Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diabetic patients have an increased cardiovascular risk. We propose to characterize the endothelial dysfunction in a disease-specific in vitro model. Human saphenous vein endothelial cells (HSVEC) were isolated from coronary artery bypass patients without and with non-insulin-dependent diabetes mellitus. Growth kinetics and proinflammatory responses (expression of adhesion molecules, cytokines) were documented under non-stimulating conditions. Diabetic HSVEC showed delayed growth kinetics with reduced cell densities of about 40%. During exponential growth of diabetic EC, the surface expression of adhesion molecules was increased 10-fold (p< or =0.05). However, in a monolayer the expression adapted to low levels of non-diabetic EC. In addition, diabetic EC produced significantly more soluble E-selectin, VCAM-1, IL-6 and MCP-1. Our results suggest a link between the pathologically proinflammatory basic state of diabetic EC and the endothelial dysfunction in diabetic disease. Therefore, this in vitro model could be used for investigating early dysfunction and environmental effects on pathological endothelium.
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PMID:Development of a disease-specific model to evaluate endothelial dysfunction in patients with diabetes mellitus. 1741 93

Type 2 diabetes and obesity with enlarged fat cells are associated with low-grade systemic inflammation, impaired adipogenesis as well as the recruitment of inflammatory cells into the adipose tissue. Cytokines like TNFalpha and IL-6 are secreted by the inflammatory cells and have been shown to impair normal adipocyte differentiation. An important mechanism whereby these cytokines inhibit adipogenesis is by maintaining an active Wnt-signaling pathway. Also other cytokines like MCP-1 and resistin are involved in the inflammatory process and are secreted by macrophages. If these cytokines also affect Wnt-signaling and adipocyte differentiation is currently unclear. In the present study, we show that while TNFalpha is able to maintain an active Wnt-signaling, induce inflammation and completely block adipose cell differentiation, no effect was found by either MCP-1 or resistin on these processes. Addition of the thiazolidinedione, pioglitazone, was found to antagonize the effect of TNFalpha on the Wnt-signaling process and, consequently, promote adipogenesis.
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PMID:Wnt-signaling is maintained and adipogenesis inhibited by TNFalpha but not MCP-1 and resistin. 1744 72

Adipokines including chemokines are able to induce insulin resistance in human skeletal muscle cells, which may also be relevant for the observed link between obesity and diabetes. This study is aimed to analyze the expression of chemokine CC motif receptors (CCRs) in the insulin-resistant state in human skeletal muscle cells. Differentiated skeletal muscle cells were incubated for 24-72 hours with high concentrations of glucose and insulin (GI) or TNFalpha. In addition, myocytes were co-stimulated with monocyte chemotactic protein (MCP)-1 or adipocyte-conditioned medium (CM) and TNFalpha for 24 and 48 hours. Treatment with GI rapidly induced insulin resistance whereas TNFalpha impaired insulin signaling in a more chronic fashion (48-72 h). CM and MCP-1 also induced insulin resistance that was, however, not increased by co-stimulation with TNFalpha. Expression of CCR2 was decreased during differentiation but up-regulated in insulin-resistant myocytes after treatment with GI (24-72 h) and TNFalpha (72 h). Expression of CCR4 and CCR10 was down-regulated after treatment with TNFalpha, MCP-1, and CM. Our data show that the expression of CCR2, CCR4, and CCR10 is differentially regulated by different insulin resistance-inducing treatments in myotubes. However, we could not find a clear correlation between the level of insulin resistance and CCR expression in myotubes. In conclusion, we propose that upregulation of CCR2 in skeletal muscle does not represent a major step leading to muscle insulin resistance.
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PMID:Expression of chemokine receptors in insulin-resistant human skeletal muscle cells. 1744 60

We investigated that the association of MCP-1 polymorphism at position -2518 with insulin sensitivity and insulin secretion by measuring the fasting and post-challenge glucose and insulin levels during 75g OGTT in 409 non-diabetic Japanese subjects. The blood sampling was performed before glucose loading and after 30 and 120 min. Polymorphism was evaluated by PCR-RFLP method by genomic DNA isolated from peripheral blood leukocytes. The genotype distribution was 44.8% for G/G, 46.0% for G/A and 9.2% for A/A. The plasma glucose levels were significantly increased in A/A as compared to G/G (p<0.05), but it was not compared with G/A at 120 min. The serum insulin levels were significantly increased in A/A as compared to G/A (p<0.05) or G/G (p<0.05) at 30 min. Moreover, the serum insulin levels in A/A were significantly increased compared with G/A (p<0.02) or G/G (p<0.005) at 120 min. Elevation in post-challenge glucose (120 min) and insulin levels (30 and 120 min) suggests that reduced insulin sensitivity during glucose loading occurs in subjects with A/A polymorphism. The present study demonstrates that the A/A polymorphism of the MCP-1 gene at position -2518 is associated with insulin resistance during glucose loading in non-diabetic Japanese subjects.
Diabetes Res Clin Pract 2007 Nov
PMID:Monocyte chemoattractant protein-1 promoter -2518 polymorphism is associated with post-challenge insulin and glucose levels in non-diabetic Japanese subjects. 1749 Jul 77

Carotid artery stenosis (CS) is a well-established risk factor for stroke. Increased proinflammatory chemokines, enhanced metallothionein (MT), and altered metal homeostasis may play roles in atherosclerosis progression and plaque destabilization. MT may sequester zinc during chronic inflammation, provoke zinc deficiency, and modulate NK cell cytotoxicity. A recent investigation of older patients with diabetes and atherosclerosis showed an association between the -209 A/G MT2A polymorphism, CS, and zinc status. In this study, we evaluated the relationship between two MT2A polymorphisms (-209 and + 838 locus), metal status, and inflammatory/immune response in older patients with CS only (the CS1 group) or with CS and previous cerebrovascular episodes (transient ischemic attack or stroke) (the CS2 group). A total of 506 individuals (188 CS1, 100 CS2, and 218 healthy controls) were studied. Atherosclerotic patients (CS1 and CS2) showed increased levels of MT, MCP-1, and RANTES, reduced NK cell cytotoxicity, and altered trace element concentrations (zinc, copper, magnesium, iron). The +838 C/G MT2A polymorphism was differently distributed in CS1 and CS2 patients, who displayed the GG genotype (C-) with significantly higher frequency than elderly controls. C- carriers showed increased MCP-1 and decreased NK cell cytotoxicity, CD56+ cells, and intracellular zinc availability along with decreased zinc, copper, and magnesium content in erythrocytes and increased iron in plasma. C- carriers also showed a major incidence of soft carotid plaques. In conclusion, the +838 C/G MT2A polymorphism seems to influence inflammatory markers, zinc availability, NK cell cytotoxicity, and trace element status, all of which may promote CS development.
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PMID:The +838 C/G MT2A polymorphism, metals, and the inflammatory/immune response in carotid artery stenosis in elderly people. 1762 11

Elevated blood levels of the proinflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), and MCP-1 (monocyte chemoattractant protein-1) increase insulin resistance and the risk of cardiovascular disease (CVD). There is no previous study that has examined the effect of ketosis and trivalent chromium on IL-6, IL-8, or MCP-1 secretion in any cell type or in human or animal model. The authors examined the hypothesis that ketosis increases and trivalent chromium decreases the levels of cytokines and oxidative stress in diabetes using a U937 monocyte cell culture model. Cells were cultured with control, high glucose (HG), and acetoacetate (AA) in the absence or presence (0.5-10 microM) of CrCl(3), chromium picolinate (Cr-P), or chromium niacinate (Cr-N) at 37 degrees C for 24 h. The data show a significant stimulation of IL-6, IL-8, and MCP-1 secretion and an increase in oxidative stress in cells treated with HG or AA. The effect of HG on cytokine secretion was reduced by Cr-N, and to a lesser extent by CrCl(3) and Cr-P. The effect of HG on oxidative stress was reduced by Cr-N and CrCl 3, but not by Cr-P. Similarly, Cr-N decreased the cytokine secretion in HG + AA-treated cells. Cr-N significantly decreased standard oxidant (H(2)O(2)) induced cytokine secretion, which suggests that reduction of cytokine secretion by Cr-N is in part mediated by its antioxidative effect. In a cell culture model, Cr-N appears to be the most effective form of chromium in inhibiting oxidative stress and proinflammatory cytokine secretion by monocytes. This study suggests that chromium niacinate supplementation may be useful in reducing vascular inflammation and the risk of CVD in diabetes.
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PMID:High glucose and ketosis (acetoacetate) increases, and chromium niacinate decreases, IL-6, IL-8, and MCP-1 secretion and oxidative stress in U937 monocytes. 1766 66

Adipokines are involved in the obesity-induced chronic inflammatory response that plays a crucial role in the development of obesity-related pathologies such as type II diabetes and atherosclerosis. We here demonstrate that capsaicin, a naturally occurring phytochemical, can suppress obesity-induced inflammation by modulating adipokine release from and macrophage behavior in obese mice adipose tissues. Capsaicin inhibited the expressions of IL-6 and MCP-1 mRNAs and protein release from the adipose tissues and adipocytes of obese mice, whereas it enhanced the expression of the adiponectin gene and protein. The action of capsaicin is associated with NF-kappaB inactivation and/or PPARgamma activation. Moreover, capsaicin suppressed not only macrophage migration induced by the adipose tissue-conditioned medium, but also macrophage activation to release proinflammatory mediators. Capsaicin may be a useful phytochemical for attenuating obesity-induced inflammation and obesity-related complications.
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PMID:Capsaicin, a spicy component of hot peppers, modulates adipokine gene expression and protein release from obese-mouse adipose tissues and isolated adipocytes, and suppresses the inflammatory responses of adipose tissue macrophages. 1771 33

Lipoprotein-associated phospholipase (Lp-PL)A2 is a recently described and potentially useful plasma biomarker associated with cardiovascular disease. The enzyme, originally named platelet-activating factor acetylhydrolase (PAF-AH), has two prominent biological activities. First, it inactivates the prominent proinflammatory mediator PAF-AH. Second, Lp-PLA2 hydrolyzes oxidatively modified polyunsaturated fatty acids producing lysophosphatidylcholine (LysoPC) and oxidized nonesterified fatty acids (OxNEFA). OxNEFA have potent monocyte chemotactic activity and LysoPC upregulates inflammatory mediators, including cytokines, adhesion molecules and the chemotactic mediator MCP-1. Whereas the first activity may be considered antiatherogenic, the prevailing consensus is that Lp-PLA2 is positively associated with coronary disease. Initial evidence for this came largely from the West of Scotland Coronary Prevention Study Group (WOSCOPS) in which Lp-PLA2 was compared among 580 cases and 1160 age-matched controls. In addition, the quantitative contribution of Lp-PLA2 to risk assessment was assessed in a substudy of the Atherosclerosis Risk in Communities (ARIC) study. Although positively correlated with disease, the addition of Lp-PLA2 did not appreciably enhance risk prediction beyond the model employing traditional risk factors. Thus, population screening for subclinical disease using Lp-PLA2 does not appear to be warranted. Presently, the most useful application of Lp-PLA2 testing is to adjust individual risk assessment for those patients found to be at borderline risk using traditional models. In this regard, the marker appears to be particularly useful for gauging risk among patients with metabolic syndrome or diabetes. There is observational evidence that Lp-PLA2 may be a useful guide for therapeutic efficacy, but prospective evaluation will be required. Considering the large number of biomarkers currently under evaluation, it is probable that useful additions to existing risk models may be found in combinatorial models.
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PMID:Lipoprotein-associated phospholipase A2: a new biomarker for cardiovascular risk assessment and potential therapeutic target. 1789 60

The aim of this study was to determine whether pitavastatin may prevent the progression of atherosclerotic changes in hyperlipidemic patients. Seventy-five hyperlipidemic patients with and without type 2 diabetes were enrolled to receive pitavastatin 2 mg daily. Cell adhesion molecules (sCD40L, sP-selectin, sE-selectin, and sL-selectin), chemokines (MCP-1 and RANTES) and adiponectin were measured at baseline and after 3 and 6 months of pitavastatin treatment. Adiponectin levels prior to pitavastatin treatment in hyperlipidemic patients with and without diabetes were lower than levels in normolipidemic controls. Both total cholesterol and the LDL-cholesterol (LDL-C) decreased significantly after pitavastatin administration. Additionally, hyperlipidemic patients with type 2 diabetes exhibited a significant increase in adiponectin levels after pitavastatin treatment (before vs. 3 months, 6 months, 2.81+/-0.95 vs. 3.84+/-0.84 microg/ml (p<0.01), 4.61+/-1.15 mug/ml (p<0.001)). Furthermore, hyperlipidemic diabetics exhibited significant decreases in sE-selectin and sL-selectin levels after 6 months of pitavastatin treatment (sE-selectin, before vs. 6 months, 74+/-21 vs. 51+/-10 ng/ml, p<0.05; sL-selectin, before vs. 6 months, 896+/-141 vs. 814+/-129 ng/ml, p<0.05). In addition, adiponectin showed significant correlation with sE-selectin and sL-selectin in diabetic hyperlipidemia. However, MCP-1, RANTES and sCD40L did not exhibit any differences before or after pitavastatin administration. These results suggest that pitavastatin possesses an adiponectin-dependent anti-atherosclerotic effect in hyperlipidemic patients with type 2 diabetes in addition to its lowering effects on total cholesterol and LDL-C.
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PMID:Correlation between adiponectin and reduction of cell adhesion molecules after pitavastatin treatment in hyperlipidemic patients with type 2 diabetes mellitus. 1792 Jun 63

Diabetic nephropathy is increasingly considered as an inflammatory disease characterized by leukocyte infiltration at every stage of renal involvement. Chemokines are important participators in the recruitment of specific subpopulations of inflammatory cells into renal compartments. MCP-1/CCL2 has been identified as having a key role in monocyte/macrophage recruitment in animal models of diabetic nephropathy, as well as in renal biopsies from patients with type 1 and 2 diabetes. Various factors of the diabetic milieu can induce renal expression of MCP-1/CCL2 and cell adhesion molecules, and thereby mediate the macrophage responses that ultimately cause renal injury. Possibly fractalkine/CX3CL1 functions as an arrest chemokine in monocyte/macrophage adhesion before migration into the kidney. T lymphocyte recruitment is influenced by up-regulation of RANTES/CCL5 throughout glomerular as well as tubulointerstitial structures as well as IP-10/CXCL10 mainly in the tubulointerstitium. Improved knowledge of gene polymorphisms of chemokines and their receptors could be useful to predict onset of diabetic nephropathy and define its progression. Blockade of the renin-angiotensin-aldosterone system is currently the only clinically used strategy to treat the inflammatory process in diabetic nephropathy. Newer strategies point to chemokine receptor antagonists and even to immunosuppressive therapy, but still remain in the experimental stage.
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PMID:The role of chemokines and chemokine receptors in diabetic nephropathy. 1798 2


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