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Open Access 01-12-2023 | Diabetic Foot | Research

Metabolic memory in diabetic foot syndrome (DFS): MICRO-RNAS, single nucleotide polymorphisms (SNPs) frequency and their relationship with indices of endothelial function and adipo-inflammatory dysfunction

Authors: Alessandro Del Cuore, Rosaria Maria Pipitone, Alessandra Casuccio, Marco Maria Mazzola, Maria Grazia Puleo, Gaetano Pacinella, Renata Riolo, Carlo Maida, Tiziana Di Chiara, Domenico Di Raimondo, Rossella Zito, Giulia Lupo, Luisa Agnello, Gabriele Di Maria, Marcello Ciaccio, Stefania Grimaudo, Antonino Tuttolomondo

Published in: Cardiovascular Diabetology | Issue 1/2023

Abstract

Background

Diabetic foot is a significant cause of morbidity in diabetic patients, with a rate that is approximately twice that of patients without foot ulcers. “Metabolic memory” represents the epigenetic changes induced by chronic hyperglycaemia, despite the correction of the glucose levels themselves. These epigenetic modifications appear to perpetuate the damage caused by persistently elevated glucose levels even in their absence, acting at various levels, mostly affecting the molecular processes of diabetic ulcer healing.

Methods

The aim of our cross-sectional study was to analyse a cohort of patients with diabetes with and without lower limb ulcers.

We examined the effects of epigenetic changes on miRNA 126, 305, and 217 expression and the frequency of the SNPs of genes encoding inflammatory molecules (e.g., IL-6 and TNF-alpha) and their correlations with serum levels of proangiogenic molecules (e.g., ENOS, VEGF and HIF-1alpha) and several adipokines as well as with endothelial dysfunction, assessed noninvasively by reactive hyperaemia peripheral artery tonometry.

Between March 2021 and June 2022, 110 patients were enrolled into the study: 50 diabetic patients with diabetic foot injuries, 40 diabetic patients without ulcerative complications and 20 nondiabetic patients as the control group.

Results

Diabetic subjects with lower limb ulcerative lesions exhibited higher levels of inflammatory cytokines, such as VEGF (191.40 ± 200 pg/mL vs. 98.27 ± 56.92 pg/mL vs. 71.01 ± 52.96 pg/mL; p = 0.22), HIF-1alpha (40.18 ± 10.80 ng/mL vs. 33.50 ± 6.16 ng/mL vs. 33.85 ± 6.84 ng/mL; p = 0.10), and Gremlin-1 (1.72 ± 0.512 ng/mL vs. 1.31 ± 0.21 ng/mL vs. 1.11 ± 0.19 ng/mL; p < 0.0005), than those without lower limb ulcers and healthy controls. Furthermore, we observed that miR-217-5p and miR-503-5p were 2.19-fold (p < 0.05) and 6.21-fold (p = 0.001) more highly expressed in diabetic foot patients than in healthy controls, respectively. Additionally, diabetic patients without lower limb ulcerative complications showed 2.41-fold (p = 0) and 2.24-fold (p = 0.029) higher expression of miR-217-5p and miR-503-5p, respectively, than healthy controls. Finally, diabetic patients with and without ulcerative complications of the lower limbs showed higher expression of the VEGFC2578A CC polymorphism (p = 0.001) and lower expression of the VEGFC2578A AC polymorphism (p < 0.005) than the healthy control population. We observed a significant increase in Gremlin-1 levels in patients with diabetic foot, suggesting that this inflammatory adipokine may serve as a predictive marker for the diagnosis of diabetic foot.

Conclusions

Our results highlighted that patients with diabetic foot showed predominant expression of the VEGF C2578A CC polymorphism and reduced expression of the AC allele. Additionally, we found an overexpression of miR-217-5p and miR-503-5p in diabetic patients with and without diabetic foot syndrome compared with healthy controls.

These results align with those reported in the literature, in which the overexpression of miR-217-5p and miR-503-5p in the context of diabetic foot is reported. The identification of these epigenetic modifications could therefore be helpful in the early diagnosis of diabetic foot and the treatment of risk factors. However, further studies are necessary to confirm this hypothesis.

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Title: Metabolic memory in diabetic foot syndrome (DFS): MICRO-RNAS, single nucleotide polymorphisms (SNPs) frequency and their relationship with indices of endothelial function and adipo-inflammatory dysfunction
Authors: Alessandro Del Cuore
Rosaria Maria Pipitone
Alessandra Casuccio
Marco Maria Mazzola
Maria Grazia Puleo
Gaetano Pacinella
Renata Riolo
Carlo Maida
Tiziana Di Chiara
Domenico Di Raimondo
Rossella Zito
Giulia Lupo
Luisa Agnello
Gabriele Di Maria
Marcello Ciaccio
Stefania Grimaudo
Antonino Tuttolomondo
Publication date: 01-12-2023
Publisher: BioMed Central
Keywords: Diabetic Foot
Epigenetics
Published in: Cardiovascular Diabetology / Issue 1/2023
Electronic ISSN: 1475-2840
DOI: https://doi.org/10.1186/s12933-023-01880-x

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