ABSTRACT
BACKGROUND: Atorvastatin (ATV) inhibits the conversion of 3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG-CoA) to mevalonate formation and promotes lowering of the LDL cholesterol fraction. However, ATV exhibits pleiotropic metabolic actions beyond cholesterol-lowering properties. OBJECTIVE: We aimed to evaluate the effect of ATV on oxidizing species generation and cytokine secretion in Peripheral Blood Mononuclear Cells (PBMNC) of Type 2 Diabetes Mellitus (T2DM) patients in comparison to healthy control. METHODS: Both NADPH-oxidase-dependent and mitochondrial ROS generation were assessed by chemoluminescence luminol-dependent assay and fluorometric experiment, using Dichlorofluorescein Assay (DCFH-DA), respectively. IL-1ß and IL-6 were quantified by classical ELISA. RESULTS: ATV inhibited NADPH-oxidase dependent ROS generation, but showed no effect on mitochondrial ROS generation and activated IL-1ß and IL-6 secretions in PBMNC from control and T2DM patients. ROS generation and cytokine secretion in the presence of an inhibitor of Protein Kinase Cß (iPKCß) and ATV led to similar results. The secretion of IL-1ß, PDB-induced in the presence of iPKCß, but not ATV, was increased. ATV and iPKCß exacerbated PDB-induced IL-6 secretion. LPS activated the secretion of IL-1ß and IL-6 which was potentiated by ATV. CONCLUSION: ATV inhibited ROS generation and activated IL-1 ß/IL-6 secretion in PBMNC of diabetes patients. Its effect was not affected by the hyperglycemia.
Subject(s)
Antioxidants/pharmacology , Atorvastatin/pharmacology , Diabetes Mellitus, Type 2/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Leukocytes, Mononuclear/drug effects , Reactive Oxygen Species/metabolism , Adult , Aged , Aged, 80 and over , Case-Control Studies , Diabetes Mellitus, Type 2/diagnosis , Female , Humans , Leukocytes, Mononuclear/metabolism , Male , Middle Aged , NADPH Oxidases/metabolism , Protein Kinase C beta/metabolism , Secretory PathwayABSTRACT
Malondialdehyde (MDA), an end product of lipid peroxidation and biomarker for oxidative stress, and its soluble receptor (sRAGE) were evaluated in 42 patients with type 1 diabetes mellitus, but without chronic complications, during the early years after diagnosis (0-10 years) and through the further progression of the disease (10-20 and > 20 years after diagnosis). Clinical and biochemical parameters of the cohort of diabetic patients were compared with those determined in 24 healthy individuals. The median levels of MDA in plasma were similar in type 1 diabetes patients and in healthy subjects. In contrast, statistically significant increases were detected in the median values of sRAGE in patients with type 1 diabetes compared with healthy subjects (2423.75 versus 1472.75 pg/ml; p=0.001, Mann-Whitney test). However, no significant between-group differences (p>0.05) were observed in levels of sRAGE when diabetic patients were grouped according to time elapsed after diagnosis. It is concluded that increased plasma levels of sRAGE in type 1 diabetes may provide protection against cell damage and may be sufficient to eliminate excessive circulating MDA during early years after disease onset.
