Update on Biomarkers of Chronic Inflammatory Processes Underlying Diabetic Neuropathy

Abstract

There is an increasing prevalence of diabetes mellitus (DM), particularly type 2 DM (T2DM), and its associated complications. T2DM is linked to insulin resistance, chronic inflammation, and oxidative stress, which can lead to both macrovascular and microvascular complications, including peripheral diabetic neuropathy (PDN). Inflammatory processes play a key role in the development and progression of T2DM and its complications, with specific markers like C-reactive protein (CRP), interleukins (ILs), and tumor necrosis factor (TNF)-α being associated with increased risk. Other key inflammatory markers such as nuclear factor kappa B (NF-κB) are activated under hyperglycemic and oxidative stress conditions and contribute to the aggravation of PDN by regulating inflammatory gene expression and enhancing endothelial dysfunction. Other important roles in the inflammatory processes are played by Toll-like receptors (TLRs), caveolin 1 (CAV1), and monocyte chemoattractant protein 1 (MCP1). There is a relationship between vitamin D deficiency and PDN, highlighting the critical role of vitamin D in regulating inflammation and immune responses. The involvement of macrophages in PDN is also suspected, emphasizing their role in chronic inflammation and nerve damage in diabetic patients. Vitamin D supplementation has been found to reduce neuropathy severity, decrease inflammatory markers, and improve glycemic control. These findings suggest that addressing vitamin D deficiency could offer therapeutic benefits for PDN. These molecular pathways are critical in understanding the pathogenesis of DM complications and may offer potential biomarkers or therapeutic targets including anti-inflammatory treatments, vitamin D supplementation, macrophage phenotype modulation, and lifestyle modifications, aimed at reducing inflammation and preventing PDN. Ongoing and more extensive clinical trials with the aim of investigating anti-inflammatory agents, TNF-α inhibitors, and antioxidants are needed to advance deeper into the understanding and treatment of painful diabetic neuropathy.

Keywords: Toll-like receptor 4 (TLR4); caveolin 1; diabetic neuropathy; inflammation; type 2 diabetes mellitus (T2DM); vitamin D.

Figure 1

Main effects produced by increased TLR expression in DM; + activation.

Figure 2

CAV1 functionality in physiologic and pathologic conditions.

Figure 3

The pro-inflammatory mechanism involved in the presence of DM. The inflammatory process from DM, involving the secretion of cytokines, such as TNF-α, IL-1β, and IL-6 acting on its receptors (TNF-αR, IL-1βR, and IL-6R), together with the activation of TLR made by lipopolysaccharides (LPSs) and lipoteichoic acid (LTA), conduces to the activation path of NF-κB. The activation of NF-κB further stimulates the translation and transcription process, with the rough endoplasmic reticulum (rER) contribution generating pro-inflammatory proteins that create a vicious cycle.

Figure 4

Cellular mechanism of DM in the development of PDN. In DM, the overstimulation of M1 TLR4 results in the release of iNOS and the activation of the COX-2 pathway. COX-2 stimulation and iNOS further activate NF-κB, leading to pro-inflammatory status. The secretion of TNF-α, IL-1β, and IL-6 has an impact on Schwann cells, causing PDN. Caveolin-1, a cell membrane protein, has an inhibitory role against the activation of M1 TLR4, showing promising preliminary results in DM.

Figure 5

Pro-inflammatory and anti-inflammatory pathways and their relationship with the occurrence of PDN.

Figure 6

The role of monocytes (M1 and M2) in inflammation and the theoretical protective effect of vitamin D. The activation of M1-type monocytes will lead to pro-inflammatory macrophages in the interstitial tissue, affecting the cellular metabolism secondary to the secretion of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6, leading to the activation of NF-κB. On the other hand, M2 monocytes, by developing in tissue macrophages, will secrete anti-inflammatory cytokines (IL-10), acting on two inhibitory intracellular proteins, such as signal transducer and activator of transcription 3 (STAT3) and signal transducer for receptors of the TGF-β family (SMAD), interfering in the activation of NF-κB. Studies showed an inhibitory effect of vitamin D in the conversion of M1 to pro-inflammatory macrophages, but without an impact on M2 macrophages.

Figure 7

Schematic illustration presenting the development of PDN from DM. The inhibitory effects of DM (either T1DM or T2DM) decrease the levels of caveolin-1 with the concomitant activation of M1 monocytes, leading to pro-inflammatory effects, by the activation of NF-κB. The concentration of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) seems to be lowered by vitamin D administration, left in the anti-inflammatory pathway of M2 monocytes, slowing down the progression of DM in PDN.