High TNF-alpha plasma levels and macrophages iNOS and TNF-alpha expression as risk factors for painful diabetic neuropathy

Abstract

Painful diabetic neuropathy (PDN) is one of the most common complications of diabetes mellitus. Recently it has become clear that nitric oxide (NO) and proinflammatory cytokines play an important role in the pathogenesis of PDN. We investigated whether the cytokine tumor necrosis factor alpha (TNF-α) and NO play a role in PDN pathogenesis by performing a cross-sectional and a case–control study in 110 type 2 diabetic patients. Of 110 subjects, 59 patients suffered from PDN (cases) and the remaining were painless DN (controls). Cross-sectionally, plasma TNF-α levels and immunoreactivity for inducible NO synthase (iNOS) and TNF-α were higher in patients with more severe pain on the visual analog scale. There were statistically significant differences between mild and severe pain for TNF-α levels, iNOS immunoreactivity, and TNF-α immunoreactivity. There were statistically significant differences between mild and severe pain for TNF-α levels (mean 15.24 pg/mL ± 5.42 vs 20.44 ± 10.34), iNOS immunoreactivity (9.76% ± 8.60% vs 15.48% ± 11.56%), and TNF-α immunoreactivity (13.0% ± 9.48% vs 20.44% ± 11.75%). The case–control study showed that TNF-α had an odds ratio of 5.053 (P < 0.001), TNF-α immunoreactivity of 4.125 (P < 0.001), and iNOS immunoreactivity of 3.546 (P = 0.002). DN patients with high TNF-α levels, and high iNOS and TNF-α expression in macrophages are at risk of suffering from pain. The higher the TNF-α level, and iNOS and TNF-α immunoreactivity, the more severe the pain. These findings could form the basis of further research into better management of PDN.

Differential Association Between Biomarkers of Subclinical Inflammation and Painful Polyneuropathy: Results From the KORA F4 Study

“…The difference compared with our study regarding CRP is interesting given that we previously found associations between CRP and the MNSI score in a sample of diabetic patients (17), but not in the general older population (13), which suggests differences in risk factors of DSPN with respect to diabetic status. One study reported an association between TNF-a plasma levels and neuropathic pain in patients with type 2 diabetes, but the analysis was not adjusted for any confounding variables (18).…”

Diabetic Peripheral Neuropathy: Should a Chaperone Accompany Our Therapeutic Approach?

“…Injury to peripheral nerves results in the production of cytokines that originate from resident and recruited lymphocytes, macrophages, neurons, and Schwann cells (Yasuda et al, 2003). Patients with both type 1 and 2 diabetes exhibit elevated blood levels of tumor necrosis factor-␣ (TNF-␣), an inflammation promoting cytokine (Gonzalez-Clemente et al, 2005;Purwata, 2011). In these patients with diabetes, the plasma levels of TNF-␣ correlated with the severity of perceived pain (Purwata, 2011).…”

“…Patients with both type 1 and 2 diabetes exhibit elevated blood levels of tumor necrosis factor-␣ (TNF-␣), an inflammation promoting cytokine (Gonzalez-Clemente et al, 2005;Purwata, 2011). In these patients with diabetes, the plasma levels of TNF-␣ correlated with the severity of perceived pain (Purwata, 2011). The relevance of increased TNF-␣ levels to DPN is supported by both pharmacologic and genetic evidence.…”

Proinflammatory Cytokines Predict the Incidence and Progression of Distal Sensorimotor Polyneuropathy: KORA F4/FF4 Study

“…However, the crosssectional design of almost all clinical and epidemiological studies (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) so far precludes inferences regarding the temporal relationship between inflammation and DSPN, which are essential for any conclusions about causality. One small prospective study assessed plasma levels of soluble adhesion molecules in 28 individuals with diabetes during a 5-year study period and suggested that endothelial activation is associated with nerve conduction slowing (18).…”