNeuropathyHealthyNervesandNervesandBloodVesselsBloodVesselsDamagedbyDPNVasanervorumUnmyelinatednervefiberMyelinatednervefiberOccludedvasanervorumDamagedunmyelinatednervefiberDamagedmyelinatednervefiberLessonsLearnedfromFailedClinicalTrialsinDiabeticNeuropathyAaronI.Vinik,MD,PhD,FCP,MACPProfessorofMedicine/Pathology/NeurobiologyDirectorofResearchandNeuroendocrineUnitEasternVirginiaMedicalSchoolStrelitzDiabetesCenterforEndocrineandMetabolicDisordersNorfolk,VirginiaDiabeticNeuropathiesareNOTaSingleHomogenousDisorderLarge-fiberSmall-fiberProximalAcutemonoEntrapmentIIIVITruncalUlnarMedianLateralpoplitealneuropathyneuropathyneuropathyneuropathiesneuropathiesSensoryloss:0–+++Sensoryloss:0–+Sensoryloss:0–+Sensoryloss:0–+Sensorylossinnerve(touchvibration)(thermalallodynia)distribution:+–+++Pain:+–+++Pain:+–+++Pain:+–+++Pain:+–+++Pain:+–++Tendonreflex:Tendonreflex:N–Tendonreflex:Tendonreflex:NTendonreflex:NN–Motordeficit:0–+++Motordeficit:0ProximalmotorMotordeficit:+–+++Motordeficit:+–+++deficit:+–+++N,normal.ModifiedfromVinikA,etal.Diabetologia.2008;24:407.AndWhatWeMistakeforDiabeticNeuropathy•Claudication•Morton’sneuroma•Osteoarthritis•Radiculopathy•Plantarfasciitis•Fibromyalgia•TarsaltunnelsyndromeWhyhaveweFailedtoDemonstrateEfficacyofTherapyinDiabeticNeuropathy• Interventionsarenotefficacious;• Presentdiabetescareinhibitsdevelopmentofcomplications;• Otherdiabeticcomplications(hypertension,hyperlipidemia,renaldisease,andother)withpossibleadverseeffectsonDSPNarenowmanagedbetter;• Thewrongkind,stage,duration,speedofevolutionofDSPNisstudied;• Endpointschosenareinsufficientlysensitive,• Combiningmeasuresofsmallandlargefiberfunctionmayobscureaneffectononeorother• Translating(measuringaconsistenttrendofworseningorimprovementwithtime)tomanymedicalcentershazardous• Excessiverecruitmentoftype2diabeticpatientsshowinglittlechangewithtimeandexcessivevariabilityofmeasuredendpoints• BothplaceboandtreatedpatientsreceivebetterthanusualmedicaltreatmentwhileModifiedfromDycketalDiabetesCare30:2619–2625,2007specific,monotonicithtil0510152025303540IntensivetherapyConventionaltherapyGlycemicControlinType1DiabetesPreventsNeuropathyPatients(%)P0.001P=0.04P0.001NeurologicAutonomicNerve-ExaminationNerveStudyConductionStudyTheDiabetesControlandComplicationsTrialResearchGroup.NEnglJMed1993;329:977.Copyright©1993MassachusettsMedicalSociety.Allrightsreserved.Epidemiologyofdiabetesinterventionandcomplications(EDIC)studyintype1diabetesMetabolicMemoryCounts8-yearfollow-upofpolyneuropathy(MNSI2)afterDCCTcompletion(n=1398)30Type1diabetesConventionaltherapyIntensivetherapy2520215%withMNSIRR(95%CI):43%(33-52%)105HbA1c0HbA1c9.1%8.3%8.2%7.9%7.4%7.9%8.1%8.0%Endof12345678EDICyearDCCTDCCT,diabetescontrolandcomplicationstrialMartinetal.DiabetesCare,2006;29:340MNSI,MichiganneuropathyscreeninginstrumentLeroith,Fonseca,Vinik,2006NeuropathyinPrediabetes:DoestheClockStartTickingEarlierthanDiabetes7.411.313.028.00510152025301.24.28.713.3051015202530%NeuropathicpainControlIFGIGTDiabetesIFG=impairedfastingglucose;IGT=impairedglucosetoleranceZiegleretal.Papanas,VinikandZieglerNaturereviews.Endocrinology2011;7(11):682-90.Neuropathy:DiseaseInitiation/ProgressionGeneticsCHT1APoE4/lipidsARZ2allelesACEpolymorphismTollrecpolymorphismCatalase262TCProgressiveFunctionalNeuronalInitiatingPathologicalInjuryChangesEventChangesGLYCATIONAGEsEPIGENETICPARPsetcmonthstoyearsINFLAMMATIONOxidative/NitrativeStressPKC,12LO/5LO,HETESelectinsVCAMSIL6,TNF,NFBROS,nitrotyrosinesModifiedfromVinikandMehrabyan.MedClinicsNorthAmerica2004DIABETESGenes,Environment,Smoking,AlcoholMETABOLICHyperglycemia,Hypoinsulinemia,GFAbnormalities,Vitdeficiency,DyslipidemiaAUTOIMMUNITYMICROVASCULARINSUFFICIENCY↑AldoseReductaseActivityPolyols,Myoinositol,LDLCNa/KATPaseOxidative/NitrosativeStress↑ROS,NFκBactivityCytokines/integrinsNERVEDYSFUNCTION±AntigenicleakageORGANIC/STRUCTURALNERVEDAMAGEAxonopathy(atrophy,loss)ApoptosisDemyelination(segmental,progressive)NERVEREGENERATION/PREVENTIONOFAPOPTOSISRESTORATIONOFNERVEFUNCTION↑DAG&β2PKCActivityEndothelialDysfunctionPGI2/NO↑,ET,A11,EDHF,HETEDeliveryofGFs(NGF,NT3,IGFI/II,Insulin,VEGF)INGAP,IGFI/II,NGF,NT3,Cpeptide,EPO,FGF,HGF,VEGF,Insulin↑NonenzymaticGlycosylationAGE/RAGEMethylGlyoxalAbtoGF’s,NGF&receptors,Insulin,IGFI/II,P75TRK↑C’fixingAb/glycolipids↑celldeath/apoptosisAchreceptorVinik,Ullal,CaselliniNatureClinicalPractice2(4),2006,Vinik,Strotmeyer,2012 Diabeticneuropathy:cellularmechanismsastherapeutictargetsDrugProposedmechanismPreclinicalstudiesClinicaltrialresultsAleglitazarDualPPAR/agonistInrats,decreasedplasmaglucoseandLDLcholesterollevels;increasedglucoseclearanceandHDLcholesterollevels;improvedinsulinresistance120ReducedglycemiainphaseIItrials;currentlyinphaseIIItrialfordiabeticcardiovascularendpoints121L‐ar