Introduction Diabetic peripheral neuropathy(DPN) is a 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, causally implicated for microangiopathy. We investigated whether baseline plasma Endothelin-1 predicted incidence of DPN in a 3-year observational, cohort study. Methods In patients with T2D(n=2057), anthropometric data, fasting blood, 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≥25volts on either foot at 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 1,767 patients without DPN, 1,250 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-SD 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.

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