Endothelin-1 Predicts Incident Diabetic Peripheral Neuropathy in Type 2 Diabetes: a Cohort Study

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S L T Pek and others Endothelin-1 and diabetic 182:4 429–438 Clinical Study peripheral neuropathy

Endothelin-1 predicts incident diabetic peripheral neuropathy in Type 2 Diabetes: a cohort study

Sharon Li Ting Pek1, Su Chi Lim1,2,3,5, Keven Ang1, Pek Yee Kwan4, Wern Ee Tang4, Chee Fang Sum2,3 and Subramaniam Tavintharan1,2,3 Correspondence 1Clinical Research Unit, Khoo Teck Puat Hospital, Singapore, Singapore, 2Diabetes Centre, Admiralty Medical Centre, should be addressed Singapore, Singapore, 3Division of Endocrinology. Khoo Teck Puat Hospital, Singapore, Singapore, 4Yishun Polyclinic, to S Tavintharan National Healthcare Group, Singapore, Singapore, and 5Saw Swee Hock School of Public Health, Email Singapore, Singapore subramaniam.tavintharan@ ktph.com.sg

Abstract

Introduction: Diabetic peripheral neuropathy (DPN) is a common microvascular complication in patients with type 2 diabetes (T2D). Apart from hyperglycemia, few modifiable risk factors have been identified. Endothelin-1 is a potent vasoconstrictor peptide, implicated in the causal pathway of microangiopathy. We investigated whether baseline plasma endothelin-1 and other metabolic and vascular risk factors predicted the incidence of DPN. Design: This is a 3-year observational, cohort study. Methods: In patients with T2D (n = 2057), anthropometric data, fasting blood, and urine were collected for biochemistry and urine albumin/creatinine measurements. Forearm cutaneous endothelial reactivity was assessed by iontophoresis and laser Doppler flowmetry/imaging. Measurements were repeated on follow-up. Incident DPN was considered present if an abnormal finding in monofilament< ( 8 of 10 points) or neurothesiometer testing was ≥25 volts on either foot at 3-year follow-up, but normal at baseline. Plasma endothelin-1 was assessed by ELISA. Results: At baseline, mean age of patients was 57.4 ± 10.8 years old and prevalence of DPN was 10.8%. Of the

European Journal of Endocrinology 1767 patients without DPN, 1250 patients returned for follow-up assessment ((2.9 ± 0.7) years), with a 10.7% incidence of DPN. Patients with incident DPN had significantly higher baseline endothelin-1 (1.43 (1.19–1.73) vs 1.30 (1.06–1.63)) pg/mL, P < 0.0001. Multivariable Cox proportional hazards ratio showed a 1-s.d. increase in log endothelin-1 (adjusted HR: 4.345 (1.451–13.009), P = 0.009), systolic blood pressure (per 10-unit) (adjusted HR: 1.107 (1.001–1.223), P = 0.047) and diabetes duration (adjusted HR: 1.025 (1.004–1.047), P = 0.017) predicted incident DPN, after adjustment for glycemic control, eGFR, albuminuria, peripheral arterial disease and retinopathy status. Conclusion: Higher baseline endothelin-1, blood pressure and diabetes duration were significant and independent predictors for incident DPN. Validation of our findings in independent cohorts and molecular mechanistic studies will help better our understanding on the role of endothelin-1 in DPN.

European Journal of Endocrinology (2020) 182, 429–438

Introduction

Prevalence of type 2 diabetes mellitus (T2D) is increasing in patients with T2D, resulting in peripheral nerve globally and has been identified as the ninth major cause of dysfunction, accompanied with typical characteristics reduced life expectancy (1). Diabetic peripheral neuropathy of pain and numbness (2, 3). DPN is one of the leading (DPN) is one of the common microvascular complications causes of lower limb amputations and morbidity in the

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-19-0523 European Journal of Endocrinology https://eje.bioscientifica.com from August2011toMarch 2014(SMART2D:Singapore This isacohortstudy, wherepatientswererecruited Methods plasma endothelin-1arepredictiveofincidentDPN. was todetermineifbaselineclinicalparametersand endothelin-1 predictsincidentDPN.Theaimofthestudy hypothesize thatinpatientswithT2D,higherbaseline and causalityofendothelin-1toDPNisunknown.We studies wereconductedinacross-sectionalmanner in patients with DPN compared to those without, these associated withelevatedplasmalevelsofendothelin-1. disease ( artery and coronary such asT2D( negative effectsonNOavailability, insulin-resistantstates causal pathwayofdiabeticmicroangiopathy. Besidesthe evidence hasimplicatedendothelin-1tobeinthe or vasodilativeeffects,respectively. Alargebodyof or smooth-musclecells,producingeithervasoconstrictive receptors, ET tubular cells( including theendothelial( peptideproducedfromvariouscelltypes, inflammatory significantly associatedwithDPN( dependent vasodilationandapolipoproteinC3were previous cross-sectionalstudythatreducedendothelial- early inthediabetespathway( states, suggesting that endothelial dysfunction occurs microcirculation have been identifiedinpre-diabetic insulin resistance( of nitricoxide(NO),isanearlyfindinginpatientswith endothelial function,characterizedbyreducedbioactivity endothelial-independent vasodilation( as evidencedbyreducedendothelial-dependentand progression ofDPNwasobserved. nephropathy andretinopathy( relative riskreductionsforautonomicneuropathy, conventional care,theSTENO-2studyshowedsignificant andthoseon with intensifiedmultifactorialintervention abnormalities inmultipleorgans( in insulinresistance, in theiraetiology, whereT2Discharacterizedbydefects but lesssoinT2D( be effectiveindelayingonsetofDPNfortype1diabetes world. Aggressiveglucose-loweringhasbeenshownto Clinical Study Endothelin-1 isapotentvasoconstrictorandpro- Patients withDPNhavemicrovasculardysfunction, While higher plasma endothelin-1 has been reported A 15 andET 14 ), obesity( ). Endothelin-1actsonendothelin-1 8 4 ) andT2D( ), probablyarisingfromdifferences B β receptors,onadjacentendothelial -cell failureandpathophysiologic 16 12 ), essentialhypertension( 18 ), neuronal( 6 ) have been shown to be S LTPekandothers ), butnochangesinthe 9 5 10 11 ). Earlyalterationsin ). Comparingpatients ). We showedina ). 7 ). Impairmentof 13 ) andrenal 17 ) additional freeze-thawcycles.Patientswereadvisednot they werestoredat collection andkeptat4 All bloodsampleswerecentrifugedwithin1hafter baseline andfollow-upinthesameroutinelaboratory. creatinine measurements(Roche,Diagnostics)atboth collected forbloodbiochemistry, urinealbuminand signed informedconsentatbothvisits. Domain SpecificReviewBoard),andallparticipants approved by our institutional Ethics Review Board (NHG at baseline,wererepeatedfollow-up.Thisstudywas through phonecallsormails.Allprocedures,performed medical centreinSingapore.Patientswerere-contacted in ourinstitution’s DiabetesCentreandacommunity adults between21and90yearsofage,withT2Dseen described previously( in Type 2Diabetes)andfollowed-upafter3years,as study ofMAcro-angiopathyandmicro-vascularReactivity performed intemperature controlledroomsbylaser Microvascular endothelial function assessmentswere Vascular measurements accreditation ( ( were performed bythesame team ofresearch nurses incident DPN.Baselineandfollow-upfootexaminations either footwasdetected.Theoutcomeinthisstudy is foot) or neurothesiometer testing of (inability todetectmorethan2of10pointsoneither DPN was presentifanabnormalfindinginmonofilament vibration andwitha10-gmonofilamentforlighttouch. Scientific, a neurothesiometer(Horwell Yorkshire, UK) for homacalculator/ (HOMA2-IR) obtained from ( using anexcel-basedHOMAindexofinsulinresistance (HOMA)-2 ofinsulinresistance(HOMA2-IR)wascalculated insulin, respectively. Thehomeostasismodelassessment inter-assay CVof8.00%and7.40%forendothelin-1 duplicates withintra-assayCVof2.02%and2.83% Sweden, respectively).Plasmasamplesweremeasuredin measured byELISA(RnDsystems,USAandMercodia, taken. Baselineplasmaendothelin-1andinsulinwere the averageofthreemostconsistentreadingswas rate (Omron,Japan)were measured at the clinic and (CKD-EPI) equation( the ChronicKidneyDiseaseEpidemiologyCollaboration was obtained.EstimatedGFR(eGFR)calculatedusing to taketheirmorningmedicationsuntilfastingblood peripheral neuropathy Endothelin-1 anddiabetic n

= 4) who received standardized training and Anthropometric data,fastingbloodandurinewere 11 ) ( ). 22 − ). Assessmentforneuropathywasby 21 80 19 ° ). Bloodpressure(BP)andheart Downloaded fromBioscientifica.com at09/28/202107:38:27PM ° , C duringthisperiod.Thereafter, C inaliquotsandusedwithout 20 ). We consecutivelyenrolled https://www.dtu.ox.ac.uk/ 182 :4 ≥ 25 volts on 430 via freeaccess

European Journal of Endocrinology two-sided withalevelofsignificance being after logarithmictransformation. Allstatisticaltestswere endothelial-independent vasodilation were analyzed ACR,endothelial-dependentand triglycerides, urinary tested usingSchoenfeldresiduals.Skeweddatasuch as in theCoxmodel.Proportionalityassumptionswere diabetic complications, were included as covariates ACR,PAD,urinary andretinopathystatus,themain significant intheunivariateanalysis,baselineeGFR, duration, baselineHbA1candsystolicBP),whichwere Age, gender, ethnicity, metabolicderangements(diabetes each riskfactorassessedatbaseline,afteradjustment. and hazards ratio (HR) for incident DPN and 95% CI for hazards modelwasusedtoestimatethecoefficient ( multivariable model.MultivariableCoxproportional confounders (genderandethnicity)wereaddedintothe independent vasodilationandmetforminusage)orknown retinopathy, endothelium-dependent,endothelium- triglyceride, systolicbloodpressure,eGFR,urineACR, in Pearson’s correlation(baselineage,BMI,HDL-C, generalized linearregression.Onlyvariablessignificant with endothelin-1wereanalyzedusingmultivariable Pearson analyses.Associationsofindependentvariables endothelin-1 withclinicalvariableswereanalyzedusing multiple testing.Bivariate associations of log-transformed normally distributed.Bonferronicorrectionwasusedfor parametric testswereusedforquantitativevariablesnot and Student’s normal distribution were analyzed using Chi-square in percentages. andcontinuousvariableswith Binary variableswerepresentedasabsolutenumbersor Binary continuous butnon-normallydistributedvariables. medians andinterquartilerangeswerepresentedfor with normaldistributionwerepresentedinmean Inc) andSTATA SE14.Resultsforcontinuousvariables All analyseswereperformedusingSPSSversion22(SPSS Statistical analyses both baselineandfollow-upmeasurements. baseline flowmetry. Similarly, thesameteamperformed Vasodilation waspresentedaspercentage changefrom vasodilation, respectively, asdescribedpreviously( endothelium-dependent andendothelium-independent of acetylcholineorsodiumnitroprussidetoassess cutaneous perfusion,accompanied by iontophoresis Development AB,Linkoping,Sweden)tomeasure (LiscaPIM3.0,Lisca Doppler flowmetry/imaging Clinical Study t -test orANOVA, respectively, whilenon- S LTPekandothers < 0.05. ±

s 23 . d β ). . ) ; baseline, hadlongerdurationofT2D,poorerglycemic 1). Patients, withincident DPN, were significantly older at Fig. with and without DPN, at baseline (Supplementary not statisticallysignificantlydifferentbetweenpatients Prevalence ofpatients,whowerelosttofollow-up,was materials supplementary Tablecohort areshowninSupplementary 1(seesectionon are shownin with incidentDPNandthosewhoremainedfreeofDPN, of patientswithno DPN at baseline, comparing those (10.7%) patientsdevelopedincidentDPN.Characteristics a meanof(2.9 1250 patientsreturnedforafollow-upassessmentwithin without DPNatbaseline(August2011–March 2014), cohort, as reported previously ( Prevalence ofDPNwas10.8%inthecross-sectional A totalof2057patientswithT2Dwererecruitedatbaseline. Results but notendothelium-independent vasodilation was model separately, endothelium-dependent vasodilation and independentvasodilation wereenteredintothe and metforminusage.When endothelium-dependent endothelium-dependent, independentvasodilation adjusting forgender, HDL-C,SBP, urineACR,retinopathy, determinants oflog-transformedendothelin-1,after BMI, log-triglyceridesandeGFRremainedsignificant regression model( Table(Supplementary 3).In the multivariable linear on metforminhadsignificantlylowerendothelin-1 (1.07–1.65)) pg/mL, retinopathy (1.44 (1.19–1.78) vs 1.42 (1.15–1.69) vs 1.32 significantly higherendothelin-1thanthosewithout retinopathy andnon-proliferativehad (1.06–1.66)) pg/mL( (1.35 (1.11–1.67))pg/mLandotherethnicities(1.27 compared toChinese(1.33(1.07–1.66))pg/mL,Indians significantly higherendothelin-1(1.45(1.18–1.77))pg/mL to men(1.38(1.11–1.70))pg/mL( endothelin-1 (1.35(1.08–1.67))pg/mLlevels,compared in ( of patientswithincident DPN wereoninsulinandaspirin 1.73) pg/mL, higher Endothelin-1 (1.30 (1.06 – 1.63) vs 1.43 (1.19 – ACR, poorerendothelium-independentvasodilationand Systolic BP(SBP),heartrate,poorereGFR,higherurine control withhigherbaselinefastingglucoseandHbA1c, peripheral neuropathy Endothelin-1 anddiabetic Table 1 Table 2 Bivariate analysesofplasmaendothelin-1isshown ). (leftcolumn).Women hadlowerplasma P Table 1

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0.0001). Atbaseline,ahigherproportion 0.7) years.Onehundredandthirty-four Table 2 P andfollow-upcharacteristicsofthe

< P

0.0001). Patientswithproliferative

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0.0001, respectively. Patients , right),age,Malayethnicity, https://eje.bioscientifica.com 11 P ). Of 1767 patients 182 .7. aas had Malays =0.07). :4 431 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com and SBPremainedassignificant predictors,evenafter and retinopathystatusatbaseline. Baselineendothelin-1 for age,gender, ethnicity, HbA1c, eGFR,urineACR,PAD significant predictors of incident DPN, after adjustment of diabetes( P log-transformed endothelin-1( Table(Supplementary 2). statistically significantforlog-transformedEndothelin-1 ^Log transformedbeforeanalysis. Current Smoker Ex-Smoker Non-Smoker Smoking History(%) Aspirin Fibrates Statins ARB ACEI Insulin Metformin % onMedications Proliferative retinopathy Non-proliferative retinopathy Prevalence ofRetinopathy(%) Prevalence ofPeripheralArterialDisease(%) Endothelium-dependent vasodilation(%)^ Endothelium-independent vasodilation(%)^ Urine ACR(mg/g) eGFR (mL/min/1.73m Heart Rate(beats/min) Diastolic BP(mmHg) Systolic BP(mmHg) Endothelin-1 (pg/mL)^ HOMA2-IR^ Fasting Insulin( HbA1c (%) Fasting glucose(mmol/L) Triglyceride (mmol/L)^ LDL-C (mmol/L) HDL-C (mmol/L) Total Cholesterol(mmol/L) Waist circumference(cm) BMI (kg/m Height (cm) Others Indian Malay Chinese Ethnicity (%) Gender (%Males) Duration ofdiabetes(years) Age (years) Baseline characteristics Table 1 0.009) SBP ( SBP =0.009) Clinical Study In the multivariable Cox regression ( Baseline characteristicsofpatientswithandwithoutincidentDPN( 2 ) μ β β U/mL)^ .2, SE =0.011, =0.025, 0.101, SE =0.051, =0.101, 2 ) S LTPekandothers P β 0.047) and duration and =0.047) .6, SE =0.559, =1.469, P .1) remained =0.017) Table 3 ), baseline 1.30 (1.06–1.63) 1.15 (0.64–1.90) 7.68 (4.58–12.5) 1.37 (1.02–1.93) No DPNonfollow-up 17.0 (5.0–63.5) 110 (52–178) 135.2 71 (41–110) 7.67 7.94 2.74 1.31 4.42 96.5 27.6 1.61 10.1 56.3 90.6 70.1 77.5 ( n 85.8 19.6 10.6 80.0 24.7 34.6 22.3 84.4 15.9 10.2 6.2 22.6 18.2 55.5 48.9 = 1116) 8.1 6.2 3.7 ± ± ± ± ± ± ± ± ± ± ± ± ± ± incident DPNinarelatively largecohortofpatientswith baseline SBPandlongerduration ofdiabetespredicted follow-up, weshowthatelevated baselineendothelin-1, longitudinalcohortstudy,In thisobservational with3-year Discussion Tableangiotensin receptorblockers)(Supplementary 4). inclusion ofBPmedicationusage(ACEinhibitorsand peripheral neuropathy Endothelin-1 anddiabetic 1.27 2.53 0.79 0.36 1.01 15.0 5.1 0.09 8.2 10.4 23.1 10.7 9.4 17.1 n = 1250). 41.0 (10.0–221.0) 1.43 (1.19–1.73) 1.16 (0.81–2.12) 1.46 (1.06–2.19) 8.00 (4.2–14.1) Incident DPN 54 (29–91) 89 (50–151) 142.6 Downloaded fromBioscientifica.com at09/28/202107:38:27PM 7.98 8.48 2.80 1.25 4.48 95.8 27.4 1.63 13.9 59.6 75.8 72.3 78.1 ( 23.1 17.9 54.5 58.2 79.5 27.6 78.2 30.3 39.6 41.8 73.1 18.1 20.5 17.3 n 10.6 4.5 9.8 8.2 = 134) ± ± ± ± ± ± ± ± ± ± ± ± ± ± 1.43 2.75 0.98 0.32 1.11 14.9 5.6 0.09 9.8 9.1 30.4 11.7 10.0 20.7 182 :4 < < < < < < < < P 0.143 0.021 0.241 0.267 0.100 0.149 0.0001 0.001 0.0001 0.003 0.083 0.002 0.0001 0.0001 0.025 0.492 0.0001 0.0001 0.123 0.704 0.031 0.017 0.094 0.429 0.057 0.586 0.684 0.714 0.016 0.971 0.025 0.0001 0.0001 -value 432 via freeaccess European Journal of Endocrinology actions, endothelin-1 possesses pro-inflammatory effects effects actions, endothelin-1possesses pro-inflammatory tissue ( of nerve toreducedbloodflowandischemia likely tobesecondary evidence suggeststhatactions attributedtoendothelin-1are polyneuropathy comparedto healthycontrols( demyelinating both chronic and acute inflammatory mechanisms. Elevatedendothelin-1hasbeenfound in DPN throughimpactonseveralpathophysiological We hypothesizethatET1maycontribute to incident endothelin-1 withincidentDPNusingaprospectivedesign. incident DPNinacohortofpatientswithT2D. first reportofelevatedbaselineendothelin-1predicting and all-causedeathingeneralpopulation( heart disease( been showntopredictincidentcoronary DPN. To ourknowledge,whilehighendothelin-1has between endothelin-1 and the development of clinical T2D. Thesefindingssuggestapotentialpathogeniclink Age (years) Baseline characteristics biochemical parameters( Table 2 BMI (kg/m Others Indian Malay Ethnicity Gender Duration ofDiabetes(years) 1 = usage. ^Log-transformedbeforeanalysis. Retinopathy, 1 = non-proliferativeretinopathyand2 = proliferativeretinopathy.**Metforminwascodedasadummyvariablewhere0 = non-usage and 3 = Indian and4 = Others. # significant inPearson’scorrelationwereenteredintothemultivariateanalysis. Pearson’s correlationisshownontheleftandmultivariateassociation,adjustedforpotentialconfoundersareright.Onlyvariables Metformin (Usagevsnon-usage)** Endothelium-dependent vasodilation(%) Endothelium-independent vasodilation(%) Proliferative Non-proliferative Retinopathy* PAD Urine ACR(mg/g)^ eGFR (mL/min/1.73m Diastolic BP(mmHg) Systolic BP(mmHg) HOMA-2IR^ Fasting Insulin^ HbA1c (%) Fasting glucose(mmol/L) Triglyceride (mmol/L)^ LDL-C (mmol/L) HDL-C (mmol/L) Total Cholesterol(mmol/L) Waist circumference(cm) Gender wascodedasadummyvariablewhere1 = femaleand2 = male. Clinical Study ## This study is the first to investigate baseline This studyisthefirsttoinvestigatebaseline # t Univariable andmultivariableassociationofplasmaendothelin-1(logtransformed)withanthropometric 2 ) 27 , 2 ## ) 28 PAD wascodedasdummyvariablewhere0 = noand1 = PAD.*Retinopathy n ). Apart from its vasoconstrictive ). Apartfromitsvasoconstrictive = 1250). S LTPekandothers 25 Pearson correlation ), thisisthe 26 − − − − − − − − ). Most ). Most 0.151 0.020 0.043 0.028 0.152 0.004 0.099 0.002 0.007 0.005 0.013 0.114 0.059 0.067 0.047 0.130 0.104 0.069 0.082 0.099 0.026 0.138 0.24 24 t ) Ethnicity wascodedasadummyvariablewhere1 = Chinese,2 = Malay, P in patientswithdiabetes and microangiopathy( in microvascularendothelium-dependent vasodilatation ET nutritive endoneurial blood flow ( conductionthroughimprovementsinsciatic sciatic nerve antagonism, with bosentan, ledtoasignificantincreasein In experimental diabeticmodels, endothelin receptor are less well-studied comparedto its vasomotor effects. incident DPN.Directneuronalactionsofendothelin-1 inpatientswith the demyelinationofperipheralnerves Raised endothelin-1,atbaseline,maydirectlypotentiate ( effects ofendothelin-1onperipheralnerves demonstrating a putative mechanism for the detrimental smooth musclecells,endothelialcellsandisolatedarteries, Endothelin-1 stimulatestheproductionofROSinarterial IL-6 ( activates macrophages,releasingmediatorslikeTNF- in vascularwalls.Ithasbeenreportedthatendothelin-1 peripheral neuropathy Endothelin-1 anddiabetic -values areinboldtoindicatestatisticalsignificanceafteradjustment. A antagonists, such as Bosentan, led to improvements antagonists,suchasBosentan, ledtoimprovements 30 < < < < < < < < < P 0.0001 0.0001 0.396 0.07 0.244 0.0001 0.865 0.0001 0.936 0.763 0.832 0.589 0.0001 0.223 0.005 0.049 0.0001 0.0001 0.004 0.001 0.0001 0.276 0.0001 -value ), IL-8( 31 ) andreactiveoxidativespecies(ROS)( Adjusted oddsratio 1.002 (1.001–1.002) 0.993 (0.990–0.997) 1.001 (0.997–1.005) 1.054 (1.016–1.093) 1.006 (0.982–1.030) 1.005 (1.003–1.006) 0.992 (0.957–1.029) 1.008 (0.990–1.026) 1.027 (1.008–1.047) 1.016 (1.000–1.032) 0.982 (0.964–1.001) 0.985 (0.968–1.002) 0.995 (0.974–1.015) 1.018 (0.991–1.046) 1.015 (0.996–1.034) 1.003 (0.994–1.012) Downloaded fromBioscientifica.com at09/28/202107:38:27PM https://eje.bioscientifica.com 35 (95% CI) ). Novel therapies of ). Novel therapies of 182 :4 < < < P 0.682 0.399 0.006 0.053 0.0001 0.064 0.091 0.607 0.188 0.126 0.486 0.0001 0.713 0.005 0.650 0.0001 -value 33 α , 433 ( 36 34 32 29 via freeaccess ), ), ). ). ), European Journal of Endocrinology https://eje.bioscientifica.com in linewithourdatathat elevatedbloodpressurein dysregulation inSchwann cell ( postulated to be associated with metalloproteinase and proteinlossatlatestages. Thesephenotypesare function anddevelopmentofmyelinthinning nerve diabetes andhypertensionledtoworseningofsensory was attributed to hyperglycemia, a combination of and hypertension,althoughneuropathydevelopment ( therapy ontheprogressionofDPNinpatientswithT2D were found in intensive and moderate blood pressure velocity inpatientswithdiabetes( conduction nerve (ACEI), improvedmotorandsensory medication, angiotensin-convertingenzymeinhibitors Type 1Diabetes( factor predictingtheincidenceofDPNinpatientswith cohort study identified hypertension as a vascular risk and thepresenceofneuropathy( studies suggestarelationshipbetweenhypertension pressure predictedincidentDPN.Previouscross-sectional and diabeticulcers. improving bloodpressure,reducingtheincidenceofDPN possibilities oftheendothelinreceptorantagonismin efforts, likeSONAR( conductionandDPN.On-goingtrial to poorernerve suggesting thathigherendothelin-1couldcontribute variable where1 = femaleand2 = male. ^Log-transformed beforeanalysis. residual test: PAD andretinopathystatuswereincludedascovariates.Schoenfeld duration, baselineHbA1candsystolicBP),eGFR,urinaryACR, derangements whichweresignificantintheunivaraiteanalysis(diabetes added sequentiallyintotheModels.Age,gender,ethnicityandmetabolic Only parameters significant in Table 1 or known confounding factors were Retinopathy vsno PAD vsnoPAD Urine ACR(mg/g)^ eGFR (mL/min/1.73m SBP (10-unit)(mmHg) Hba1c (%) Duration ofDiabetes Malay Ethnicity (Reference:Non-Malay) Gender Age (years) Endothelin-1 (pg/mL)^ Model Variables incident dabeticperipheralneuropathy. Table 3 41 Clinical Study Retinopathy (years) ). Inanimalmodelsofimpairedglucosetolerance Our studyshowedthat elevated baselineblood # Multivariable Coxregressionanalysispredicting P = 0.2090. 39 ). Whilethebloodpressurelowering 37 2 ) ), may provide better insights and ), mayprovidebetterinsightsand Hazards ratio 1.152 (0.776–1.709) 1.448 (0.892–2.350) 1.171 (0.929–1.476) 0.996 (0.989–1.003) 1.107 (1.001–1.223) 1.148 (0.988–1.333) 1.025 (1.004–1.047) 0.902 (0.552–1.476) 1.283 (0.886–1.860) 1.013 (0.992–1.035) 4.345 (1.451–13.009) # Gender wascodedasadummy S LTPekandothers 42 ). Thesefindingsare 40 38 (95% CI) ), nodifferences ). Aprospective P 0.483 0.135 0.182 0.217 0.047 0.071 0.017 0.681 0.187 0.214 0.009 -value so, we would concede that HBA1c observed at baseline so, we would concede that HBA1c observed with and without intensive glucose control. Having said a difference in development of DPN between groups Veterans AffairsDiabetesTrial (VADT) ( lowering reduced incident DPN ( Indeed, whileACCORDshowedthatintensiveglucose- status, isacriticaldeterminantinDPNpathogenesis. notion thatdurationofdiabetes,ratherthanglycemic the fully adjusted model. This further supports the HbA1c predictedincidentDPN,itwasattenuatedin by others( incident DPNinourcohort,linewithdatareported DPN. whether earlyblood-pressureloweringmaydelayonsetof studies on bloodpressure trajectories might shed light on or angiotensin-receptorblocker(ARB)atbaseline.Future cohort, approximately60%ofpatientswereonACEIand/ patients withT2DacceleratesDPNdevelopment.Inour is thedisruptionofactincytoskeleton inpodocytesby the relationshipofhigherendothelin-1 andlowereGFR (CKD) ( endothelin-1 predictedincident chronickidneydisease unexpected, asothershave shownthathigherbaseline The relationshipbetweeneGFRandendothelin-1isnot association of lower eGFR with baseline endothelin-1. in healthyvolunteers( levels ledtosignificant increaseinarterialendothelin-1 intralipid infusion to increase triglyceride observation, adipocytes in aninsulin resistant state. Congruent to this might leadtodyslipidemiaasaresultofdysfunctional derived lipids.Althoughspeculative,thesemechanisms by endothelin-1( well-reported ( and waistcircumference) and triglycerides have been Significant association ofendothelin-1 withobesity (BMI increased theincidenceofDPN,withina3-yearfollow-up. have beenreflectiveofpoorerendothelialfunctionand a highplasmacirculating endothelin-1,atbaseline,could addition toitsdirectvasoconstrictioneffects.Therefore, reported toreduceavailabilityofnitricoxide( endothelial dysfunction/inflammation,whichhasbeen Endothelin-1 isawell-knownmarkerforvascular endothelin-1, afteradjustmentforvariousriskfactors. and poorereGFRwereindependentlyassociatedwith age, Malayethnicity, higherBMI,elevatedtriglycerides association withincidentDPN. of theparticipantsandmaythereforeexplainnull may notbesufficienttocaptureglobalglycemicburden peripheral neuropathy Endothelin-1 anddiabetic In ourcohort, we showedthat at baseline, older Duration ofdiabeteswasanindependentpredictor 52 ). Onepossiblemechanism which mayexplain 43 ). Intheunivariateanalyses,although 48 , 50 49 ) mayreducestorageofglucose- ). Impairment of glucoseuptake 51 Downloaded fromBioscientifica.com at09/28/202107:38:27PM ). We showedanindependent 44 182 ), Steno-2 ( 46 :4 ) didnotshow 45 47 ) and 434 ), in via freeaccess European Journal of Endocrinology plasma biomarker, whichmaypredictincident DPN. se contribute to incident DPN, rather than endothelin-1, ( diabetic proliferativeretinopathy remainscontroversial ( macrovascular complicationssuchasmicroalbuminuria been previously linkedtoincreasedriskofmicrovascularand reduced renalclearance.Increasedplasmaendothelin-1has arterial stiffness( responsetoretinopathy ( of compensatory endothelin-1 atbaselinecouldbeaconsequence had multiplecomplicationsofT2Datbaseline.Raised this ishighlyspeculative.PatientswithincidentDPN DPN, whichmightreflectautonomicdysfunction,though elevated heartrate,atbaseline,inpatientswithincident which predictedincidentDPN.We amarginally observed neuropathy ledtoanincreaseinendothelin-1atbaseline, to excludethepossibilitythatpresenceofsmallfiber not specificallyassessedatbaseline,henceweareable and impairedNO.Inourstudy, smallfiberneuropathywas autonomic systems,leadingtomicrovasculardysfunction 57 large fiberdamage(myelinated(A (A (affecting unmyelinatednerve damage prevailing hypothesisthatsmallfibernerve baseline isunknown.Recentpublicationssupportthe indicator asaresultofotherdiabetic complications at in thepathophysiologicalpathwayofDPNorasurrogate complex. Whether elevated endothelin-1 is directly causal its useasaprognosticmarker. large variabilityinourmulti-ethnicpopulationmaylimit that endothelin-1isagoodpredictorofincidentDPN,its Endothelin-1 isinfluencedbyethnicity. Whileitislikely habitswillberequiredtoexploreifplasma dietary focused ongenotypingofendothelin-1,lifestyleor endothelin-1 isinfluencedbyethnicity. Futurestudies habitswillberequiredtodecipherifplasma and dietary Chinese cohort( to diabeticnephropathy, thestudywasconductedina C-terminal pro-endothelin-1,conferringsusceptibility endothelin-1 maycontributetodifferencesinplasma While wepreviouslyshowedthatdifferentgenotypesof plasma endothelin-1hasneverbeenreportedbefore. Significant associationbetweenMalayethnicityand ( in renaltubularcells, resulting in kidney injury also induceendoplasmicreticulumstressandapoptosis glomerular filtration barrier ( endothelin-1, leadingtoincreasedpermeabilityofthe 62 60 . Nonetheless, endothelin-1 remains an interesting early . Nonetheless,endothelin-1 remains aninterestingearly Clinical Study ). Small fiber neuropathy usually affects nociceptive and ). Smallfiberneuropathyusuallyaffectsnociceptiveand , ), PAD ( The pathogenesis of DPN in patients with T2D is The pathogenesisofDPNinpatientswithT2Dis 63 , 64 61 ). These complications may collectively ). Thesecomplicationsmay collectively ), while its expression in patients with ), whileitsexpressioninpatientswith 55 59 ). Largegenotypingefforts,lifestyle ), endothelialdysfunction( 53 S LTPekandothers δ and C) fibers) precedes andC)fibers)precedes α ). Endothelin-1 may andA β ) inDPN( 58 ), increased ), increased 11 ) or ) or 54 56 per per ). , hence mayunderestimatetheprevalenceandincidence we didnotevaluatesmall-fibreneuropathyinourcohort, reflect thedynamicpost-prandialchanges.Additionally, endothelin-1, measuringatasingletimepointwouldnot Given thepossibleinfluenceonfastingchangesofplasma animal modelsledtoraisedplasmaendothelin-1( no changeofendothelin-1( glucose tolerancetestsshowedeitherareduction( Health PteLtdEndowmentFundSIGII/15202. Alexandra and (MOH-000066) CS-IRG its under Council Research Medical This research was supported by the Singapore Ministry of Health’s National Funding be could that interest of conflict perceived asprejudicingtheimpartialityofthisstudy. no is there that declare authors The Declaration ofinterest EJE-19-0523 This islinkedtotheonline version ofthepaperat Supplementary materials development ofclinicalsymptomswillbebeneficial. these patients,who may benefitfromtreatment, before the potentially modifiable.Theabilitytorecognizeandstratify DPN isimportant,giventhatsomeofthesefactorsare of diabetespredictedincidentDPN.Elucidatingriskfor elevated baseline endothelin-1, SBP and longer duration to precluderesidualconfoundingeffects. from anon-randomizeddiabetescohortdoesnotallowus limitation isthatourstudydesignofselectingpatients elucidation of otherrisk factors for incident DPN. Another precise. Alongerfollow-upperiod,infuture,willallow study; hence,thetrueincidentdateofonsetmaybenot event wasestimatedwhenpatientfollowed-upforthe at differentstages.Duetothestudyprotocol,time-to- hence ourresultscannotbeappliedtodiabetespopulation cohort had adiabetes duration of 10.0years (4.0–16.0), of neuropathyinourcohort.Onentry, patientsinour are notgeneralizeabletootherpopulations. in a T2D cohort at a single time point and our findings the limitationthatwehaveonlyanalyzedendothelin-1 collection afteranovernightfast,weacknowledgethat with T2D.Whileweattemptedtostandardizeblood in arelativelylargecohortofmulti-ethnicpatients ability toassessprognosticvalueofplasmaendothelin-1 large numberofT2Dpatients.Asecondadvantageisthe detailed, carefulandstandardizedassessmentinarelatively criteria, longitudinaldesignandtheabilitytoperform peripheral neuropathy Endothelin-1 anddiabetic In conclusion, this study demonstrated that baseline In conclusion,thisstudydemonstratedthatbaseline Strengths of the study include the strict enrolment . Downloaded fromBioscientifica.com at09/28/202107:38:27PM 66 https://eje.bioscientifica.com ), whilefastingstatesin 182 https://doi.org/10.1530/ :4 In vivo human 65 435 67 ) or via freeaccess ). European Journal of Endocrinology https://eje.bioscientifica.com References this study. collection anddataentry,thankallthepatientswhovolunteeredfor Unit ofourinstitution, Yeo intheClinicalResearchwhohelped with data The authors would like to acknowledge the research nurses and Mr Darren Acknowledgements 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Clinical Study Kohan DE, Inscho EW, Wesson D &Pollock DM.Physiology of Giaid A, Gibson SJ,Ibrahim BN,Legon S,Bloom SR,Yanagisawa M, Yanagisawa M, Kurihara H,Kimura S,Tomobe Y, Kobayashi M, Pek SLT, Sum CF, Yeoh LY, Lee SBM, Tang WE, Lim SC& Green AQ, Krishnan S,Finucane FM&Rayman G.Altered De Vriese AS, Verbeuren TJ, Van deVoorde J, Lameire NH& Wheatcroft SB, Williams IL, Shah AM&Kearney MT. Stirban A. 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