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ABSTRACT: One in five diabetic patients suffers from chronic pain with neuropathic characteristics, but the pathophysiological mechanisms underlying the development of neuropathic pain in diabetic distal symmetrical polyneuropathy (DSP) patients are poorly understood. Systemic low-grade inflammation has been implicated, but there is still a considerable knowledge gap concerning its scope and meaning in this context. The aim of the study was to establish the broad inflammatory signature of painful diabetic DSP in serum samples from the Pain in Neuropathy Study (PiNS), an observational cross-sectional multicentre study in which participants underwent deep phenotyping. In the present two-cohorts exploration-replication study (180 participants in each cohort), serum samples from PiNS participants were analyzed with the Olink INFLAMMATION panel (Olink Bioscience, Uppsala, Sweden) which enables the simultaneous measurement of 92 inflammation-related proteins (mainly cytokines, chemokines and growth factors). In both the exploration and the replication cohort, we identified a high-inflammation subgroup where 14 inflammation-related proteins in particular were associated with more neuropathy and higher pain intensity. The top 3 proteins were HGF, CSF-1 and CD40 in both cohorts. In the exploratory cohort, additional clinical data were available, showing an association of inflammation with insomnia and self-reported psychological distress. Hence, this cross-sectional exploration-replication study seems to confirm that low-grade systemic inflammation is related to the severity of neuropathy and neuropathic pain in a subgroup of diabetic DSP patients. The pathophysiological relevance of these proteins for the development of neuropathic pain in diabetic DSP patients must be explored in more depth in future studies.

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