Skin deep: carbonyl stress is a trigger for nerve dysfunction in early type 2 diabetes

Aims: Advanced glycation end-products (AGEs) are implicated as a major pathway for the development of diabetic peripheral neuropathy (DPN). As endogenous carbonyl stress leads to the formation of AGEs this study aimed to characterize cutaneous carbonyl stress, oxidative stress, immune cells, and endothelial cell damage in individuals with early type 2 diabetes (T2DM).

Methods: 160 people who were diagnosed with T2DM in the last 12 months and 144 people with normal glucose tolerance (NGT) were recruited from the German Diabetes Studies with 80 people with T2DM being followed up at 5 years. They underwent a detailed DPN assessment which included nerve conduction studies, quantitative sensory and clinical testing. Skin biopsies were taken and assessed for intraepidermal nerve fiber density, AGEs autofluorescence, argpyrimidine area, and endothelial cell area as well as skin autofluorescence which was measured non-invasively using the AGE reader.

Results: Argpyrimidine area (17.5±18.8 vs 11.7±12.7%, P<0.05) was significantly higher in the T2DM group compared to NGT. AGEs autofluorescence was inversely correlated with nerve conduction (e.g. peroneal motor nerve conduction velocity: r=-0.346) and positively with AGE reader measurements in T2DM (r=0.358, all P<0.05), but not in NGT. Higher baseline AGEs autofluorescence and lower endothelial cell area predicted the deterioration of clinical and neurophysiological measures after 5 years. In those with T2DM AGEs autofluorescence was inversely correlated with nerve conduction parameters and positively with AGE reader measurements. This was not found in the NGT group. In the 80 people followed up, a higher baseline AGE autofluorescence and a lower endothelial cell area was able to predict the deterioration of clinical and neurophysiological measures after 5 years.

Conclusions: There is a role for carbonyl stress in the development of early DPN in people with recently diagnosed T2DM.  AGEs autofluorescence was able to predict the progression of DPN after 5 years.

Comments: The pathophysiology of DPN is multifactorial with several established pathogenetic pathways. However, conventional strategies often fail to prevent the progression of DPN. Of particular concern is the presence of DPN in individuals with non-diabetic hyperglycaemia and newly diagnosed T2DM, suggesting the involvement of additional mechanisms. Among these, AGEs are considered a key pathogenetic pathway in T2DM, with pre-clinical studies providing valuable insights. However, the role of carbonyl stress and its association with DPN in human studies remains limited. In this study, Argpyrimidine (a methylglyoxal-derived AGE) area was significantly higher in the T2DM group compared to the NGT group, indicating ongoing carbonyl stress in a cohort of well-controlled, recently diagnosed T2DM patients. This finding was further supported by an inverse relationship between AGEs autofluorescence and nerve conduction study parameters in the T2DM group, but not in those with NGT. Furthermore, higher baseline AGEs autofluorescence and lower endothelial cell area were predictive of nerve function deterioration over 5 years. This finding underscores the potential of AGEs as a target for future therapeutic interventions.

Additionally, the study explored the use of point-of-care, non-invasive measurement of skin autofluorescence, which showed a reasonable correlation with AGEs autofluorescence measured in skin biopsies. Thus, skin autofluorescence could serve as a potential surrogate marker for DPN, though further validation through larger studies is required.

These results are promising yet it is important to note that while several markers for DPN development have been investigated pre-clinically, their translation into meaningful human studies remains limited. This study highlights a potentially significant avenue for further research into the pathophysiology of DPN in T2DM and offers insights into possible biomarkers for early detection and monitoring of DPN.

Shazli Azmi

Reference: Bönhof GJ, Strom A, Jung T, Bódis KB, Szendroedi J, Wagner R, Grune T, Roden M, Ziegler D. Cutaneous Carbonyl Stress Is Associated With Nerve Dysfunction in Recent-Onset Type 2 Diabetes. Diabetes Care. 2024 Nov 25:dc241799. doi: 10.2337/dc24-1799. Epub ahead of print. PMID: 39585943.

https://diabetesjournals.org/care/article-abstract/doi/10.2337/dc24-1799/157484/Cutaneous-Carbonyl-Stress-Is-Associated-With-Nerve?