Impaired glyoxalase activity is associated with reduced expression of neurotrophic factors and pro‐inflammatory processes in diabetic skin cells

Abstract

Patients suffering from type II diabetes develop several skin manifestations including cutaneous infections, diabetic dermopathy, diabetic bullae and acanthosis nigricans. Diabetic micro- and macroangiopathy as well as diabetic neuropathy are believed to play a crucial role in the development of diabetic skin disorders. A reduced cutaneous nerve fibre density was reported in diabetic subjects, which subsequently leads to impaired sensory nerve functions. Using an innervated skin model, we investigated the impact of human diabetic dermal fibroblasts and keratinocytes on porcine sensory neurons. Diabetic skin cells showed a reduced capacity to induce neurite outgrowth due to a decreased support with neurotrophic factors, such as NGF. Furthermore, diabetic keratinocytes displayed insulin resistance and increased expression of pro-inflammatory cytokines demonstrating the persistent effect of diabetes mellitus on human skin cells. Dysregulations were related to a significantly reduced glyoxalase enzyme activity in diabetic keratinocytes as experimentally reduced glyoxalase activity mimicked the increase in pro-inflammatory cytokine expression and reduction in NGF. Our results demonstrate an impaired crosstalk of diabetic skin cells and sensory neurons favouring hypo-innervation. We suggest that reduced methylglyoxal detoxification contributes to an impaired neurocutaneous interaction in diabetic skin.

Evaluation of Immunomodulatory Responses and Changed Wound Healing in Type 2 Diabetes—A Study Exploiting Dermal Fibroblasts from Diabetic and Non-Diabetic Human Donors

“…Remarkably, the activity of glyoxalase I was reduced in diabetic fibroblasts as compared with non-diabetic fibroblasts ( Figure 4 B). Comparable observations have been obtained from human keratinocytes, with the expression of glyoxalase I being comparable in keratinocytes from diabetic and non-diabetic donors but with the activity being reduced in keratinocytes from diabetic donors [ 43 ]. In this study, the activity of glyoxalase I was found to be reduced upon treatment of dermal fibroblasts with MIF( Figure 4 D), suggesting that MIF activates a signalling pathway that negatively regulates glyoxalase I activity.…”

“…However, the data on secretion of MIF and PICP exhibited relatively large values of the standard deviation and p -values higher than 0.05 ( Figure 2 ). Large values of the standard deviation and p -values higher than 0.05 seem to be associated with the usage of primary cells, e.g., the secretion of several pro-inflammatory factors from keratinocytes of diabetic donors tended to be increased (albeit non-significantly) [ 43 , 44 ]. A higher number of donors (if available) might help to find statistical significance.…”

Ameliorating Methylglyoxal-Induced Progenitor Cell Dysfunction for Tissue Repair in Diabetes

“…Proteomic analysis on MGO-modified intra/extracellular proteins will likely unveil more protein glycation hot spots in patients with diabetes. Second, MGO-induced BMPC dysfunction was investigated in this study, but MGO affects various cell types that participate in diabetic wound repair, including keratinocytes and fibroblasts (49,50). Although beyond the scope of the current study, it would be interesting to evaluate the impact of pathophysiological levels of MGO on these cell types.…”

In Vitro Sensitive Skin Models: Review of the Standard Methods and Introduction to a New Disruptive Technology

“…To better mimic the physiological environment of sensory neurons, several teams created 2D and 3D coculture models, including sensory neurons and various cell types such as Schwann cells [29][30][31], fibroblasts [30][31][32][33][34][35][36][37][38][39], endothelial cells [31,35,36], and/or keratinocytes [29,[31][32][33][34][35][36][37][38]40]. Indeed, some of these cells have been shown to modulate neurite growth [41], and one can expect a sensory neuron response to be closer to the in vivo response in a more physiological environment.…”