Human Leukocyte/Endothelial Cell Interactions and Mitochondrial Dysfunction in Type 2 Diabetic Patients and Their Association With Silent Myocardial Ischemia

Abstract

OBJECTIVEDiabetes is associated with oxidative stress and increased mortality, but a possible correlation between leukocyte-endothelium interactions, oxidative stress, and silent myocardial ischemia (SMI) is yet to be confirmed.RESEARCH DESIGN AND METHODSMitochondrial dysfunction and interactions between leukocytes and human umbilical vein endothelial cells were evaluated in 200 type 2 diabetic patients (25 with SMI) and 60 body composition– and age-matched control subjects. A possible correlation between these parameters and the onset of SMI was explored, and anthropometric and metabolic parameters were also analyzed.RESULTSWaist, levels of triglycerides, proinflammatory cytokines (interleukin-6 and tumor necrosis factor-α), HbA1c, high-sensitivity C-reactive protein (hs-CRP), glucose, and insulin, and homeostasis model assessment of insulin resistance were higher in diabetic patients than in control subjects. However, no statistical differences in hs-CRP and insulin levels were detected when the data were adjusted for waist. None of these parameters varied between SMI and non-SMI patients. Mitochondrial function was impaired and leukocyte-endothelium interactions were more frequent among diabetic patients, which was evident in the lower mitochondrial O2 consumption, membrane potential, polymorphonuclear cell rolling velocity, and GSH/GSSG ratio, and in the higher mitochondrial reactive oxygen species production and rolling flux, adhesion, and vascular cell adhesion molecule-1 (VCAM-1) and E-selectin molecules observed in these subjects. Moreover, these differences correlated with SMI. Statistical differences were maintained after adjusting the data for BMI and waist, with the exception of VCAM-1 levels when adjusted for waist.CONCLUSIONSOxidative stress, mitochondrial dysfunction, and endothelium-inducing leukocyte-endothelium interactions are features of type 2 diabetes and correlate with SMI.

myo-Inositol Oxygenase Overexpression Accentuates Generation of Reactive Oxygen Species and Exacerbates Cellular Injury following High Glucose Ambience

“…4C), which seems to be attributable to MIOXmediated cellular events, because, following its siRNA treatment, the intensity of fluorogenic MBB and the ratio were largely restored. Such changes in the GSH/GSSG ratio have been described in diabetic patients as well (50).…”

“…5). The fact that NOX4 siRNA treatment partially blocked the generation of ROS would also suggest that ROS are derived from dual sources in MIOX-overexpressing cells under high glucose ambience, as has been described in various investigations related to diabetic nephropathy in various animal models (1,3,9,10,50).…”

Myeloperoxidase levels predicts the vascular dysfunction in patients with Type 2 Diabetes Mellitus

“…Although endothelial dysfunction and endothelial/leukocyte interactions are key features of diabetes and are thought to be a major cause of diabetes-associated vascular complications, the underlying molecular mechanisms remain unclear [14,15]. In the present study, we observed that serum myeloperoxidase levels were significantly increased in type 2 diabetic patients and also positively correlated with ACR indicating its relevance for diagnosis of vascular dysfunction.…”

Effects of metformin on mitochondrial function of leukocytes from polycystic ovary syndrome patients with insulin resistance

“…Mitochondrial mass was measured in cells treated with the fluorescent dye 10-N-nonyl acridine orange (NAO, 5! 10 K6 mol/l), which specifically binds to cardiolipin independently of DJ m (27).…”

“…A Clark-type O 2 electrode (Rank Brothers, Bottisham, UK) was used to measure O 2 consumption (27). Sodium cyanide (10 K3 mol/l) was employed to evaluate whether or not O 2 consumption was mitochondrial (95-99%).…”