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)

IgA1 was identified as the most prominent O-glycosylated protein of human serum. Desialylation by bacterial (Clostridium perfringens) neuraminidase rendered dot-blotted IgA1 recognizable by the naturally occurring serum antibody (anti-T) directed against Thomsen-Friedenreich antigen, Galbeta1-->3GalNAc-alpha-. On Western blot of serum O-glycosylated proteins anti-T recognized nearly all the bands including IgA1 as did the T antigen-specific animal lectin galectin-1 but only after their desialylation. Agglutination of desialylated human erythrocytes by anti-T was effectively inhibited by desialylated IgA1, but not by native IgA1 or other immunoglobulins. Desialylation of serum by neuraminidase led to significantly increased formation of immune complexes containing IgM, the major immunoglobulin type in anti-T on one hand and O-glycosylated proteins/IgA1 on the other. In further evidence for anti-T-desialylated IgA1 immune complex formation, purified anti-T added to desialylated, but not native serum led to formation of additional IgA-IgM immune complexes. Also neuraminidase treatment significantly reduced the titre of free (non-immune complexed) anti-T in serum, while selective removal of anti-T by affinity absorption resulted in considerable decrease in the amount of IgA1 that got converted to immune complexes following enzymatic desialylation of serum. Formation of immune complex between anti-T and neuraminidase-treated IgA1 in serum may be significant since many disease pathogens release neuraminidase and since IgA1 is a powerful ligand for tissue galectin-1 more so after desialylation. Diabetes also raises serum IgA and neuraminidase levels.
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PMID:IgA1 desialylated by microbial neuraminidase forms immune complex with naturally occurring anti-T antibody in human serum. 1804 97

Type 2 diabetes is associated with an increased incidence of coronary heart disease and cardiovascular complications. One crucial step in the initiation and progression of atherosclerosis is the unregulated uptake of oxidized low-density lipoprotein (oxLDL) by vascular wall components through scavenger receptors. Identification of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) as the major receptor for oxLDL in endothelial cells has provided a new clue to the mechanisms involved in oxLDL accumulation in the vessel wall. This receptor, by facilitating the uptake of oxLDL, induces endothelial dysfunction and mediates numerous oxLDL-induced proatherogenic effects. Besides endothelial cells, LOX-1 is also expressed by smooth muscle cells and macrophages. In these cells, LOX-1 may function as a scavenger receptor and promote foam cell formation. Notably, LOX-1 is induced by multiple stimuli relevant to atherogenesis and inflammation and is up-regulated in various proatherogenic conditions, including diabetes. As such, activation of vascular cells by oxLDL through LOX-1 may be relevant to the development and progression of human diabetic vasculopathy. This review summarizes recent advances related to the role of LOX-1 in atherosclerosis, its regulation by metabolic and inflammatory factors relevant to diabetes and the impact of these factors on LOX-1-mediated proatherogenic events linked to diabetic vasculopathy.
Curr Diabetes Rev 2007 May
PMID:Diabetic vasculopathy and the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). 1822 Jun 61

Plasma is an important biological material for biomarker discovery. However, the wide dynamic range in protein concentration remains a major challenge. In this paper, we introduce the development of a proteomic platform for analysis of plasma samples. The method utilizes a double fractionation approach which combines the MARS immunodepletion column with multi-lectin affinity chromatography, M-LAC, to deplete the most abundant proteins in plasma, the majority of which are glycosylated. To determine the suitability of this methodology, we applied the workflow described in this study to a sample set composed of four groups: a control pool and three different disease pools: obesity, diabetes, and hypertension. We were able to identify changes in the level of several proteins; for example, a protein such as angiotensinogen was found to be present at high levels in patients with obesity plus diabetes and hypertension. On the other hand, apolipoprotein CI was shown to be elevated in all disease groups. A review of the literature supported our observation. The methodology presented in this report was shown to be effective for profiling changes in the plasma proteome of subjects with obesity and its associated complications such as diabetes and hypertension.
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PMID:A two step fractionation approach for plasma proteomics using immunodepletion of abundant proteins and multi-lectin affinity chromatography: Application to the analysis of obesity, diabetes, and hypertension diseases. 1830 31

Increasing evidence indicates that mammalian SIRT1 mediates calorie restriction and influences lifespan regulating a number of biological molecules such as FoxO1. SIRT1 controls the angiogenic activity of endothelial cells via deacetylation of FoxO1. Endothelial dysfunction and reduced new blood vessel growth in diabetes involve a decreased bioactivity of endothelial progenitor cells (EPCs) via repression of FoxO1 transcriptional activity. The relative contribution of SIRT1 with respect to the direct effects of high glucose on EPC number is poorly understood. We report that treatment of EPCs with high glucose for 3 days determined a consistent downregulation of EPC positive to DiLDL/lectin staining and, interestingly, this was associated with reduced SIRT1 expression levels and enzyme activity, and increased acetyl-FoxO1 expression levels. Moreover, EPCs responded to high glucose with major changes in the expression levels of cell metabolism-, cell cycle-, and oxidative stress-related genes or proteins. Proteomic analysis shows increased expression of nicotinamide phosphoribosyl transferase and mitochondrial superoxide dismutase whereas a glucose-related heat shock protein is reduced. These findings show that SIRT1 is a critical modulator of EPCs dysfunction during alteration of glucose metabolism.
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PMID:High glucose downregulates endothelial progenitor cell number via SIRT1. 1842 18

Galectin 3 (Gal-3) is an antiapoptotic and a proinflammatory lectin. We hypothesized that the proinflammatory properties of Gal-3 may influence disease induction in the multiple low doses of streptozotocin model of diabetes. Diabetes was induced in C57BL/6 Gal-3(+/+) and Gal-3(-/-) mice and disease monitored by blood glucose level, immuno-histology, insulin content of islets and expression of the proinflammatory cytokines, TNF-alpha, IFN-gamma, IL-17, and iNOS in pancreatic lymph nodes. Gal-3(+/+) mice developed delayed and sustained hyperglycemia, mononuclear cellular infiltration and reduced insulin content of islets accompanied with expression of proinflammatory cytokines. Gal-3(-)/(-) mice were relatively resistant to diabetogenesis as evaluated by glycemia, quantitative histology and insulin content. Further, we observed the weaker expression of IFN-gamma and complete absence of TNF-alpha, and IL-17 in draining pancreatic lymph nodes. Macrophages, the first cells that infiltrate the islet in this model of diabetes, produce less TNF-alpha and NO in Gal-3(-/-) mice. Thus, Gal-3 is involved in immune mediated beta cell damage and is required for diabetogenesis in this model of disease.
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PMID:Targeted disruption of the galectin-3 gene results in decreased susceptibility to multiple low dose streptozotocin-induced diabetes in mice. 1884 86

Healthy vascular function is primarily regulated by several factors including EDRF (endothelium-dependent relaxing factor), EDCF (endothelium-dependent contracting factor) and EDHF (endothelium-dependent hyperpolarizing factor). Vascular dysfunction or injury induced by aging, smoking, inflammation, trauma, hyperlipidaemia and hyperglycaemia are among a myriad of risk factors that may contribute to the pathogenesis of many cardiovascular diseases, such as hypertension, diabetes and atherosclerosis. However, the exact mechanisms underlying the impaired vascular activity remain unresolved and there is no current scientific consensus. Accumulating evidence suggests that the inflammatory cytokine TNF (tumour necrosis factor)-alpha plays a pivotal role in the disruption of macrovascular and microvascular circulation both in vivo and in vitro. AGEs (advanced glycation end-products)/RAGE (receptor for AGEs), LOX-1 [lectin-like oxidized low-density lipoprotein receptor-1) and NF-kappaB (nuclear factor kappaB) signalling play key roles in TNF-alpha expression through an increase in circulating and/or local vascular TNF-alpha production. The increase in TNF-alpha expression induces the production of ROS (reactive oxygen species), resulting in endothelial dysfunction in many pathophysiological conditions. Lipid metabolism, dietary supplements and physical activity affect TNF-alpha expression. The interaction between TNF-alpha and stem cells is also important in terms of vascular repair or regeneration. Careful scrutiny of these factors may help elucidate the mechanisms that induce vascular dysfunction. The focus of the present review is to summarize recent evidence showing the role of TNF-alpha in vascular dysfunction in cardiovascular disease. We believe these findings may prompt new directions for targeting inflammation in future therapies.
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PMID:Role of TNF-alpha in vascular dysfunction. 1911 93

Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease that targets the beta-cells of the pancreas. We investigated the ability of soluble galectin-1 (gal-1), an endogenous lectin that promotes T cell apoptosis, to down-regulate the T cell response that destroys the pancreatic beta-cells. We demonstrated that in nonobese diabetic (NOD) mice, gal-1 therapy reduces significantly the amount of Th1 cells, augments the number of T cells secreting IL-4 or IL-10 specific for islet cell Ag, and causes peripheral deletion of beta-cell-reactive T cells. Administration of gal-1 prevented the onset of hyperglycemia in NOD mice at early and subclinical stages of T1D. Preventive gal-1 therapy shifted the composition of the insulitis into an infiltrate that did not invade the islets and that contained a significantly reduced number of Th1 cells and a higher percentage of CD4(+) T cells with content of IL-4, IL-5, or IL-10. The beneficial effects of gal-1 correlated with the ability of the lectin to trigger apoptosis of the T cell subsets that cause beta-cell damage while sparing naive T cells, Th2 lymphocytes, and regulatory T cells in NOD mice. Importantly, gal-1 reversed beta-cell autoimmunity and hyperglycemia in NOD mice with ongoing T1D. Because gal-1 therapy did not cause major side effects or beta-cell toxicity in NOD mice, the use of gal-1 to control beta-cell autoimmunity represents a novel alternative for treatment of subclinical or ongoing T1D.
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PMID:Suppression of autoimmune diabetes by soluble galectin-1. 1923 58

Intrauterine growth restriction (IUGR) induced by uterine artery ligation in pregnant rats leads to low birth weight and early insulin secretory defects followed by the development of insulin resistance, decline in beta-cell mass, and diabetes in adulthood. Neonatal administration of Exendin-4 (Ex-4) prevents the deterioration of beta-cell mass and the onset of adult-onset diabetes. Our aim was to determine whether this effect occurs through preservation of islet vascularization. In 2 wk-old IUGR rats, endothelial-specific lectin staining revealed a 40% reduction in islet vascular density (p = 0.027), which was normalized by neonatal Ex-4. VEGF-A protein expression was reduced in IUGR islets compared with controls at postnatal d 1 (P). Neonatal Ex-4 normalized islet VEGF protein expression at P7. Neither IUGR nor Ex-4 administration to IUGR rats affected relative VEGF splice isoform RNA levels. Together, the reduced vascularity in IUGR islets before the deterioration of beta-cell mass, and the enhancement of VEGF expression and normalization of islet vascularity by neonatal Ex-4, suggest islet vascularity as an early determinant of beta-cell mass and as a potential therapeutic target for diabetes prevention.
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PMID:Exendin-4 normalizes islet vascularity in intrauterine growth restricted rats: potential role of VEGF. 1928 46

Coupling factor 6 (CF6) is composed of 76 amino acids and is present in the peripheral stalk of mitochondrial ATP synthase. The generation of CF6 is positively regulated by tumor necrosis factor alpha and shear stress via nuclear factor kappaB, and by high glucose via protein kinase C and p38 mitogen-activated protein kinase. CF6 is released outside of the cells from vascular endothelial cells, and binds to the beta-subunit of the plasma membrane-bound ATP synthase in vascular endothelial cells and leads to intracellular acidosis. CF6 produces vasoconstriction, and the biological active site resides at the C-terminal portion. CF6 suppresses prostacyclin generation via inhibition of cytosolic phospholipase A(2). CF6 also suppresses nitric oxide synthase activity via an increase in asymmetric dimethylarginine and a decrease in platelet/endothelial cell adhesion molecule-1. CF6 induces the gene and protein expression of proatherogenic molecules such as endothelin 2, urokinase type plasminogen activator receptor, estrogen receptor beta, a soluble short form of vascular endothelial growth factor receptor-1, and lectin-like oxidized low-density lipoprotein receptor-1. The plasma level of CF6 is elevated in patients with essential hypertension, diabetes mellitus, end-stage renal disease, acute myocardial infarction, and coronary heart disease. It is likely that CF6 contributes to the pathogenesis of cardiovascular diseases, but further intensive investigation is needed.
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PMID:Coupling factor 6 as a novel vasoactive and proatherogenic peptide in vascular endothelial cells. 1948 38

Preeclampsia is characterized by vascular endothelial dysfunction partly attributed to oxidative stress. In the vasculature of preeclamptic women, we have shown increased lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) and arginase expression, which can contribute to vascular oxidative stress. However, the mechanisms of such upregulation are unknown. Methylglyoxal (MG) that plays a role in the vascular complications of diabetes mellitus and the development of hypertension can be one potential factor that can affect LOX-1 and arginase through its ability to induce oxidative stress in vascular cells. MG also reacts with lysine residues in proteins to generate advanced glycation end product, N(epsilon)-carboxy ethyl lysine, which also serves as a marker of MG. We hypothesized that markers of MG formation will be increased in the vasculature of preeclamptic women and that exogenous MG will induce oxidative stress by the upregulation of LOX-1 via arginase. We observed increased N(epsilon)-carboxy ethyl lysine expression in the vasculature of women with preeclampsia in comparison with normotensive pregnant women. Moreover, glyoxalase I and II, enzymes that detoxify MG, and glutathione reductase, which generates reduced glutathione, a cofactor for glyoxalase, are also reduced in preeclampsia. In cultured endothelial cells, MG increased arginase expression by 6 hours and LOX-1 expression by 24 hours. Inhibition of arginase or NO synthase significantly reduced MG-induced LOX-1 expression, superoxide levels, and nitrotyrosine staining. In conclusion, MG-induced LOX-1 expression is mediated via arginase upregulation likely because of uncoupling of NO synthase, which may have implications in preeclampsia.
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PMID:Evidence for increased methylglyoxal in the vasculature of women with preeclampsia: role in upregulation of LOX-1 and arginase. 1968 46


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