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Microvascular Reactivity and Inflammatory Cytokines in Painful and Painless Peripheral Diabetic Neuropathy

Microcirculation Laboratory and Joslin-Beth Israel Deaconess Foot Center (J.D., T.E.L., T.D., S.W., A.V.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston Massachusetts 02215; and Technological Educational Institute of Messolonghi (C.G.), 30200 Messolonghi, Greece

Address all correspondence and requests for reprints to: Aristidis Veves, M.D., Microcirculation Laboratory, Palmer 318, Beth Israel Deaconess Medical Center, One Deaconess Road, Boston, Massachusetts 02215. E-mail: aveves{at}bidmc.harvard.edu.

Objective: We investigated the association between inflammation, microvascular reactivity, and the development of peripheral diabetic neuropathy.

Research Design and Methods: We studied three groups: 55 healthy control subjects, 80 nonneuropathic patients, and 77 neuropathic diabetic patients. We also subdivided the neuropathic patients into a subgroup of 31 subjects with painless neuropathy and 46 with painful neuropathy. We measured the foot skin endothelium-dependent and -independent vasodilation, the nerve axon reflex-related vasodilation (NARV), and inflammatory cytokines and biochemical markers of endothelial function.

Results: The endothelium-dependent and -independent vasodilation and NARV were lower in the neuropathic group (P < 0.05). NARV was further reduced in the subgroup of painless neuropathy when compared to painful neuropathy (P < 0.05). Compared to the other two groups, the neuropathic group also had higher serum levels of PDGF AA/BB (P < 0.05), RANTES (P < 0.01), leptin (P < 0.0001), osteoprotegerin (P < 0.01), G-CSF (P < 0.05), sE-Selectin (P < 0.01), sICAM (P < 0.0001), sVCAM (P < 0.001), CRP (P < 0.0001), TNF (P < 0.05), and fibrinogen (P < 0.05). Patients with painful neuropathy had higher sICAM-1 (P < 0.05) and CRP levels (P < 0.01) when compared to painless neuropathy. No major changes in the above results were observed in 78 diabetic patients who were seen for a second visit 21 months after the first visit.

Conclusions: Peripheral diabetic neuropathy is associated with increased biochemical markers of inflammation and endothelial dysfunction. Painful neuropathy is associated with further increase in inflammation and markers of endothelial dysfunction and preservation of the nerve axon reflex.