Autophagy, oxidative stress and endoplasmic reticulum stress are upregulated in the leukocytes of type 2 diabetic patients and are related to enhanced leukocyte-endothelial interactions

Abstract

We aimed to assess oxidative stress, ER stress and autophagy in the leukocytes of T2D patients and to establish potential correlations among these mechanisms and leukocyte-endothelial interactions. 267 T2D patients and 193 healthy controls were enrolled in the study. Anthropometric and metabolic determinations were studied and peripheral blood leukocytes were isolated. Reactive oxygen species (ROS) production, both total and mitochondrial, was enhanced in the leukocytes of T2D patients. Furthermore, we observed higher levels of the ER stress markers GRP78, sXBP1, ATF6, P-eIF2α and CHOP in T2D vs. control subjects. Autophagy was also increased in T2D subjects, as LC3-II and Beclin1 protein levels were upregulated with respect to the control group. Leukocyte rolling velocity over the endothelium was decreased in T2D patients, and rolling flux and adhesion were increased. Interestingly, we observed correlations among oxidative/ER stress markers and autophagy, with these processes increasing in parallel. Leukocyte endothelial interactions correlated with increased ER stress. Therefore, autophagy is activated in the leukocytes of T2D patients and oxidative and ER stress signalling pathways are implicated in the induction of autophagy. Moreover, increased ER stress correlates with exacerbated leukocyte-endothelial interactions in T2D patients, which could contribute to the development of diabetic vascular complications.