PC1157: Association of Serum Irisin Levels with Endothelial Dysfunction Markers in a Model of Endothelial Cells Challenged with Serum from Pediatric Patients with Diabetes Mellitus and Metabolic Syndrome

Background: Endothelial dysfunction is a crucial pathophysiological mechanism for cardiovascular diseases and a potential consequence of metabolic disorders. Preclinical studies have revealed that irisin, an adipomyokine, can exert beneficial effects in preventing endothelial dysfunction by decreasing the production of oxidative stress, promoting endothelial production of nitric oxide (NO), and increasing the endothelial cell viability. However, these studies have the limitation to studying single damage inductors for endothelium, escaping from the reality of the adverse metabolic extracellular milieu in humans. Furthermore, the available data regarding the possible associations among circulating irisin levels and endothelial dysfunction markers in pediatric populations with Type 2 Diabetes Mellitus (T2DM) and Metabolic Syndrome (MetS) is scarce. The objective of this study was to investigate the associations between serum irisin levels and endothelial dysfunction markers in an in vitro model of human umbilical vein endothelial cells (HUVEC) challenged with the serum from pediatric patients diagnosed with T2DM and MetS.

Methods: We obtained serum samples from a cohort of 55 pediatric patients aged 6 to 16 years old. These patients were grouped depending on their metabolic status into T2DM patients (n=21), MetS (n=18) patients, and healthy controls (n=16). We performed measurements of serum irisin levels and soluble leucocyte adhesion molecules concentrations (sICAM1, sICAM2, sNCAM, sVCAM1, sL-Selectin, sE-Selectin, sP-Selectin). Cell viability assays and endothelial NO production measurements were carried out on HUVEC cell cultures challenged for 24 hours with individual matched serum samples corresponding to each patient from the cohort.

Results: Serum irisin levels in the MetS and T2DM groups were significantly lower than healthy controls (p=0.004). HUVEC cell cultures challenged with the serum of patients with T2DM and MetS showed substantially lower endothelial NO production (p < 0.05), lower cell viability (p < 0.01), and higher rates of late apoptotic (p < 0.01) and necrotic cells (p < 0.05) in comparison with the ones treated with serum from healthy controls. We observed significant positive correlations between serum irisin levels and NO production (R= 0.27, p< 0.05) and cell viability (R=0.37, p< 0.05). Inverse correlations between serum irisin levels and rates of late apoptotic cells (R=-0.41, p< 0.05) and necrotic cells (R=-0.32, p< 0.05) were identified. Additionally, serum irisin levels demonstrated significantly negative correlations with sICAM2 (R=-0.3, p< 0.05) and sVCAM (R=-0.3, p< 0.05), respectively.

Conclusion: Overall, these results suggest that irisin exerts beneficial effects on endothelial integrity in the presence of adverse metabolic scenarios by maintaining endothelial cell functionality through nitric oxide production, sustaining cell viability and down regulating their late apoptosis. The loss of these protection mechanisms in patients with MetS and T2DM, which show low circulant irisin levels, translates into the detrimental functional effects on endothelial cells and their association with endothelial dysfunction markers such as the expression of leucocyte adhesion molecules.