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)

The purpose of this study was to assess the effects of PPAR-gamma agonists (pioglitazone and rosiglitazone) on mediators of endothelial dysfunction and markers of angiogenesis in patients with type-2 diabetes. Pioglitazone group showed favorable reductions in serum total cholesterol, triglycerides, LDL cholesterol, VLDL cholesterol and increase in HDL cholesterol as compared to rosiglitazone group, after 16 weeks of treatment and also with control group. There was significant reduction of CRP level in pioglitazone and rosiglitazone group. The level of serum TNF-alpha decreased significantly in pioglitazone and mildly decreased in rosiglitazone group. The level of VEGF, IL-8 and Angiogenin were increased in pioglitazone than rosiglitazone group. There were no significant changes observed in the serum angiogenin and IL-8 levels in the control group. Pioglitazone and rosiglitazone therapy in type-2 diabetes subjects have additional benefits of reducing mediators of endothelial dysfunction. Increase in angiogenesis markers in patients receiving pioglitazone could have variable effects in diabetic nephropathy and retinopathy as there may be increased vascular neogenesis. Pioglitazone has advantage over rosiglitazone in lowering lipid and proinflammatory cytokines.
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PMID:Effect of pioglitazone and rosiglitazone on mediators of endothelial dysfunction, markers of angiogenesis and inflammatory cytokines in type-2 diabetes. 1875 84

Large, prospective, clinical trials have confirmed the efficacy of intensive blood-glucose control to prevent the onset and progression of diabetic complications. However, since it is difficult to maintain blood glucose concentrations close to the normal range, the effect of intensive therapy to prevent diabetic complications may be limited. Other approaches are therefore required to prevent the progression of diabetic complications based on the elucidation of the biological mechanisms. In this review, the impacts of mitochondrial reactive oxygen species (ROS) on diabetes-related complications are described. In endothelial cells, high glucose levels increase mitochondrial ROS, and the normalization of mitochondrial ROS production by inhibitors of mitochondrial metabolism, or by the overexpression of UCP-1 or MnSOD, prevents the glucose-induced accumulation of sorbitol, activation of protein kinase C, and formation of advanced glycation end products, all of which are believed to be major molecular mechanisms of diabetic complications. We also demonstrated that 8-hydroxydeoxyguanosine, which represents mitochondrial oxidative damage, was elevated in patients with either retinopathy, albuminuria, or the increased intima-media thickness of carotid arteries compared to patients without diabetic vascular complications. In addition, to investigate the impact of mitochondrial ROS on diabetic retinopathy in vivo, we established a novel transgenic mouse, which specifically expressed MnSOD in endothelial cells. By the introduction of diabetes, levels of urinary 8-hydroxydeoxyguanosine and expressions of VEGF and fibronectin mRNA in retinas were increased in wild type littermates; however, these observations were ameliorated in transgenic mice. Taking the results together, hyperglycemia could induce mitochondrial ROS production, associating it with the pathogenesis of diabetic vascular complications.
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PMID:[Investigation of a novel mechanism of diabetic complications: impacts of mitochondrial reactive oxygen species]. 1880 Jun 28

VEGF plays protective roles on a variety of non-diabetic renal diseases. However, in diabetes VEGF exhibits deleterious roles to mediate the development/progression of diabetic nephropathy in spite of high VEGF. The protective role of VEGF could be predominantly dependent on its ability to stimulate nitric oxide production in endothelial cell in non-diabetic renal disease. However, it has been known that nitric oxide bioavailability is reduced in diabetes, indicating that diabetic status does not allow high VEGF to lead to an increase in NO bioavailability. As a result, VEGF could engage to NO-independent pathway, and cause deleterious effects on vascular system. Thus, we have hypothesized that uncoupling of VEGF with endothelial NO can be a mechanism by which VEGF causes diabetic nephropathy. We found that diabetic eNOS knockout (KO) mice exhibit masangiolysis, glomerular capillary microaneurysm, Kimmelstiel-Wilson-like nodular lesions, abnormal angiogenesis and a marked macrophage infiltration in addition to mesangial expansion and thickening of GBM, all of that resemble human diabetic nephropathy. Interestingly these lesions were associated with an increase in renal VEGF expression, suggesting uncoupling of VEGF with endothelial NO could be a mechanism. Compatibly, our in vitro experiments demonstrated that VEGF-induced endothelial cell proliferation was enhanced by NO blocking (with LNAME) and suppressed by exogenous NO administration whereas macrophage migration in response to VEGF was inhibited by exogenous NO, suggesting that uncoupling condition could cause abnormal angiogenesis and macrophage infiltration.
Diabetes Res Clin Pract 2008 Nov 13
PMID:Uncoupling of VEGF with NO as a mechanism for diabetic nephropathy. 1892 84

Several factors are incriminated in the genesis of diabetic nephropathy (DN). To elucidate their interplays, we utilized a diabetic rat model with nephropathy (SHR/NDmcr-cp). This model is characterized by hypertension, obesity with the metabolic syndrome, diabetes with insulin resistance, and intrarenal AGE accumulation. Various therapeutic approaches were used to achieve renoprotection. Caloric restriction corrects metabolic abnormalities and protects the kidney without correcting hypertension. Anti-hypertensive agents, angiotensin II receptor blocker (ARB) and calcium channel blocker, lower blood pressure to the same extent, but only ARBs protect the kidney without changes in metabolic abnormalities. Glycemic control is better with insulin than with pioglitazone. The plasma insulin level is increased by insulin but decreased by pioglitazone which worsens the obesity. Nevertheless, pioglitazone provides renoprotection unlike insulin, perhaps as a result of the up-regulation of TGF-beta by hyperinsulinemia. Cobalt up-regulates the expression of a hypoxia-inducible factor (HIF) and its downstream genes (erythropoietin, VEGF, HO-1). It protects the kidney without correcting hypertension and metabolic abnormalities. Altogether, renoprotection is not necessarily associated with blood pressure or glycemic control. By contrast, it is almost always associated with a decreased AGE formation. AGE reduction may reflect a decreased oxidative stress as it is concomitant with a marked reduction of oxidative stress markers.
Diabetes Res Clin Pract 2008 Nov 13
PMID:Inhibition of advanced glycation end products (AGEs): an implicit goal in clinical medicine for the treatment of diabetic nephropathy? 1895 18

This review describes the possible interactions between several retinal diseases, their treatment, and intraocular pressure (IOP). The use of the intravitreal route in the delivery of drugs to the retina has recently gained widespread acceptance with the development of the VEGF inhibitors and glucocorticoids such as triamcinolone. Although the intravitreal route offers high local concentrations in the vitreous, in the retina these advantages are offset by side effects, particularly short-term and chronic elevation of IOP. This review describes the clinical features of steroid glaucoma induced by triamcinolone or sustained-release systems of glucocorticoid drugs. Another aspect of the relationships between glaucoma and retina is also described: published reports of the occurrence of cystoid macular edema (CME) in eyes being treated with the prostaglandin analogs (PGAs) have led to concern regarding a possible causal relationship between the two. A review of the literature suggests that most PGA-treated eyes with CME had independent risk for development of CME, with a disruption of the blood-aqueous barrier: open or absent posterior capsule, history of dipivefrin-associated CME, epiretinal membrane, complicated cataract surgery, history of macular edema associated with branch retinal vein occlusion, ocular inflammation, and diabetes mellitus. In eyes at risk for CME, the use of PGAs is acceptable but must be prudent.
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PMID:[Retina and glaucoma: therapeutic considerations]. 1895 16

Cell-based therapies offer considerable promise for prevention or cure of diabetes. We explored the potential of autologous, self-renewing, mesenchymal stem cells (MSC) as a clinically-applicable approach to promote glucose homeostasis. In vitro-expanded syngeneic bone marrow-derived MSC were administered following or prior to diabetes induction into a rat model of streptozotocin-induced beta cell injury. MSC were CD45(-)/CD44(+)/CD54(+)/CD90(+)/CD106(+). MSC spontaneously secreted IL-6, HGF, TGF-beta1 and expressed high levels of SDF-1 and low levels of VEGF, IL-1beta and PGE(2), but no EGF, insulin or glucagon. MSC homed to the pancreas and this therapy allowed for enhanced insulin secretion and sustained normoglycemia. Interestingly, immunohistochemistry demonstrated that, the islets from MSC-treated rats expressed high levels of PDX-1 and that these cells were also positive for insulin staining. In addition, peripheral T cells from MSC-treated rats exhibited a shift toward IL-10/IL-13 production and higher frequencies of CD4(+)/CD8(+) Foxp3(+) T cells compared to the PBS-treated rats. These data suggest that the bioactive factors secreted by MSC establish a tissue microenvironment that supports beta cell activation/survival in the pancreas. In addition, because of anti-inflammatory and immunoregulatory effects of MSC on T cells, this work can lead to clinical trial of autologous MSC to prevent/cure type-1 diabetes.
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PMID:Autologous bone marrow-derived rat mesenchymal stem cells promote PDX-1 and insulin expression in the islets, alter T cell cytokine pattern and preserve regulatory T cells in the periphery and induce sustained normoglycemia. 1906 54

Investigations into the role of the adenosine A2b receptor have been enigmatic due to the lack of good selective high affinity agonists and antagonists. Over the last few years several new antagonist compounds, based either on a xanthine or pyrrolpyrimidine (polyheterocyclic) structure have been designed and these have been used to localise A2b receptors in different tissues and to determine their function. Recently, animals harbouring either a loss or an over-expression of the A2b receptor have been created and these suggest an anti-inflammatory role for the receptor. In this short review, we describe how the A2b receptor influences inflammation in different tissues. In the anterior pituitary gland the A2b receptors exist predominantly in folliculostellate cells where it stimulates secretion of IL-6 and VEGF and influences gap-junctional communication via connexin-43. The A2b receptor also mediates the release of pro-inflammatory cytokines from many tissues such as bronchial smooth muscle, intestinal epithelial cells and mast cells. The presence of a HIF-1alpha binding site in the promoter region of the A2b receptor gene shows that it is strongly implicated in hypoxia and angiogenesis. Targeting the A2b receptor may also be useful in combating autoimmune type I diabetes. These findings, together, indicate that the A2b receptor plays a role in inflammation; its precise action, whether pro- or anti-inflammatory however may be cell type dependent. Nevertheless several A2b receptor antagonists are being developed for therapeutic intervention and these are either at the preclinical stage or in phase I clinical trials as is the case for CVT-6883 for asthma.
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PMID:The adenosine a2b receptor: its role in inflammation. 1907 78

The study included 20 patients with diabetes mellitus type I (DM I) and 16 with type II (DM II) suffering from prolipherative diabetic retinopathy (PDR) for which they underwent vitrectomy. The quantity of VEGF and its receptors in the vitreous of investigated patients were measured by immunoassay and results compared between patients with DM I and II. The mean levels in the vitreous were significantly higher in diabetics with PDR and diabetes mellitus I (432.2 pg/mL, 1460.4 pg/mL and 1054.6 pg/mL) than in diabetics with PDR and diabetes mellitus II (147.5 pg/mL, 641.4 pg/mL and 448.5 pg/mL) and in control group (63.26 pg/mL). Considering that VEGF VEGFR1 and VEGFR2 levels were significantly higher in diabetics with PDR than in controls and that the patients with DM I had higher levels than with DM II, anti-VEGF therapy might be beneficial for diabetics with PDR, especially those with DM I.
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PMID:Expression of vascular endothelial growth factor in proliferative diabetic retinopathy. 1913 4

Diabetic retinopathy, a secondary microvascular complication of diabetes mellitus is the leading cause of blindness in the Unites States amongst individuals age 20 to 64. Two major retinal problems cause most of the diabetes-related vision loss: diabetic macular edema and complications from abnormal retinal blood vessel growth, angiogenesis. Secondary to angiogenesis, increased retinal blood flow is of pathogenic importance in the progression of diabetic retinopathy. Understanding the role of hyperglycemia seems to be the most critical factor in regulating retinal blood flow, as increased levels of blood glucose are thought to have a structural and physiological effect on retinal capillaries causing them to be both functionally and anatomically incompetent. High blood glucose induces hypoxia in retinal tissues, thus leading to the production of VEGF-A (vascular endothelial growth factor protein). Hypoxia is a key regulator of VEGF-induced ocular neovascularization. Secondary to the induction of VEGF by hypoxia, angiogenesis can be controlled by angiogenic inducers and inhibitors. The balance between VEGF and angiogenic inhibitors may determine the proliferation of angiogenesis in diabetic retinopathy. Since VEGF-A is a powerful angiogenic inducer, utilizing anti-VEGF treatments has proved to be a successful protocol in the treatment of proliferative diabetic retinopathy.
Curr Diabetes Rev 2009 Feb
PMID:Diabetic retinopathy and angiogenesis. 1919 92

Ranibizumab (Lucentis) is a Fab-Antibody with high affinity for VEGF, and is being designed to bind to all VEGF isoforms. This quality makes it a powerful drug for VEGF inhibition. Diseases of retinal and choroidal blood vessels are the most prevalent causes of moderate and severe vision loss in developed countries. Vascular endothelial growth factor plays a critical role in the pathogenesis of many of these diseases. Results of the pilot studies showed that intraocular injections of ranibizumab (Lucentis) decrease the mean retinal thickness and improve the BCVA in all the subjects. Proliferative diabetic retinopathy, currently treated with destructive laser photocoagulation, represents another potential target for anti-VEGF therapy. The early experience in animal models with proliferative retinopathy and neovascular glaucoma shows that posterior and anterior neovascularizations are very sensitive to anti-VEGF therapy. The outcome of two phase III clinical trials will increase our knowledge of the role of Lucentis in the treatment of DME.
Curr Diabetes Rev 2009 Feb
PMID:Ranibizumab for diabetic retinopathy. 1919 98


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