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

Abstract

OBJECTIVEExperimental and epidemiological studies have implicated inflammatory processes in the pathogenesis of distal sensorimotor polyneuropathy (DSPN), but prospective studies are lacking. We hypothesized that biomarkers of inflammation predict the development and progression of DSPN in a population-based cohort. RESEARCH DESIGN AND METHODSThis study was based on participants aged 62-81 years from the Cooperative Health Research in the Region of Augsburg (KORA) F4/FF4 cohort, with a mean follow-up of 6.5 years. The predictive value of systemic levels of eight biomarkers of inflammation was assessed for incident DSPN in 133 incident case subjects and 397 individuals without incident DSPN, and for DSPN progression in 57 patients with prevalent DSPN at both time points. RESULTSHigher hs-CRP, interleukin (IL)-6, tumor necrosis factor (TNF)-a, IL-1 receptor antagonist (IL-1RA), and soluble intercellular adhesion molecule (sICAM-1) and lower adiponectin levels were associated with incident DSPN in age-and sexadjusted analysis; IL-18 and omentin were not. IL-6 (odds ratio 1.31 [95% CI 1.00-1.71]) and TNF-a (odds ratio 1.31 [95% CI 1.03-1.67]) remained associated with incident DSPN after adjusting for known DSPN risk factors. The addition of both cytokines to a clinical risk model improved model fit and reclassification. sICAM-1 and IL-1RA were positively associated with progression of DSPN. CONCLUSIONSSystemic subclinical and vascular inflammation predicted both the onset and progression of DSPN over 6.5 years in an older general population. Thus modulation of inflammatory processes may be relevant to prevent and/or treat diabetic neuropathy.Distal sensorimotor polyneuropathy (DSPN) is the most frequent neurological complication of type 2 diabetes (1). The pathomechanisms leading to the onset and progression of DSPN are not completely understood, which profoundly limits current prevention and treatment. Advanced age and diabetes duration represent the most important known risk factors, but there is increasing evidence that height,

Role of inflammatory biomarkers in diabetic peripheral neuropathy

“…In addition to these inflammatory molecules, circulating and locally produced ICAM‐1, vascular cell adhesion molecule‐1, E‐selectin and chemokines have increased expression in diabetes and DPN, and have been shown to be associated with the development and progression of DPN only by cross‐sectional trials. Although, in this prospective study6, it was reported that IL‐6 and TNF‐α elevation increased DPN development, and elevation of the levels of these systemic cytokines is not specific to DPN, but is observed in cardiovascular disease, obesity and other diabetic complications, such as diabetic nephropathy. Therefore, we should confirm the difference in systemic cytokine change between DPN and other low‐grade inflammatory disease6.…”

“…Although, in this prospective study6, it was reported that IL‐6 and TNF‐α elevation increased DPN development, and elevation of the levels of these systemic cytokines is not specific to DPN, but is observed in cardiovascular disease, obesity and other diabetic complications, such as diabetic nephropathy. Therefore, we should confirm the difference in systemic cytokine change between DPN and other low‐grade inflammatory disease6.…”

“…After adjustment for known DPN risk factors, increased IL‐6 and TNF‐α remained associated with incident DPN. Higher plasma soluble ICAM‐1 and IL‐1RA were associated with the progression of DPN6.…”

“…In 2017, Herder et al 6. reported that systemic inflammation predicted both the onset and progression of DPN over 6.5 years for the large population of older adults in the Cooperative Health Research in the Region of Augsburg F4/FF4 cohort prospective study.…”

“…Herder et al 6. suggested that soluble ICAM‐1 and IL‐1RA can be used as biomarkers for DPN progression.…”