Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Type 1 diabetes mellitus is an autoimmune disease characterized by progressive destruction of pancreatic beta cells by genetic and environmental factors which leads to an absolute dependence of insulin for survival and maintenance of health. Although the majority of mechanisms of beta cell destruction remain unclear, many molecules, including proinflammatory cytokines and chemokines such as tumor necrosis factor alpha and monocyte chemoattractant protein-1, are implicated in the development of beta cell damage. Furthermore, beta cell destruction is enhanced by the Th1 and Th17 subsets of CD4+ T cells. In contrast, there are mechanisms involved in the maintenance of peripheral tolerance by regulatory T cells, the function of which depends on the pleiotropic cytokine transforming growth factor beta. Development and progression of renal injuries in patients with diabetic nephropathy are also associated with several growth factors and proinflammatory cytokines, including tumor necrosis factor alpha, insulin-like growth factor-1, monocyte chemoattractant protein-1, vascular endothelial growth factor, and transforming growth factor beta. Although the pathogenic mechanisms underlying type 1 diabetes and diabetic nephropathy are principally different, i.e., autoimmunity and inflammation, some common factors, including susceptibility genes and proinflammatory cytokines, are involved in both mechanisms, including infiltrating cell recruitment, upregulation of other cytokines and chemokines, or apoptosis.
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PMID:Recent advancement of understanding pathogenesis of type 1 diabetes and potential relevance to diabetic nephropathy. 1782 3

During the last few years, the incidence of microvascular complications in diabetes mellitus has rapidly increased as a consequence of both an increase in incidence of type 2 and type 1 diabetes mellitus. The pathogenesis of diabetic microvascular complications is still largely unknown. Among the many hypotheses, a dysfunction in angiogenesis has been suggested as a common origin for retinopathy, nephropathy, and neuropathy. Based on this hypothesis, inhibition of vascular endothelial growth factor (VEGF) has been tested as a potential therapeutic approach to prevent and cure diabetic microvascular complications. Several VEGF inhibitors are currently under evaluation or are approved for the treatment of wet age-related macular degeneration and macular edema. These include inhibitors of intracellular transcription of VEGF (e.g. bevasiranib), inhibitors of extracellular VEGF (e.g. pegaptanib), inhibitors of VEGF receptor expression (e.g. aflibercept [VEGF-TRAP]) and inhibitors of the intracellular signaling cascade activating VEGF (e.g. midostaurin). According to the existing evidence base, although inhibition of VEGF results in a better outcome in the case of diabetic retinopathy and also, despite some discrepant results, in the case of diabetic nephropathy, there is no final confirmation that VEGF inhibition is a valid approach for diabetic neuropathy. The latter complication actually, in line with other chronic neuropathies, seems to improve with stimulation of angiogenesis through increased expression of VEGF.
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PMID:The therapeutic potential of VEGF inhibition in diabetic microvascular complications. 1807 6

Proliferative diabetic retinopathy is characterized by neovascularization originating from the retina and/or optic disk in patients with diabetes mellitus. The role of vascular endothelial growth factor appears to be central in the pathogenesis of proliferative diabetic retinopathy. Advanced glycation end products are important in the development of vitreous abnormalities in proliferative diabetic retinopathy. The majority of the neovascular membranes are adherent to the posterior vitreous cortex. When the posterior hyaloid exerts traction, the edges of the neovascular complex are pulled forward, resulting in vitreous hemorrhage. Tractional and/or rhegmatogenous retinal detachments can occur. The Diabetic Retinopathy Study demonstrated the ability of panretinal photocoagulation to reduce the rate of severe visual loss by 50% for eyes with high-risk characteristics, defined as neovascularization originating from the optic disk > 1/3 disk diameter, any neovascularization originating from the optic disk with hemorrhage, and neovascularization originating from the retina with vitreous hemorrhage. The Early Treatment Diabetic Retinopathy Study showed that patients with type II diabetes mellitus who were older than 40 with severe nonproliferative diabetic retinopathy (defined as hemorrhages in four quadrants, venous beading in two quadrants, or intraretinal microvascular abnormalities in one quadrant) also benefited from early panretinal photocoagulation. The Diabetic Retinopathy Vitrectomy Study showed that early vitrectomy (within 6 months of onset of vitreous hemorrhage) was associated with better results in type I diabetes mellitus patients only. The goals of vitreous surgery are to remove the vitreous, including the posterior hyaloid, and to relieve traction from fibrovascular tissue. Delamination and segmentation techniques have been used in the excision of fibrovascular growth on the internal limiting membrane and extending into the vitreous. Panretinal photocoagulation is an integral component of vitrectomy for proliferative diabetic retinopathy. Anti-vascular endothelial growth factor agents may be used in addition to laser as an adjunct to reduce the risk of neovascularization. Vitrectomy surgery may have intraoperative and postoperative complications, including cataract, anterior hyaloidal fibrovascular proliferation, fibrovascular ingrowth, retinal detachment, and recurrent vitreous hemorrhage. Visual potential depends on the preoperative and postoperative status of the macula, as well as on retinal perfusion and the health of the optic nerve. With the improvement in instruments, techniques, and drugs, the results of vitrectomy in proliferative diabetic retinopathy are improving.
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PMID:Management of proliferative diabetic retinopathy. 1820 11

Retinopathy is the most feared complication of diabetes, compromising quality of life in most sufferers. Almost all patients with type 1 diabetes will develop retinopathy over a 15- to 20-year period, and approximately 20-30% will advance to the blinding stage of the disease[1]. Greater than 60% of patients with type 2 diabetes will have retinopathy. This situation is highlighted by the frightening statistic that diabetic retinopathy (DR) remains the most common cause of vision impairment in people of working age in Western society. With the global epidemic of type 2 diabetes, this predicament is set to worsen as over 360 million people are projected to suffer from diabetes and its complications by 2030. Vision loss from diabetes is due to a number of factors, including haemorrhage from new and poorly formed blood vessels, retinal detachment due to contraction of deposited fibrous tissue, and neovascular glaucoma resulting in an increase in intraocular pressure. Diabetic macular oedema is now the principal cause of vision loss in diabetes and involves leakage from a disrupted blood-retinal barrier. In terms of treatment, there is clear evidence that strict metabolic and blood pressure control can lower the risk of developing DR and reduce disease progression. Laser photocoagulation and vitrectomy are effective in preventing severe vision loss in DR, particularly in the most advanced stages of the disease. However, both procedures have limitations. This review examines evidence from preclinical and clinical studies that shows that targeting inhibition of the renin-angiotensin system, vascular endothelial growth factor, corticosteroids, protein kinase C, growth hormone, and advanced glycation end-products are potential treatments for DR.
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PMID:Update on the treatment of diabetic retinopathy. 1826 28

The influence of vascular endothelial growth factor (VEGF) on the course of diabetic retinopathy (DR) was studied in 35 patients, including 11 males and 24 females, aged 21 to 56 years (mean 37 +/- 2.6 years) who had type 1 diabetes mellitus (DM) whose history was 14 to 40 years (mean 21.4 +/- 2.7 years). Tear and serum VEGF was examined by solid-phase enzyme-linked immunosorbent assay (ELISA), by using diagnostic Bender MedSystems (Austria) on a Stat Fax-2100 (USA). In the active phase of proliferative DR, the patients with type 1 DM were found to have the highest level of tear VEGF; when the process changed to a inactive phase, the content of this factor significantly reduced. There was a relationship between the tear level of VEGF and the degree of various manifestations of DR. There is an agreement of the tear and serum levels of VEGF in patients with different stages and manifestations of DR, which may be evidence for the single mechanism responsible for vascular endothelial damage in DM. There is a relationship between the presence of VEGF, the proliferative stage of DR, and diabetic nephropathy.
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PMID:[Role of vascular endothelial growth factor in the development of diabetic retinopathy in patients with type 1 diabetes mellitus]. 1831 5

Islet transplantation has great potential as an effective means of treating type 1 diabetes. However, its successful application greatly depends on the rapid revascularization of islets and prevention from their apoptotic cell death. We co-expressed human vascular endothelial growth factor (hVEGF) and human interleukin-1 receptor antagonist (hIL-1Ra) after transduction of human islets with Adv-hVEGF-hIL-1Ra. Since hepatocyte growth factor (HGF) increases beta-cell proliferation and promotes revascularization of islets, we also constructed Adv-hHGF-hIL-1Ra. There was dose and time dependent expression of hVEGF and hIL-1Ra or hHGF and hIL-1Ra by islets, which led to decrease in caspase-3 activity and apoptosis induced by a cocktail of TNF-alpha, IL-1beta and IFN-gamma. Compared to non-treated islets, transduction of islets with these bipartite Adv vectors prior to transplantation under the kidney capsules of diabetic NOD-SCID mice reduced the blood glucose levels, and increased serum insulin and c-peptide levels. Immunohistochemical staining of the islet bearing kidney sections was positive for human insulin, growth factor (hVEGF or hHGF) and von Willebrand factor. Transduction with Adv-caspase-3-shRNA also prevented islets from cytokine induced apoptosis and improved islet transplantation. In conclusion, bipartite Adv vector efficiently co-expressed both growth factor and antiapoptotic genes or shRNA targeting pro-apoptotic genes, decreases apoptosis and improves the outcome of islet transplantation.
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PMID:Gene expression and silencing for improved islet transplantation. 1937 68

Type 1 diabetes is associated with a unique form of cardiomyopathy that is present without atherosclerosis. Redox imbalance and/or changes in vascular endothelial growth factor (VEGF) expression have been associated with diabetes-related cardiomyopathy. However, the mechanisms of these changes and their interrelationships remain unclear. Using a murine type 1 diabetes model, we tested the hypothesis that alterations in cardiac performance are associated with decreased cardiac microvascular prevalence, as well as downregulation of VEGF isoforms. We also investigated oxidative stress as a contributor to regulate individual VEGF isoforms and microvascular rarefaction. Significant and rapid hyperglycemia was observed at 1 wk post-streptozotocin (STZ) and persisted throughout the 5-wk study. Left ventricular (LV) fractional shortening was reduced at week 1 and 5 post-STZ insult relative to age-matched controls. We also observed the early reduction in E/A ratio at 1 wk. Immunostaining for CD31 and digital image analysis demonstrated a 35% reduction in microvessels/myocardial area, indicative of rarefaction, which was highly correlated with fractional shortening. Furthermore, a significant increase in the prevalence of protein 3-nitrotyrosine was observed in the diabetic cardiac tissue, which was inversely associated with microvascular rarefaction. The expressions of three VEGF isoforms were significantly reduced to different extents. The reduction of VEGF(164) was associated with GSSG accumulation. These data demonstrate that the mouse model of STZ-induced diabetes has hallmark features observed in humans with respect to nonischemic systolic and diastolic performance and microvascular rarefaction, which are associated with changes in VEGF isoform expression and redox imbalance in the myocardium.
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PMID:Decreased cardiac expression of vascular endothelial growth factor and redox imbalance in murine diabetic cardiomyopathy. 1956 13

In healthy adults, levels of vascular endothelial growth factor (VEGF) increase in response to mild hypoglycemia. VEGF is implicated in glucose transport over the blood-brain barrier, and the increase during hypoglycemia has been positively correlated with preservation of cognitive function during hypoglycemia. High activity in the renin-angiotensin system (RAS) is associated with an increased risk of severe hypoglycemia in patients with type 1 diabetes mellitus. Renin-angiotensin system possibly exerts its mechanism in hypoglycemia via VEGF. We studied the impact of mild hypoglycemia on plasma VEGF in patients with type 1 diabetes mellitus and high or low RAS activity and analyzed associations between VEGF levels and cognitive function during hypoglycemia. Eighteen patients with type 1 diabetes mellitus-9 with high and 9 with low RAS activity-underwent a single-blinded, placebo-controlled, crossover study with either mild hypoglycemia or stable glycemia. Cognitive function was assessed by the California Cognitive Assessment Package and the Alzheimer Quick Test. Nadir plasma glucose was 2.2 (0.3) mmol/L. During the control study, plasma VEGF did not change. During hypoglycemia, plasma VEGF increased from 39 to 58 pg/L in the high-RAS group (P = .004) and from 76 to 109 pg/L in the low-RAS group (P = .01), with no difference between RAS groups (P = .9). A weak association between reduced preservation of cognitive function during hypoglycemia and low VEGF response was observed. Plasma VEGF levels increase during mild, short-term hypoglycemia in patients with type 1 diabetes mellitus. The VEGF response is not dependent on RAS activity and only weakly associated with preservation of cognitive function during hypoglycemia. Thus, the previously described association between low RAS activity and better cognitive performance during hypoglycemia does not seem to be mediated by VEGF.
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PMID:Vascular endothelial growth factor during hypoglycemia in patients with type 1 diabetes mellitus: relation to cognitive function and renin-angiotensin system activity. 1957 85

Angiotensin II (Ang II) and vascular endothelial growth factor (VEGF) are important mediators of kidney injury in diabetes. VEGF expression is increased in proximal tubules of mice with type 1 diabetes. In mouse proximal tubular epithelial cells (MCT) cultured with 30 mM glucose (HG) for 24h, VEGF expression is increased at the protein and the mRNA level, suggesting a transcriptional mechanism. HG stimulation of VEGF synthesis is prevented by captopril, an inhibitor of angiotensin-converting enzyme, and, by losartan, a specific antagonist of angiotensin type 1 receptor (AT1), suggesting that VEGF synthesis is mediated by Ang II. Synthesis of angiotensinogen (AGT), a precursor of angiotensin II, is increased in MCTs cultured in HG. Although synthesis of renin and ACE is not affected by HG, their activity is increased in the conditioned medium. Concentrations of Ang I and Ang II are also increased in conditioned medium from HG-treated MCTs and captopril prevents increased Ang II, but not Ang I, synthesis. Finally, AT1 is activated in MCTs treated with HG, and its activation is prevented by captopril and losartan. The ERK pathway is activated by HG within minutes of stimulation and lasting for up to 24h. The initial phase of ERK activation is due to HG itself and leads to AGT upregulation and the sustained phase is mediated for the most part by Ang II-activated AT1 receptor and leads to increased VEGF synthesis. These data show that: (1) HG increases AGT synthesis and activation of renin and ACE by MCTs, leading to local production of Ang I and Ang II. (2) Ang II activates endogenous AT1 and stimulates synthesis of VEGF. (3) HG activation of ERK starts within minutes and lasts for up to 24h. Early ERK activation is involved in AGT upregulation and sustained ERK activation, mediated via AT1, is responsible for VEGF synthesis. In conclusion, our study shows that MCTs express an endogenous renin-angiotensin system that is activated by high glucose to stimulate the synthesis of VEGF, through activation of the ERK pathway.
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PMID:Mechanism of VEGF expression by high glucose in proximal tubule epithelial cells. 1976 32

This study was aimed at evaluating the role for poly(ADP-ribose) polymerase (PARP) in early nephropathy associated with type 1 diabetes. Control and streptozotocin-diabetic rats were maintained with or without treatment with one of two structurally unrelated PARP inhibitors, 1,5-isoquinolinediol (ISO) and 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de] anthracen-3-one (GPI-15427), at 3 mg/kg(-1) x d(-1) ip and 30 mg/kg(-1) x d(-1), respectively, for 10 wk after the first 2 wk without treatment. PARP activity in the renal cortex was assessed by immunohistochemistry and Western blot analysis of poly(ADP-ribosyl)ated proteins. Variables of diabetic nephropathy in urine and renal cortex were evaluated by ELISA, Western blot analysis, immunohistochemistry, and colorimetry. Urinary albumin excretion was increased about 4-fold in diabetic rats, and this increase was prevented by ISO and GPI-15427. PARP inhibition counteracted diabetes-associated increase in poly(ADP-ribose) immunoreactivities in renal glomeruli and tubuli and poly(ADP-ribosyl)ated protein level. Renal concentrations of TGF-beta(1), vascular endothelial growth factor, endothelin-1, TNF-alpha, monocyte chemoattractant protein-1, lipid peroxidation products, and nitrotyrosine were increased in diabetic rats, and all these changes as well as an increase in urinary TNF-alpha excretion were completely or partially prevented by ISO and GPI-15427. PARP inhibition counteracted diabetes-induced up-regulation of endothelin (B) receptor, podocyte loss, accumulation of collagen-alpha1 (IY), periodic acid-Schiff-positive substances, fibronectin, and advanced glycation end-products in the renal cortex. In conclusion, PARP activation is implicated in multiple changes characteristic for early nephropathy associated with type 1 diabetes. These findings provide rationale for development and further studies of PARP inhibitors and PARP inhibitor-containing combination therapies.
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PMID:Poly(Adenosine 5'-diphosphate-ribose) polymerase inhibition counteracts multiple manifestations of experimental type 1 diabetic nephropathy. 1985 69


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