Endothelial Dysfunction as a Link Between Cardiovascular Risk Factors and Peripheral Neuropathy in Diabetes

J Clin Endocrinol Metab. 2016 Sep;101(9):3401-8. doi: 10.1210/jc.2016-2030. Epub 2016 Jul 11.


Context: Cardiovascular risk factors are well-known predictors of the development of diabetic peripheral neuropathy (DPN), which has traditionally been considered as a manifestation of diabetes-associated microangiopathy. Because endothelial dysfunction is strongly associated with all cardiovascular risk factors, we hypothesized that it may be a link between cardiovascular risk factors and DPN.

Objective: The primary objective of this study was to test whether endothelial dysfunction is a predictor of DPN.

Design and setting: This is a cross-sectional analysis of a cohort composed of patients followed at the Microcirculatory Laboratory, Beth Israel Deaconess Medical Center.

Patients: Participants with diabetes without DPN (n = 192) and with DPN (n = 166), subjects with prediabetes (n = 75), and nondiabetic controls (n = 59) were included.

Interventions: Endothelial function was assessed with flow-mediated dilation (FMD) of the brachial artery. Inflammatory cytokines and biomarkers of endothelial function (soluble intercellular and vascular cell adhesion molecules) were quantified using a multiplex bead-based immunoassay. Neurological assessment included the neuropathy disability score (NDS).

Main outcome measure: The relationship between FMD and NDS assessed using multiple linear regression.

Results: In addition to already known risk factors of DPN, FMD was strongly associated with NDS (β = -0.24; P < .001). Sensitivity analysis that removed FMD from the model provided similar results for soluble intercellular cell adhesion molecule-1, another biomarker of endothelial function. Confirmatory factor analysis further showed that endothelial dysfunction is a significant mediator between glycosylated hemoglobin and diabetes duration and diabetic complications.

Conclusions: This study shows that endothelial dysfunction occurs early in the pathophysiology of diabetes and is a link between cardiovascular risk factors and DPN.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers / analysis
  • Cardiovascular Diseases / etiology
  • Cardiovascular Diseases / metabolism
  • Cardiovascular Diseases / pathology*
  • Case-Control Studies
  • Cohort Studies
  • Cross-Sectional Studies
  • Diabetes Complications / etiology
  • Diabetes Complications / metabolism
  • Diabetes Complications / pathology*
  • Diabetes Mellitus / physiopathology*
  • Diabetic Neuropathies / etiology
  • Diabetic Neuropathies / metabolism
  • Diabetic Neuropathies / pathology*
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology*
  • Female
  • Follow-Up Studies
  • Humans
  • Israel
  • Male
  • Microcirculation
  • Middle Aged
  • Prognosis
  • Risk Factors
  • Vascular Diseases / etiology
  • Vascular Diseases / metabolism
  • Vascular Diseases / pathology*


  • Biomarkers