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)

In patients with diabetes, non-enzymatic glycation of low-density lipoprotein (LDL) has been suggested to be involved in the development of atherosclerosis. alpha-Dicarbonyl compounds were identified as intermediates in the non-enzymatic glycation and increased levels were reported in patients with diabetes. We studied the effect of the alpha-dicarbonyl compound methylglyoxal (MG) on the physicochemical and biological properties of LDL. MG dose-dependently modifies LDL, as indicated by the formation of fluorescent products and the increase of a net negative charge. MG (10 mmol/l) induced major modifications of arginine residues (up to 85%) and minor lysine modifications (less than 6%). MG-LDL preparations generated small amounts of superoxide anion radicals as measured by the reduction of cytochrome c, but this was not accompanied by peroxidation of the polyunsaturated fatty acids of MG-LDL. MG-LDL showed diminished recognition and uptake by the human LDL receptor in cultured cells and a markedly increased plasma clearance rate in vivo in rats. The reduced association and degradation of 125I-oxidised LDL by murine macrophages indicates recognition of MG-LDL by a scavenger receptor. Surprisingly, MG-LDL caused significantly less cholesteryl ester synthesis in murine macrophages, as compared to native LDL and oxidised or acetylated LDL. Highly modified MG-LDL did not induce activation of human endothelial cells, as measured by the expression of monocyte chemoattractant protein-1 and vascular cell adhesion molecule-1.
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PMID:Effect of methylglyoxal on the physico-chemical and biological properties of low-density lipoprotein. 979 11

Migration of CD4 cells into the pancreas represents a hallmark event in the development of insulin-dependent diabetes mellitus. Th1, but not Th2, cells are associated with pathogenesis leading to destruction of islet beta-cells and disease onset. Lymphocyte extravasation from blood into tissue is regulated by multiple adhesion receptor/counter-receptor pairs and chemokines. To identify events that regulate entry of CD4 cells into the pancreas, we transferred Th1 or Th2 cells induced in vitro from islet-specific TCR transgenic CD4 cells into immunodeficient (NOD.scid) recipients. Although both subsets infiltrated the pancreas and elicited multiple adhesion receptors (peripheral lymph node addressin, mucosal addressin cell adhesion molecule-1, LFA-1, ICAM-1, and VCAM-1) on vascular endothelium, entry/accumulation of Th1 cells was more rapid than that of Th2 cells, and only Th1 cells induced diabetes. In vitro, Th1 cells were also distinguished from Th2 cells by the capacity to synthesize several chemokines that included lymphotactin, monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1alpha, whereas both subsets produced macrophage inflammatory protein-1beta. Some of these chemokines as well as RANTES, MCP-3, MCP-5, and cytokine-response gene-2 (CRG-2)/IFN-inducible protein-10 (IP-10) were associated with Th1, but not Th2, pancreatic infiltrates. The data demonstrate polarization of chemokine expression by Th1 vs Th2 cells, which, within the microenvironment of the pancreas, accounts for distinctive inflammatory infiltrates that determine whether insulin-producing beta-cells are protected or destroyed.
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PMID:Islet-specific Th1, but not Th2, cells secrete multiple chemokines and promote rapid induction of autoimmune diabetes. 1007 90

Vascular endothelial growth factor (VEGF) has been suggested to play a role in the pathogenesis of diabetic vascular complications. In the present study, we investigated whether expression of monocyte chemoattractant protein-1 (MCP-1), a chemokine that has been proposed to recruit leukocytes to sites of inflammation, neovascularization, and vascular injury, can be modulated by VEGF in bovine retinal microvascular endothelial cells (BRECs). VEGF induced expression of MCP-1 mRNA in BRECs in a concentration- and time-dependent manner. Secretion of MCP-1 into the culture medium of BRECs treated with VEGF for 24 h was increased by 2.2-fold compared with the control. Inhibitors of transcription factor NF-kappaB, N-alpha-tosyl-L-lysine chloromethylketone (TLCK) and N-acetylcysteine (NAC), as well as an inhibitor of the extracellular signal-regulated kinase (ERK) pathway, PD 98059, attenuated VEGF-induced expression of MCP-1 mRNA. Using electrophoretic gel mobility shift assay, we observed that VEGF stimulated binding activity of NF-kappaB. VEGF-induced NF-kappaB activation was inhibited by TLCK and NAC, but not by PD 98059. Binding activity of transcription factor AP-1, which is suggested to regulate induction of the MCP-1 gene together with NF-kappaB, was also stimulated by VEGF. PD 98059 inhibited the VEGF-induced activation of AP-1. These results indicate that VEGF induces MCP-1 expression in BRECs most likely by activating NF-kappaB and AP-1 via ERK-independent and -dependent pathways. Activation of NF-kappaB and induction of MCP-1 by VEGF in microvascular endothelial cells may contribute to the development of diabetic vascular complications.
Diabetes 1999 May
PMID:Vascular endothelial growth factor activates nuclear factor-kappaB and induces monocyte chemoattractant protein-1 in bovine retinal endothelial cells. 1033 20

Insulin resistance is one of the risk factors for the progression of atherosclerosis and glomerulosclerosis. Recently, the new oral insulin-sensitizing agent troglitazone has been thought to offer potential in the treatment of diabetes. If adopted for this use, it might be helpful in protecting against the development of atherosclerosis and microvascular complications via its improvement of insulin resistance. However, it has not yet been clarified whether troglitazone acts directly on the vascular cells and inhibits the progression of atherosclerosis, including glomerulosclerosis. Meanwhile, monocyte chemoattractant protein-1 (MCP-1) is known to play an important role in the pathogenesis of atherosclerosis and glomerulosclerosis through the induction of monocyte migration. Therefore, we investigated the effect of troglitazone on the expression of MCP-1 in human mesangial cells (HMCs). HMCs were treated with or without troglitazone (1 or 10 micromol/L) in the presence or absence of tumor necrosis factor alpha (TNF-alpha) at various concentrations (50 or 500 ng/mL), and then MCP-1 secretion from the HMCs was measured. We found that TNF-alpha increased the secretion of MCP-1 by 55-fold versus the control and troglitazone significantly inhibited this TNF-alpha-induced increase in MCP-1 secretion (49.3%). Moreover, Northern blot analysis showed that troglitazone decreased the MCP-1 mRNA level in HMCs. We demonstrated that alpha-tocopherol also inhibited TNF-alpha-induced MCP-1 production in HMCs, although its effects were not as strong as troglitazone. The present study indicates that troglitazone may prevent the progression of atherosclerosis by inhibiting MCP-1 expression in mesangial cells.
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PMID:Inhibitory effect of troglitazone on tumor necrosis factor alpha-induced expression of monocyte chemoattractant protein-1 in human mesangial cells. 1069 Sep 39

Previously, we have reported that the lipoprotein fraction containing intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) isolated from diabetics stimulates an atherogenic cytokine in cultured endothelial cells. To study which lipoprotein fraction isolated from diabetics can modulate the gene expression in endothelial cells, we isolated IDL and LDL fractions from 14 type 2 diabetics and seven age- and BMI- adjusted non-diabetics. We measured the effects of the lipoproteins on mRNA expression of atherogenic molecules in cultured endothelial cells. We found that the IDL fraction stimulated monocyte chemoattractant protein-1 (MCP-1) mRNA expression in endothelial cells as time- and dose-dependent fashions, while the LDL fraction was not effective. IDL isolated from diabetics also increased not only platelet-derived growth factor B-chain, but also intercellular adhesion molecule-1 mRNA contents. Furthermore, the HbA(1c) levels in diabetics were significantly correlated with their abilities of IDL to increase MCP-1 mRNA content in the cells and the increment coincided with the increase in MCP-1 protein release into culture media. These results indicate that qualitative as well as quantitative changes in IDL fraction in diabetes are atherogenic through stimulating gene expression of atherogenic molecules in endothelial cells.
Diabetes Res Clin Pract 2000 May
PMID:IDL can stimulate atherogenic gene expression in cultured human vascular endothelial cells. 1080 50

Advanced glycation end product (AGE) activation of the signal-transducing receptor for AGE (RAGE) has been linked to a proinflammatory phenotypic change within cells. However, the precise intracellular signaling pathways involved have not been elucidated. We demonstrate here that human serum albumin modified with N(epsilon)-(carboxymethyl)lysine (CML), a major AGE adduct that progressively accumulates with aging, diabetes, and renal failure, induced nuclear factor (NF)-kappaB-driven reporter gene expression in human monocytic THP-1 cells. The NF-kappaB response was blocked with a synthetic peptide corresponding to the putative ligand-binding domain of RAGE, with anti-RAGE antiserum, and by coexpression of truncated receptors lacking the intracellular domain. Signal transduction from RAGE to NF-kappaB involved the generation of reactive oxygen species, since reporter gene expression was blocked with the antioxidant N-acetyl-L-cysteine. CML-modified albumin produced rapid transient activation of tyrosine phosphorylation, extracellular signal-regulated kinase 1 and 2, and p38 mitogen-activated protein kinase (MAPK), but not c-Jun NH(2)-terminal kinase. RAGE-mediated NF-kappaB activation was suppressed by the selective p38 MAPK inhibitor SB203580 and by coexpression of a kinase-dead p38 dominant-negative mutant. Activation of NF-kappaB by CML-modified albumin increased secretion of proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta, and monocyte chemoattractant protein-1) severalfold, and inhibition of p38 MAPK blocked these increases. These results indicate that p38 MAPK activation mediates RAGE-induced NF-kappaB-dependent secretion of proinflammatory cytokines and suggest that accelerated inflammation may be a consequence of cellular activation induced by this receptor.
Diabetes 2001 Jun
PMID:Requirement for p38 and p44/p42 mitogen-activated protein kinases in RAGE-mediated nuclear factor-kappaB transcriptional activation and cytokine secretion. 1137 53

We investigated the capacity of human islets to produce monocyte chemoattractant protein-1 (MCP-1). Primary cultures of pancreatic islets expressed and secreted MCP-1, as determined by Northern blot, immunohistochemistry, in situ hybridization, and enzyme-linked immunosorbent assay. The produced MCP-1 was biologically active as it attracted monocytes in chemotaxis assay, and chemotactic activity was almost abrogated by a neutralizing anti-MCP-1 monoclonal antibody. Expression of MCP-1 was increased by primary inflammatory cytokines (interleukin-1 beta, tumor necrosis factor-alpha) and lipopolysaccharide at both the mRNA and protein levels but not by glucose. However, MCP-1 did not modulate insulin secretion. MCP-1 secreted by pancreatic islets plays a relevant role in the clinical outcome of islet transplant in patients with type 1 diabetes. In fact, low MCP-1 secretion resulted as the most relevant factor for long-lasting insulin independence. This finding opens new approaches in the management of human islet transplantation. Finally, the finding that MCP-1 appears constitutively present in normal human islet beta-cells (immunohistochemistry and in situ hybridization), in the absence of an inflammatory infiltrate, suggests that this chemokine could have functions other than monocyte recruitment and opens a new link between the endocrine and immune systems.
Diabetes 2002 Jan
PMID:Human pancreatic islets produce and secrete MCP-1/CCL2: relevance in human islet transplantation. 1175 23

According to the model of "response to injury," the arterial endothelium is occasionally injured in hyperlipidemia, hypertension, diabetes mellitus and in other states known as risk factors. The ensuing inflammatory response is modulated by cytokines and growth factors, among them platelet-derived growth factor (PDGF), and monocyte chemoattractant protein-1 (MCP-1). In two independent studies, we demonstrated that mRNA levels for PDGF-A and -B and for MCP-1 are reduced after ingestion of n-3 fatty acids by human volunteers. This reduction persists after monocyte stimulation/differentiation by adherence. Moreover, the reduction is brought about only by dietary n-3 fatty acids and not by other classes of unsaturated fatty acids (n-6 or n-9). This appears to be one major mechanism of action of reduced progression/increased regression of established coronary artery disease by ingestion of 1.5 g/d n-3 fatty acids, as assessed by coronary angiography in a randomized placebo-controlled double-blind intervention study in 223 patients. The study was conducted according to "Good Clinical Practice," comprehensive rules regulating investigations with pharmaceutical compounds. Together, our investigations lend support to the importance of PDGF-A, PDGF-B, and MCP-1 in the pathogenesis of atherosclerosis, and the beneficial role of n-3 fatty acids therein.
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PMID:The effect of n-3 fatty acids on coronary atherosclerosis: results from SCIMO, an angiographic study, background and implications. 1183

Advanced glycation end products (AGE) have been implicated in the pathogenesis of glomerulosclerosis in diabetes. However, their involvement in the development of the early phase of diabetic nephropathy has not been fully elucidated. We investigated the effects of AGE on growth and on vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1) expression in human cultured mesangial cells. We prepared three immunochemically distinct AGE by incubating bovine serum albumin (BSA) with glucose, glyceraldehyde, or glycolaldehyde. When human mesangial cells were cultured with various types of AGE-BSA, viable cell numbers as well as DNA syntheses were significantly decreased. All of the AGE-BSA were found to significantly increase p53 and Bax protein accumulations and subsequently induce apoptotic cell death in mesangial cells. An antioxidant, N-acetylcysteine, significantly prevented the AGE-induced apoptotic cell death in mesangial cells. Human mesangial cells stimulated prostacyclin production by co-cultured glomerular endothelial cells. Furthermore, various types of AGE-BSA were found to up-regulate the levels of mRNAs for VEGF and stimulate the secretion of VEGF and MCP-1 proteins in mesangial cells. The results suggest that AGE disturbed glomerular homeostasis by inducing apoptotic cell death in mesangial cells and elicited hyperfiltration and microalbuminuria by stimulating the secretion of VEGF and MCP-1 proteins, thereby being involved in the pathogenesis of the early phase of diabetic nephropathy.
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PMID:Advanced glycation end product-induced apoptosis and overexpression of vascular endothelial growth factor and monocyte chemoattractant protein-1 in human-cultured mesangial cells. 1191 19

Low-density lipoprotein (LDL) may undergo more glycation or oxidation in patients with diabetes mellitus than in nondiabetic subjects. We investigated whether glycoxidized LDL (goLDL) induces monocyte chemoattractant protein-1 (MCP-1) mRNA expression through activation of nuclear factor-kappaB (NFkappaB), and determined the effect of nitric oxide (NO) on MCP-1 mRNA expression in human umbilical vein endothelial cells (HUVEC). Oxidized (oxLDL) or goLDL enhanced MCP-1 mRNA expression in HUVEC, and preincubation with NOR3, a NO donor, abrogated such stimulation. goLDL increased NFkappaB-DNA binding activity in HUVEC and this effect was also suppressed by NOR3. We measured lysophosphatidylcholine (lyso-PC) contents in modified LDL using electrospray ionization liquid chromatography/mass spectrometry (LC/MS) to identify its molecular species. MCP-1 mRNA expression and NFkappaB activation correlated significantly with palmitoyl- and stearoyl-lyso-PC contents in LDL. Our results suggest that LDL modified by glycation and oxidation may contribute to the development of accelerated atherosclerosis in the presence of diabetes, a process that may be prevented by increased vascular NO availability.
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PMID:Glycoxidized low-density lipoprotein enhances monocyte chemoattractant protein-1 mRNA expression in human umbilical vein endothelial cells: relation to lysophosphatidylcholine contents and inhibition by nitric oxide donor. 1220 Jul 57


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