Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenosine, an intercellular messenger that is a product of the metabolism of ATP, plays a major role in neuronal and vascular responses of the retina to alterations in oxygen delivery. Significant changes in adenosine concentration have been measured in the retina during both ischemia and during the subsequent reperfusion period which result in important, but complex, functional effects. Adenosine A1 receptor stimulation produces a protective effect during ischemia, whereas overstimulation of the A2a receptor has deleterious effects. The mechanisms underlying these findings have not been completely determined, but most likely are the result of alterations in excitotoxicity, gene expression, and blood flow. Paradoxically, prolonged increases in adenosine concentration may be injurious to the retina, a consequence of superoxide radical formation secondary to adenosine catabolism. Adenosine is a critical mediator of blood flow changes in response to ischemia. It is a significant component of the retina's compensatory hyperemic response to ischemia, hypoxia, and hypoglycemia. Increasing endogenous adenosine concentrations may be useful in ameliorating post-ischemic hypoperfusion. Overall, current evidence suggests that adenosine is a vital component of the endogenous retinal response to substrate deprivation. Additionally, in vitro studies provide strong evidence that adenosine is a mediator of the formation and effects of vascular endothelial growth factor, which in turn promotes neovascularization. Finally, the ability of the retina to develop an ischemia-tolerant state by ischemic preconditioning is an intriguing phenomenon that reveals yet another essential role for adenosine in the retina's endogenous response to ischemia. The experimental results described in this review suggest that continued investigation into the role of adenosine in the retina may lead to important clinical applications for adenosine-based therapies that could decrease the incidence of retinal damage in ischemic vasculopathies such as diabetes, glaucoma, and retinal vascular occlusion.
 ...
PMID:The purine nucleoside adenosine in retinal ischemia-reperfusion injury. 1039 21

Insulin-dependent diabetes mellitus (IDDM), is characterized by a lack of insulin production from beta cells in the pancreas. One of the metabolic consequences of this insulin deficit is an increased hepatic synthesis of ketone bodies, resulting in a serious medical complication, diabetic ketoacidosis (DKA). DKA, in turn, has been associated with the development of cerebral edema. The severity of this complication ranges from death to a subclinical presentation, but seems to be invariably present to some degree. The etiology of the cerebral edema is unknown, but changes in osmolality, pH, and insulin effects on the blood-brain barrier have all been suggested as possible culprits. Blood-brain barrier impermeability is maintained by the endothelial cells (EC) lining the blood vessels. Thus, it would seem likely that alterations in EC function would be necessary for the development of cerebral edema. However, no studies have examined the effects of ketone bodies on brain endothelial cells. The two major ketone bodies in DKA are acetoacetate (AcAc) and beta-hydroxybutyrate (BOHB). In the present study we examined the effect of these ketone bodies on a major intracellular signalling pathway. The changes in intracellular calcium concentration, and the production of two vasoactive peptides, endothelin-1 (ET-1) and vascular permeability factor (VPF/VEGF) in mouse brain microvascular endothelial cells (MBMEC). The present studies demonstrate the BOHB can increase vascular permeability factor. In contrast, AcAc increases the production of the potent vasoconstrictor, endothelin-1. This data would suggest that brain ECs are potential targets of the metabolic alterations in DKA.
J Diabetes Complications
PMID:Acetoacetate and beta-hydroxybutyrate differentially regulate endothelin-1 and vascular endothelial growth factor in mouse brain microvascular endothelial cells. 1043 73

Much of the morbidity and mortality associated with diabetes is primarily attributable to sequelae of microvascular and macrovascular disease. Over the past decade, dramatic progress has been achieved in elucidating the fundamental processes underlying the pathogenesis of these complications. Angiogenic factors in particular now appear to play a pivotal role in the development of microvascular complications as well as the response to macrovascular disease. Hyperglycemia, other growth factors, advanced glycation end products, oxidative stress, and ischemia can increase growth factor expression. In some microvascular tissues, the result is pathologic neovascularization and increased vascular permeability. These responses account for much of the visual loss associated with diabetic retinopathy and may, in addition, serve a significant role in nephropathy and neuropathy. In contrast, recent data suggest that vascular collateralization resulting from ischemia-induced growth factor release in tissues compromised by macrovascular disease may be important in reducing clinical symptoms and tissue damage. This angiogenic response, which may be beneficial in coronary artery and peripheral limb disease, appears to be reduced in patients with diabetes. Thus, two apparently diametrically opposed therapeutic paradigms are arising for the treatment of vascular complications in diabetes. Indeed, growth factor antagonists have been used successfully in diabetes-related animal models to block angiogenic and permeability complications in the retina and kidney. Conversely, growth factor agonists have been successfully used to stimulate collateral vessel formation and reduce ischemic symptoms from macrovascular disease in the coronary arteries and peripheral limbs. Both of these approaches are currently being evaluated in clinical trials for their respective indications. Thus, as these divergent therapeutic modalities begin to enter the clinical arena, this apparent paradox necessitates careful consideration of the potential risks, benefits, and interactions of the opposing regimens. Using vascular endothelial growth factor as a classic example of growth factor involvement, we discuss the current preclinical and clinical data supporting these approaches and the implications arising from the probable coexistence of these two therapeutic modalities.
Diabetes 1999 Oct
PMID:Vascular endothelial growth factor and diabetes: the agonist versus antagonist paradox. 1051 52

It has been suggested that the cytokine vascular endothelial growth factor (VEGF) has an important role in the pathogenesis of diabetic retinopathy, but its role in nephropathy has not been clearly demonstrated. Assessment of VEGF, 125I-VEGF binding, and vascular endothelial growth factor receptor-2 (VEGFR-2) in the kidney was performed after 3 and 32 weeks of streptozotocin-induced diabetes. Gene expression of both VEGF and VEGFR-2 was assessed by Northern blot analysis and the localization of the ligand and receptor was examined by in situ hybridization. VEGF and VEGFR-2 protein were also evaluated by immunohistochemistry. Binding of the radioligand 125I-VEGF was evaluated by in vitro and in vivo autoradiography. Diabetes was associated with increased renal VEGF gene expression. VEGF mRNA and protein were localized to the visceral epithelial cells of the glomerulus and to distal tubules and collecting ducts in both diabetic and nondiabetic rats. Renal VEGFR-2 mRNA was increased after 3 weeks of diabetes but not in long-term diabetes. In situ hybridization and immunohistochemical studies revealed that glomerular endothelial cells were the major site of VEGFR-2 expression. In addition, VEGFR-2 gene expression was detected in cortical and renomedullary interstitial cells and on endothelial cells of peritubular capillaries. There was an increase in 125I-VEGF binding sites after 3 but not 32 weeks of diabetes. The major VEGF binding sites were in the glomeruli. 125I-VEGF binding was also observed in medullary rays and in the renal papillae. These studies indicate an early and persistent increase in renal VEGF gene expression in association with experimental diabetes. In addition, an early and transient increase in renal VEGF receptors was also observed in diabetic rats. These findings are consistent with a role for VEGF in mediating some of the changes observed in the diabetic kidney.
Diabetes 1999 Nov
PMID:Increased renal expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in experimental diabetes. 1053 59

Although insulin-like growth factor 1 (IGF-1) has been associated with retinopathy, proof of a direct relationship has been lacking. Here we show that an IGF-1 receptor antagonist suppresses retinal neovascularization in vivo, and infer that interactions between IGF-1 and the IGF-1 receptor are necessary for induction of maximal neovascularization by vascular endothelial growth factor (VEGF). IGF-1 receptor regulation of VEGF action is mediated at least in part through control of VEGF activation of p44/42 mitogen-activated protein kinase, establishing a hierarchical relationship between IGF-1 and VEGF receptors. These findings establish an essential role for IGF-1 in angiogenesis and demonstrate a new target for control of retinopathy. They also explain why diabetic retinopathy initially increases with the onset of insulin treatment. IGF-1 levels, low in untreated diabetes, rise with insulin therapy, permitting VEGF-induced retinopathy.
 ...
PMID:Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor. 1058 Oct 81

Hyperglycemia in diabetes induces increased levels of hydrogen peroxide (H2O2), a reactive oxygen species generated by reduced nicotinamide adenine dinucleotide (NADH) oxidase. Nontoxic levels of H2O2 increase endothelial cell permeability. Using a model of non-insulin-dependent diabetes, the BBZ/Wor rat, we investigated retinal levels of H2O2, vascular endothelial growth factor (VEGF) and its receptors, VEGF-R1 and VEGF-R2 by transmission electron microscopy at sites of the blood-retinal barrier (BRB). H2O2 localization was done by the cerium NADH oxidase method, and extravasation of endogenous serum albumin was used to document disruption of the BRB. Higher levels of H2O2 were detected in blood vessels of diabetic (78.7 +/- 4.84%) as compared with vessels from nondiabetic rats (39.0 +/- 4.47%). VEGF immunoreactivity was statistically higher in the inner BRB (24.67 +/- 0.33 colloidal gold particles/63 microm2 vs. 21.52 +/- 0.43 colloidal gold particles/63 microm2, p = .0001) and outer BRB (42.56 +/- 0.45 colloidal gold particles/63 microm2 vs. 15.51 +/- 0.51 colloidal gold particles/63 microm2, p = .0001) of diabetic rats as compared with age matched nondiabetic control rats. VEGF-R1 immunoreactivity was significantly higher in diabetic retinas in both the inner BRB (21.66 +/- 0.75 colloidal gold particles/63 microm2 vs. 12.69 +/- 0.61 colloidal gold particles/63 microm2, p = .0001) and outer BRB (22.76 +/- 2.36 colloidal gold particles/63 microm2 vs. 8.53 +/- 2.67 colloidal gold particles/63 microm2, p = .0013). VEGF-R2 was statistically higher in the inner BRB (8.97 +/- 0.57 colloidal gold particles/63 microm2 versus 7.03 +/- 0.65 colloidal gold particles/63 microm2, p = .0419) but not in the outer BRB (29.42 +/- 1.25 colloidal gold particles/63 microm2 vs. 28.07 +/- 1.42 colloidal gold particles/63 microm2, p = .4889). H2O2 levels correlated with increased VEGF (correlation coefficient = 0.82, p = .001) in this model of nonproliferative diabetic retinopathy. These results support that hyperglycemia is one factor that induces retinal endothelial cells in vivo to increase H2O2 via NADH oxidase and stimulates increases in VEGF resulting in disruption of the BRB.
 ...
PMID:Increased H2O2, vascular endothelial growth factor and receptors in the retina of the BBZ/Wor diabetic rat. 1065 95

We investigated the effect of diabetes-associated growth factors on the expression of insulin-like growth factor-I (IGF-I) and IGF-binding proteins (IGFBPs) in cultured endothelial cells from bovine aorta. Gene expression was measured by solution hybridization, and proteins were measured by enzyme-linked immunosorbent assay, RIA, or Western blot. The cells expressed messenger RNA (mRNA) for IGFBP-2 through -6 and IGFBP-2 through -5 proteins were detected in conditioned medium. Vascular endothelial growth factor inhibited IGFBP-3 mRNA (P < 0.01) and protein expression and increased IGFBP-5 mRNA (P < 0.001) and protein. Transforming growth factor-beta1 inhibited IGFBP-3 (P < 0.01), IGFBP-4 (P < 0.01), and IGF-I mRNA expression, whereas at the protein level only IGFBP-3 was significantly decreased. IGF-I, insulin, or angiotensin II did not affect IGF-I or IGFBP mRNA expression. At the protein level, IGF-I clearly increased IGFBP-5 levels in conditioned medium. In conclusion, vascular endothelial growth factor and transforming growth factor-beta1 regulate IGFBP expression in bovine aortic endothelial cells. These observations provide a new aspect of regulation for the IGF-system in macrovascular endothelium, with possible implications for subendothelial smooth muscle cells and development of diabetic angiopathy.
 ...
PMID:Vascular endothelial growth factor and transforming growth factor-beta1 regulate the expression of insulin-like growth factor-binding protein-3, -4, and -5 in large vessel endothelial cells. 1083 Feb 91

This study concerns whether advanced glycation endproducts (AGE) are related to microvascular derangement in diabetes, exemplified by pericyte loss and angiogenesis in retinopathy and by mesangial expansion in nephropathy. AGE caused a decrease in viable pericytes cultivated from bovine retina. On the other hand, AGE stimulated the growth and tube formation of human microvascular endothelial cells (EC), this being mediated by autocrine vascular endothelial growth factor. In AGE-exposed rat mesangial cells, type IV collagen synthesis was induced. Those AGE actions were dependent on a cell surface receptor for AGE (RAGE), because they were abolished by RAGE antisense or ribozyme. The AGE-RAGE system may thus participate in the development of diabetic microangiopathy. This proposition was supported by experiments with animal models; several indices characteristic of retinopathy were correlated with circulating AGE levels in OLETF rats. The predisposition to nephropathy was augmented in RAGE transgenic mice when they became diabetic.
 ...
PMID:Roles of the AGE-RAGE system in vascular injury in diabetes. 1086 36

Alteration of endothelins (ET) and/or their receptors may be important in mediating vascular dysfunction in diabetes. We investigated mechanisms regulating ET-1 expression in human umbilical vein endothelial cells (HUVEC) in response to glucose and the functional significance of these mechanisms. Permeability across HUVEC, grown in medium containing either low (5 mmol/l) or high (25 mmol/l) D-glucose were investigated. L-glucose was used as a control. ET-1, ET(A), and ET(B) mRNA were assessed by semiquantitative RT-PCR. ET-1 immunoreactivity and F-actin microfilament assembly were investigated using confocal microscopy. Increased transendothelial permeability was noted in cells cultured in high glucose or when the cells grown in low (physiologic) glucose were incubated with ET-1, vascular endothelial growth factor (VEGF), or N (G) -nitro-L-arginine methyl ester but not when they were incubated with ET-3, N(G)-nitro-D-arginine methyl ester, or L-glucose. Increased permeability was associated with increased ET-1, ET(A), and ET(B) mRNA expression and augmented ET-1 immunoreactivity. High glucose induced increased permeability, increased ET-1, ET(A), and ET(B) mRNA expression. ET-1 immunoreactivity was blocked by the protein kinase C (PKC) inhibitor chelerythrine, the specific PKC isoform inhibitor 379196, VEGF-neutralizing antibody, or the ET(A) blocker TBC11251, but was not blocked by the specific ET(B) blocker BQ788 or by a VEGF-non-neutralizing antibody. Increased permeability was also associated with deranged F-actin assembly in the endothelial cells and by derangement of endothelial cell junctions as assessed by electron microscopy. Data from this study suggest that high glucose-induced increased permeability may be induced through increased ET-1 expression and disorganization of F-actin assembly. ET-1 expression and increased permeability may occur secondary to PKC isoform activation and may be modulated by VEGF and nitric oxide.
 ...
PMID:Interaction of endothelin-1 with vasoactive factors in mediating glucose-induced increased permeability in endothelial cells. 1095 Jan 22

Macrophage dysfunction is a likely mechanism underlying common diabetic complications such as increased susceptibility to infection, accelerated atherosclerosis, and disturbed wound healing. There are no available studies on the function of tissue macrophages in diabetes in humans. We have therefore studied peritoneal macrophages from diabetic type 2-like db/db mice. We found that the release of tumor necrosis factor-alpha and interleukin-1beta from lipopolysaccharide plus interferon-gamma-stimulated macrophages and vascular endothelial growth factor from both stimulated and nonstimulated macrophages was significantly reduced in diabetic animals compared with nondiabetic controls. Nitric oxide production from the stimulated db/db macrophages was significantly higher than that in the db/+ cultures, whereas there was no difference in their ability to generate reactive oxygen species. When studied both at light and electron microscopic levels, macrophages in diabetic animals had an altered morphological appearance compared with those of normal controls. We conclude that the function and morphology of the macrophages are disturbed in db/db mice and that this disturbance is related to the mechanisms underlying common inflammatory and degenerative manifestations in diabetes.
Diabetes 2000 Sep
PMID:Altered cytokine and nitric oxide secretion in vitro by macrophages from diabetic type II-like db/db mice. 1096 28


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>