title: Endothelial Dysfunction as a Link Between Cardiovascular Risk Factors and Peripheral Neuropathy in Diabetes.
abstract: 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.
  
  
  
  The primary objective of this study was to test whether endothelial dysfunction is a predictor of DPN.
  
  
  
  This is a cross-sectional analysis of a cohort composed of patients followed at the Microcirculatory Laboratory, Beth Israel Deaconess Medical Center.
  
  
  
  Participants with diabetes without DPN (n = 192) and with DPN (n = 166), subjects with prediabetes (n = 75), and nondiabetic controls (n = 59) were included.
  
  
  
  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).
  
  
  
  The relationship between FMD and NDS assessed using multiple linear regression.
  
  
  
  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.
  
  
  
  This study shows that endothelial dysfunction occurs early in the pathophysiology of diabetes and is a link between cardiovascular risk factors and DPN.
authors.affiliation: Microcirculatory Lab and Rongxiang Xu, MD, Center for Regenerative Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Roustit
authors.affiliation: Microcirculatory Lab and Rongxiang Xu, MD, Center for Regenerative Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Jordan
authors.initials: J
authors.lastname: Loader
authors.affiliation: Microcirculatory Lab and Rongxiang Xu, MD, Center for Regenerative Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Carly
authors.initials: C
authors.lastname: Deusenbery
authors.affiliation: Microcirculatory Lab and Rongxiang Xu, MD, Center for Regenerative Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Baltzis
authors.affiliation: Microcirculatory Lab and Rongxiang Xu, MD, Center for Regenerative Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Aristidis
authors.initials: A
authors.lastname: Veves
mesh_terms: D015415:Biomarkers / Q000032:analysis; D002318:Cardiovascular Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D048909:Diabetes Complications / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D003920:Diabetes Mellitus / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007557:Israel; D008297:Male; D008833:Microcirculation; D008875:Middle Aged; D011379:Prognosis; D012307:Risk Factors; D014652:Vascular Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology*
chemical_list: D015415:Biomarkers