Peripheral Mononuclear Cell Resistin mRNA Expression Is Increased in Type 2 Diabetic Women

Resistin has been shown to cause insulin resistance and to impair glucose tolerance in rodents, but in humans its physiological role still remains elusive. The aim of this study was to examine whether resistin mRNA expression in human peripheral mononuclear cells (PBMCs) and its corresponding plasma levels are altered in type 2 diabetes. Resistin mRNA levels were easily detectable in human PBMC, and found to be higher in DM2 compared to healthy women (P = .05). Similarly, mononuclear mRNA levels of the proinflammatory cytokines IL-1β, TNF-α, and IL-6 were all significantly higher in DM2 compared to control women (P < .001). The corresponding plasma resistin levels were slightly, but not significantly, increased in DM2 women (P = .051), and overall, they correlated significantly with BMI (r = 0.406, P = .010) and waist circumference (r = 0.516, P = .003), but not with fasting insulin levels or HOMA-IR. Resistin mRNA expression is increased in PBMC from DM2 women, together with increased expression of the inflammatory cytokines IL-1β, TNF-α, and IL-6, independent of obesity. These results suggest that resistin and cytokines might contribute to the low-grade inflammation and the increased atherogenic risk observed in these patients

Stress, the endoplasmic reticulum, and insulin resistance

Stress, such as nutrient deprivation, viral infections, inflammation, heat shock, or lipid accumulation, imposes a serious threat to the body. These stimuli, acting both on the central control stations of the stress system and its final effectors, catecholamines and glucocorticoids, and on the peripheral target tissues, can modulate insulin action in the body. Metabolic complications, such as diabetes, visceral obesity, and atherosclerosis have emerged as major health threats in the modern societies. Indeed, obesity and atherosclerosis are regarded as states of chronic low-grade inflammation, while inflammatory mediators and lipid accumulation can evoke a chronic stress at the cellular level, principally affecting the endoplasmic reticulum (ER). It has recently been shown that ER responds to metabolic stressors through a well coordinated molecular response that involves the transcriptional activation of multiple genes, the attenuation of protein synthesis and degradation of the ER-localized misfolded proteins, and the onset of apoptosis. This article examines the emerging role of stress on ER and its possible link with obesity, insulin resistance, and type 2 diabetes

High Insulin and Leptin Increase Resistin and Inflammatory Cytokine Production from Human Mononuclear Cells

Resistin and the proinflammatory cytokines, such as TNF-α, IL-6, and IL-1β, produced by adipocytes, and macrophages, are considered to be important modulators of chronic inflammation contributing to the development of obesity and atherosclerosis. Human monocyte-enriched mononuclear cells, from ten healthy individuals, were exposed to high concentrations of insulin, leptin, and glucose (alone or in combination) for 24 hours in vitro. Resistin, TNF-α, IL-6, and IL-1β production was examined and compared to that in untreated cells. High insulin and leptin concentrations significantly upregulated resistin and the cytokines. The subsequent addition of high glucose significantly upregulated resistin and TNF-α mRNA and protein secretion, while it did not have any effect on IL-6 or IL-1β production. By comparison, exposure to dexamethasone reduced TNF-α, IL-6, and IL-1β production, while at this time point it increased resistin protein secretion. These data suggest that the expression of resistin, TNF-α, IL-6, and IL-1β from human mononuclear cells, might be enhanced by the hyperinsulinemia and hyperleptinemia and possibly by the hyperglycemia in metabolic diseases as obesity, type 2 diabetes, and atherosclerosis. Therefore, the above increased production may contribute to detrimental effects of their increased adipocyte-derived circulating levels on systemic inflammation, insulin sensitivity, and endothelial function of these patients

High Insulin and Leptin Increase Resistin and Inflammatory Cytokine Production from Human Mononuclear Cells

Resistin and the proinflammatory cytokines, such as TNF-alpha, IL-6, and IL-1 beta, produced by adipocytes, and macrophages, are considered to be important modulators of chronic inflammation contributing to the development of obesity and atherosclerosis. Human monocyte-enriched mononuclear cells, from ten healthy individuals, were exposed to high concentrations of insulin, leptin, and glucose (alone or in combination) for 24 hours in vitro. Resistin, TNF-alpha, IL-6, and IL-1 beta production was examined and compared to that in untreated cells. High insulin and leptin concentrations significantly upregulated resistin and the cytokines. The subseuent addition of high glucose significantly upregulated resistin and TNF-alpha mRNA and protein secretion, while it did not have any effect on IL-6 or IL-1 beta production. By comparison, exposure to dexamethasone reduced TNF-alpha, IL-6, and IL-1 beta production, while at this time point it increased resistin protein secretion. These data suggest that the expression of resistin, TNF-alpha, IL-6, and IL-1 beta from human mononuclear cells, might be enhanced by the hyperinsulinemia and hyperleptinemia and possibly by the hyperglycemia in metabolic diseases as obesity, type 2 diabetes, and atherosclerosis. Therefore, the above increased production may contribute to detrimental effects of their increased adipocyte-derived circulating levels on systemic inflammation, insulin sensitivity, and endothelial function of these patients

Peripheral Mononuclear Cell Resistin mRNA Expression Is Increased in Type 2 Diabetic Women

Resistin has been shown to cause insulin resistance and to impair glucose tolerance in rodents, but in humans its physiological role still remains elusive. The aim of this study was to examine whether resistin mRNA expression in human peripheral mononuclear cells (PBMCs) and its corresponding plasma levels are altered in type 2 diabetes. Resistin mRNA levels were easily detectable in human PBMC, and found to be higher in DM2 compared to healthy women (P = .05). Similarly, mononuclear mRNA levels of the proinflammatory cytokines IL-1 beta, TNF-alpha, and IL-6 were all significantly higher in DM2 compared to control women (P &lt; .001). The corresponding plasma resistin levels were slightly, but not significantly, increased in DM2 women (P = .051), and overall, they correlated significantly with BMI (r = 0.406, P = .010) and waist circumference (r = 0.516, P = .003), but not with fasting insulin levels or HOMA-IR. Resistin mRNA expression is increased in PBMC from DM2 women, together with increased expression of the inflammatory cytokines IL-1 beta, TNF-alpha, and IL-6, independent of obesity. These results suggest that resistin and cytokines might contribute to the low-grade inflammation and the increased atherogenic risk observed in these patients. Copyright (C) 2008 Panayoula C. Tsiotra et al

Adiponectin levels and expression of adiponectin receptors in isolated monocytes from overweight patients with coronary artery disease

Abstract Background Adiponectin has insulin-sensitizing and anti-atherosclerotic effects, partly mediated through its action on monocytes. We aimed to determine adiponectin levels and expression of its receptors (AdipoR1 and AdipoR2) in peripheral monocytes from overweight and obese patients with coronary artery disease (CAD). Methods Fifty-five overweight/obese patients, suspected for CAD, underwent coronary angiography: 31 were classified as CAD patients (stenosis ≥ 50% in at least one main vessel) and 24 as nonCAD. Quantitative RT-PCR and flow cytometry were used for determining mRNA and protein surface expression of adiponectin receptors in peripheral monocytes. A high sensitivity multiplex assay (xMAP technology) was used for the determination of plasma adiponectin and interleukin-10 (IL-10) secreted levels. Results Plasma adiponectin levels were decreased in CAD compared to nonCAD patients (10.9 ± 3.1 vs. 13.8 ± 5.8 μg/ml respectively, p = 0.033). In multivariable analysis, Matsuda index was the sole independent determinant of adiponectin levels. AdipoR1 and AdipoR2 protein levels were decreased in monocytes from CAD compared to nonCAD patients (59.5 ± 24.9 vs. 80 ± 46 and 70.7 ± 39 vs. 95.6 ± 47.8 Mean Fluorescence Intensity Arbitrary Units respectively, p Conclusions Overweight patients with CAD compared to those without CAD, had decreased plasma adiponectin levels, as well as decreased surface expression of adiponectin receptors in peripheral monocytes. This fact together with the reduced adiponectin-induced IL-10 secretion from CAD macrophages could explain to a certain extent, an impaired atheroprotective action of adiponectin.</p

Genetic variation in the adiponectin receptor 2 (ADIPOR2) gene is associated with coronary artery disease and increased ADIPOR2 expression in peripheral monocytes

Background: Adiponectin is an adipose tissue secreted protein known for its insulin sensitising and anti-atherogenic actions. To this date two adiponectin receptors have been discovered, adiponectin receptor 1 (ADIPOR1) and adiponectin receptor 2 (ADIPOR2). The aim of this study was to investigate the association of ADIPOR2 gene variations with coronary artery disease (CAD). Methods: Eight common single nucleotide polymorphisms (SNPs) spanning the entire ADIPOR2 locus were chosen to perform association studies with anthropometric and metabolic parameters in a Greek population. They were classified as either CAD (stenosis &gt;50% in at least one main vessel) or non-CAD individuals in accordance with coronary angiography data. Genotyping was performed using a microsphere-based suspension array and the Allele Specific Primer Extension (ASPE) method. Expression of ADIPOR2 protein and mRNA in circulating CD14(+) monocytes were determined using flow cytometry and real time Polymerase Chain Reaction assays respectively. Results: There was a significant difference in the distribution of genotypes of polymorphism rs767870 of ADIPOR2 between CAD and non-CAD individuals (p = 0.017). Furthermore, heterozygotes of the rs767870 polymorphism had significantly lower Flow Mediated Dilatation (FMD) values, higher values of Intima-Media Thickness (IMT) and increased ADIPOR2 protein levels in peripheral monocytes, compared to homozygotes of the minor allele after adjustment for age, sex, waist to hip ratio and HOMA. Conclusions: Our findings suggest that variants of ADIPOR2 could be a determinant for atherosclerosis independent of insulin resistance status, possibly by affecting ADIPOR2 protein levels