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)

Endothelial progenitor cells (EPCs) have been implicated in vascular repair and found to be functionally impaired in patients with diabetes. We evaluated the effects of the anti-diabetic drug pioglitazone on human EPC function and the involvement of PPAR-gamma and TGF-beta1. EPCs in culture were characterized at day 7 by the development of colony-forming units (CFUs) and flow cytometry assessment of differentiation marker (DiI-ac-LDL/lectin, KDR and CD31). Adhesion on fibronectin and fibrinogen in flow was analyzed as functional parameter. Treatment with pioglitazone for 72 hours increased the number of EPC-CFUs, DiI-ac-LDL(+)/lectin(+), CD31(+) and KDR(+) EPCs at 1 microM but not at 10 microM. Since pioglitazone did not significantly alter proliferation and apoptosis in cultured EPCs, the increase in EPC number was most likely attributable to augmented adhesion and differentiation. Indeed, pioglitazone increased EPC adhesion in flow at 1 microM, an effect prevented by PPAR-gamma and beta2-integrin blockade. In contrast, pioglitazone did not promote EPC adhesion at 10 microM; however, increased adhesion became evident by co-incubation with a blocking TGF-beta1 antibody. As determined by ELISA, pioglitazone induced a persistent increase in TGF-beta1 secretion only at 10 microM when a significantly elevated expression of endoglin, the accessory receptor for TGF-beta1, was also observed. Taken together, pioglitazone exerts biphasic effects on the function of isolated EPCs, causing a PPAR-gamma-dependent stimulation at 1 microM and a TGF-beta1-mediated suppression at 10 microM. These results may help to define optimal therapeutic doses of pioglitazone for improving endothelial dysfunction.
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PMID:Biphasic effect of pioglitazone on isolated human endothelial progenitor cells: involvement of peroxisome proliferator-activated receptor-gamma and transforming growth factor-beta1. 1754 1

Recent studies have shown a close correlation between advanced diabetic retinopathy and the late stages of atherosclerosis. The purpose of this study was to analyse the association between diabetic retinopathy and early atherosclerotic changes in adolescents with type 1 diabetes. We studied 28 adolescents with type 1 diabetes. Eight patients with nonproliferative retinopathy were compared with the remaining 20 patients, and with 11 healthy controls. The function of endothelium was assessed by measuring flow-mediated dilatation (FMD), the intima-media thickness (IMT) of the common carotid arteries and adhesion molecules (sICAM-1, sVCAM-1, sE-selectin). In the group with retinopathy FMD equalled 7.8+/-4.1% vs. 12.1+/-5.1% in the control group (p=0.04), and in the group without retinopathy, 7.6+/-5.5% (p=0.04 compared to controls). Higher IMT was found in all patients with diabetes in comparison with healthy controls: 0.49+/-0.06 mm vs. 0.42+/-0.03 mm (p=0.001). Patients with retinopathy had a significantly higher value of IMT in comparison not only with controls but also with patients without complications: 0.56+/-0.06 mm vs. 0.47+/-0.03 mm (p=0.0001). Adhesion molecule levels were not changed in patients with retinopathy. Higher IMT was found in adolescents with diabetic retinopathy in comparison with patients without complications, which may suggest that macrovascular changes are more advanced in these patients than in their diabetic peers without retinopathy.
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PMID:The association of early atherosclerosis and retinopathy in adolescents with type 1 diabetes: preliminary report. 1772 51

Adhesion molecules have been implicated in the development and progression of cardiovascular disease, which is highly prevalent in people with diabetes. Adhesion molecules can mediate adhesion of leukocytes to the endothelium. Furthermore, P-selectin expressed on platelets is able to mediate the adhesion of leukocytes to platelets. In this study, we examine the in-vivo and in-vitro effects of rosiglitazone with particular emphasis on three important adhesion molecules (VCAM-1, ICAM-1 and P-selectin). In the aorta of STZ-diabetic apolipoprotein E-deficient (apoE KO) mice, rosiglitazone significantly reduced both total and arch plaque area. The mechanism for this appeared to be reduced macrophage infiltration into the atherosclerotic plaque which was also associated with reduced mRNA levels for VCAM-1, ICAM-1, MCP-1 and P-selectin in the aorta. In-vitro studies revealed reduced cell adhesion of monocytic cells (THP-1) to fibrinogen and endothelial cells (HUVEC) after incubation with rosiglitazone. Furthermore, the reduction in leukocyte adhesion also correlated with significant reductions in mRNA levels for VCAM-1, ICAM-1 and P-selectin indicating that reduced macrophage infiltration in atherosclerotic plaques may occur as a result of a direct effect of rosiglitazone on adhesion molecules in both monocytes and endothelial cells. Thus, we have shown that rosiglitazone appears to have direct anti-atherosclerotic effects in an animal model of diabetes-associated atherosclerosis which are at least partly due to effects on VCAM-1, ICAM-1, MCP-1 and P-selectin expression which leads to decreased leukocyte adhesion and macrophage infiltration.
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PMID:Reduced plaque formation induced by rosiglitazone in an STZ-diabetes mouse model of atherosclerosis is associated with downregulation of adhesion molecules. 1809 96

Inflammation is one of the recognised mechanisms involved in the development of atherosclerotic plaque and insulin resistance. Inflammatory or endothelial markers such as C-Reactive Protein (CRP), Interleukin-6 (IL-6), fibrinogen, Vascular Cell Adhesion Molecule-1 (VCAM-1) and Intracellular Adhesion Molecule-1 (ICAM-1) have been identified as independent predictors of cardiovascular disease (CVD) or diabetes in human prospective studies. Epidemiological and clinical studies suggest that some dietary factors, such as n-3 polyunsaturated fatty acids, antioxidant vitamins, dietary fiber, L-arginine and magnesium may play an important role in modulating inflammation. The relationship observed between frequent nut consumption and the reduced risk of cardiovascular mortality and type 2 diabetes in some prospective studies could be explained by the fact that nuts are rich in all of these modulator nutrients. In fact, frequent nut consumption has been associated with lower concentrations of some peripheral inflammation markers in cross-sectional studies. Nut consumption has also been shown to decrease the plasma concentration of CRP, IL-6 and some endothelial markers in recent clinical trials.
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PMID:The effect of nuts on inflammation. 1829 71

Adhesion and degranulation promoting adapter protein (ADAP), a positive regulator of T cell receptor (TCR) signaling, is required for thymocyte development and T cell homeostasis. To investigate the role of ADAP in a T cell-driven autoimmune response, we generated ADAP-deficient, BDC2.5 TCR transgenic, diabetes-prone (C57BL/6) mice (BDC/B6). We observed a striking enhancement of diabetes incidence in ADAP-deficient mice, both in animals homozygous for I-Ag7, and in mice carrying one I-Ab allele (BDC/B6g7/b). Increased disease correlates with significantly reduced numbers of pathological CD4(+) T cells in the mice. Consistent with a state of functional lymphopenia in ADAP-deficient BDC/B6g7/b mice, T cells display increased homeostatic proliferation. Transfer of syngeneic lymphocytes or T cells both blocks ADAP-dependent diabetes and relieves exaggerated homeostatic T cell proliferation observed in ADAP-deficient mice. Marked attenuation in cellularity of the CD4+ single-positive thymocyte compartment in ADAP-deficient BDC/B6g7/b animals suggests a mechanism for induction of the lymphopenia. We conclude that inefficient positive selection in ADAP deficiency results in lymphopenia that leads to enhanced autoimmune diabetes in the BDC/B6g7/b model. Our findings support the notion that ineffective thymic T cell output can be a powerful causative factor in lymphopenia-driven autoimmune diabetes.
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PMID:Defective positive selection results in T cell lymphopenia and increased autoimmune diabetes in ADAP-deficient BDC2.5-C57BL/6 mice. 1838 41

While circulating levels of soluble Intercellular Adhesion Molecule 1 (sICAM-1) have been associated with diverse conditions including myocardial infarction, stroke, malaria, and diabetes, comprehensive analysis of the common genetic determinants of sICAM-1 is not available. In a genome-wide association study conducted among 6,578 participants in the Women's Genome Health Study, we find that three SNPs at the ICAM1 (19p13.2) locus (rs1799969, rs5498 and rs281437) are non-redundantly associated with plasma sICAM-1 concentrations at a genome-wide significance level (P<5x10(-8)), thus extending prior results from linkage and candidate gene studies. We also find that a single SNP (rs507666, P = 5.1x10(-29)) at the ABO (9q34.2) locus is highly correlated with sICAM-1 concentrations. The novel association at the ABO locus provides evidence for a previously unknown regulatory role of histo-blood group antigens in inflammatory adhesion processes.
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PMID:Novel association of ABO histo-blood group antigen with soluble ICAM-1: results of a genome-wide association study of 6,578 women. 1860 67

Endothelial progenitor cell (EPC) dysfunction is an important mediator of vascular disease in diabetes. We aimed to elucidate the mechanism of adhesion of EPC to diabetic and non-diabetic arteries and to study the effect of the anti-diabetic drug pioglitazone. Peripheral blood mononuclear cells were isolated from healthy donors. Human internal mammary arteries (HIMA) were isolated from patients who underwent coronary artery bypass surgery. EPC were labelled with 111In-oxine and perfused to HIMA in a perfusion chamber. Stromal derived factor-1 (SDF-1) and cyclooxygenase-2 (COX-2) were assessed by immunohistochemical analysis. CXCR-4 expression was assessed by flow cytometry. Adhesion of EPC was increased in HIMA from diabetic patients and was reduced after preincubation with 15 mM glucose for 72 h. EPC adhesion and CXCR-4 expression were inversely correlated. COX-2 and SDF-1 immunostaining in HIMA were positively correlated. Pioglitazone (1 microM) increased the adhesion of EPC to HIMA and the expression of CXCR-4 in EPC. Therefore, EPC-recruiting capability is increased in diabetic arteries, although EPC adhesion is notably impaired by high glucose concentrations. Interestingly, pioglitazone treatment enhances EPC adhesiveness.
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PMID:EPC adhesion to arteries from diabetic and non-diabetic patients: effect of pioglitazone. 1927 97

Onychomycosis is a common fungal infection affecting nails. The primary cause for onychomycosis is dermatophytes, while Candida species have emerged as second-line pathogens. Onychomycosis due to Candida (candidal onychomycosis) is increasingly found in individuals having defective immunity consequential to aging, diabetes mellitus, vascular diseases, HIV infection and drug therapies such as immunosuppressives and broad-spectrum antibiotics. Breached local immunity at the nail complex due to trauma, chronic exposure to moisture and chemicals including smoke, detergents, soap, etc., also contribute to candidal onychomycosis. Adhesion, filamentation, secretion of extracellular enzymes and the development of antifungal resistance are some of the virulence mechanisms of Candida species associated with onychomycosis. Diagnosis of onychomycosis depends on history and clinical examination, direct microscopic investigation, mycological culture and histopathology. Restoration of immune defenses, elimination of fungi using appropriate drug therapy and improvement of nail hygiene with the removal of predisposing factors are key aspects in the management of candidal onychomycosis.
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PMID:Candidal onychomycosis: a mini-review. 1948 5

Activation of the renin-angiotensin system plays an important role in the pathogenesis of vascular complications of hyperglycemia. Clinical studies have demonstrated that hypoglycemic effects of peroxisome proliferation-activated receptor-gamma (PPAR-gamma) activation is potentially associated with a significant decrease of cardiovascular disease events in diabetes patients. We assessed the effect of high glucose on the angiotensin II (Ang II), which induced the inactivation of PPAR-gamma and its signal pathways in human coronary artery endothelial cells (HCAECs). The expression of angiotensin II receptor I (AT1R) protein was analyzed by Western blot and knocked down using siRNA. PPAR-gamma activation was examined using a luminometer and a Dual Luciferase Reporter Assay System. Adhesion molecule expressions of HCAECs were measured using ELISA. Both high glucose and Ang II induced a progressive increase in AT1R protein expression on the HCAECs. Troglitazone, a PPAR-gamma activator, significantly increased the transcription activity of PPAR-gamma in HCAECs in vitro. However, activation of PPAR-gamma was significantly inhibited by high glucose and Ang II stimulation. Furthermore, silencing of AT1R expression was able to inhibit the inactivation of PPAR-gamma induced by Ang II and high glucose. Meanwhile, expression of proinflammatory adhesion molecules was increased by high glucose and Ang II in HCAECs, which is blocked by troglitazone and silencing of AT1R expression. These data strongly suggest high glucose enhanced Ang-II-mediated peroxisome proliferation-activated receptor-gamma inactivation and expression of proinflammatory adhesion molecules in human coronary artery endothelial cells.
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PMID:High glucose enhances angiotensin-II-mediated peroxisome proliferation-activated receptor-gamma inactivation in human coronary artery endothelial cells. 1979 34

Diabetes is increasing in the world and causes severe cardiovascular complications. Diabetes-induced limb ischemia leads to foot amputation and therapeutic remedies are urgently needed. Here we report that local injection of mesenchymal stem cells (MSCs) prestimulated with epidermal growth factor (EGF) restored blood flow and vasculogenesis in the ischemic hind-limb of type II diabetic (db(-)/db(-)) mice. Bone marrow cells from db(-)/db(-) mice are altered as evidenced by increased oxidative stress and reduced Akt and adhesion molecules when compared with control (db(-)/db(+)). Femoral artery ligation-induced ischemia was performed in the hind-limb of db(-)/db(-) and db(-)/db(+) mice for 28 days. Enhanced green fluorescent protein (EGFP)-MSCs stimulated+/-exogenous EGF for 24 h were injected locally into the ischemic muscle. Blood flow measured with MoorLDI-Laser and microangiography assessed with X-ray showed 100% recovery in db(-)/db(+) compared to 50% recovery in db(-)/db(-) mice. Interestingly, db(-)/db(-) mice had 60 and 96% blood flow recovery and 61 and 98% of vasculogenesis when treated with MSCs alone or MSCs modified with EGF, respectively. Western blot analysis of hind-limb muscles revealed an increase in Akt and vascular endothelial growth factor receptor phosphorylation and hypoxia-inducible factor) expression in db(-)/db(-) mice injected with MSCs or MSCs+EGF compared to db(-)/db(-) mice. Fluorescent microscopic images show that EGFP-MSCs differentiate into new microvessels. Adhesion and migration of MSCs on cultured endothelial cells were ICAM1-, VCAM1- and Akt-dependent mechanism and elevated when MSCs were prestimulated with EGF compared with nonstimulated MSCs. Our novel study data provide evidence that in type II diabetes, stimulated MSCs with EGF enhance the recovery of blood flow and angiogenesis.
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PMID:Modified multipotent stromal cells with epidermal growth factor restore vasculogenesis and blood flow in ischemic hind-limb of type II diabetic mice. 2044 Feb 73


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