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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The introduction of ocular photocoagulation, almost thirty years ago, was the first successful prevention of blindness from diabetic retinopathy in some patients. The development of lasers, and the growing knowledge of indications for their application, reached the point at which the growth of new blood vessels could be stopped or reversed, and legal blindness from macular oedema avoided in about half of the treated eyes. The attempts at the very prevention of diabetic retinal microvascular complications at some more physiological, even molecular level, aside from the palliative treatment by photocogulation, brought some new and exciting results which are reviewed here. First, and foremost, is the understanding of the importance of the tight blood glucose control which, if started early and kept long enough, slows down the development of retinal lesions and offers a better prognosis for vision in a substantial number of diabetic patients. Second, the development of a unique animal model of proliferative retinopathy which mirrors human disease both chemically and histopathologically offers a field for investigation of both pathogenesis and therapy of this most dreadful complication of diabetes. Finally, there is a bulk of new evidences about the key role of vascular endothelial growth factor/vascular permeability factor in ocular angiogenesis which will probably result in the new approach to the prevention of neovascular growth by inhibition or modulation of VEGF/VPF activity.
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PMID:[On the threshold of new treatment of diabetic retinopathy]. 922 17

We determined the plasma concentration of immunoreactive vascular endothelial growth factor (IR-VEGF) and searched for a relationship between it and the degree of microangiopathy. The plasma VEGF level was measured using an enzyme immunoassay in 110 non-insulin-dependent diabetes mellitus (NIDDM) patients with varying degrees of nephropathy or retinopathy (RP) and in 39 healthy controls and 30 nondiabetic patients for comparison. One fourth of the control subjects, 60% of whom were currently smokers, had plasma levels of IR-VEGF higher than the lower limit (15.6 pg/mL) of detection for this assay, whereas this was the case in half of the NIDDM patients. Plasma IR-VEGF was detectable in all patients with cerebral infarction, chronic renal failure, and severe infection, suggesting that tissue hypoxia might be a common cause for the elevation of plasma VEGF in these disorders. The prevalence of measurable plasma IR-VEGF levels increased in parallel with increases in the urinary albumin excretion rate ([UAER] 35.1% for UAER <30 mg/24 h, 54.8% for UAER 30 to 300 mg/24 h, and 61.3% for UAER >300 mg/24 h; P < .05 v UAER <30 mg/24 h). The mean measurable plasma concentration tended to increase with increasing UAER. However, there was no such correlation with the severity of RP. Smoking caused an acute increase of plasma IR-VEGF in only 22.6% (12 of 53) of the patients with a smoking habit. In conclusion, these findings suggest that circulating IR-VEGF may be linked to the progression of nephropathy, and smoking may facilitate this process by causing tissue hypoxia in susceptible patients.
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PMID:Plasma concentration of immunoreactive vascular endothelial growth factor and its relation to smoking. 944 Apr 73

Diabetes mellitus is complicated with vascular disorders such as atherosclerosis (macroangiopathy) and retinopathy (microangiopathy). In macroangiopathy, AGE plays an important role in atherogesis through NF-kappa B activation, that induces VCAM-1 and MCP-1. Diabetic retinopathy is based on the microangiopathy characteristic of angiogenesis. VEGF is a key substance in the angiogenesis in the retina. VEGF is produced from retinal cells exposed to AGE, adenosine, bFGF. VEGF elictes angiogenesis and increased vascular permeability (retinal edema). I consider that AGE is the most important substance in diabetic vascular disorder. Therefore, I expect a new application for diabetic angiopathy to suppress the effect of AGE.
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PMID:[Vascular endothelial cell dysfunction in diabetes mellitus]. 1019 36

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

Prostacyclin-stimulating factor (PSF) acts on vascular endothelial cells to stimulate the synthesis of the vasodilatory molecule prostacyclin (PGI2). We have examined the expression, regulation, and hemodynamic bioactivity of PSF both in whole retina and in cultured cells derived from this tissue. PSF was expressed in all retinal cell types examined in vitro, but immunohistochemical analysis revealed PSF mainly associated with retinal vessels. PSF expression was constitutive in retinal pericytes (RPCs) but could be modulated in bovine retinal capillary endothelial cells (RECs) by cell confluency, hypoxia, serum starvation, high glucose concentrations, or inversely by soluble factors present in early vs. late retinopathy, such as TGF-beta, VEGF, or bFGF. In addition, RPC-conditioned media dramatically increased REC PGI2 production, a response inhibited by blocking PSF with a specific antisense oligodeoxynucleotide (ODN). In vivo, PGI2 increased retinal blood flow (RBF) in control and diabetic animals. Furthermore, the early drop in RBF during the initial weeks after inducing diabetes in rats, as well as the later increase in RBF, both correlated with levels of retinal PSF. RBF also responded to treatment with RPC-conditioned media, and this effect could be partially blocked using the antisense PSF ODN. We conclude that PSF expressed by ocular cells can induce PGI2, retinal vascular dilation, and increased retinal blood flow, and that alterations in retinal PSF expression may explain the biphasic changes in RBF observed in diabetes.
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PMID:Retinal expression, regulation, and functional bioactivity of prostacyclin-stimulating factor. 1095 29

Coagulation abnormalities, including an increased platelet turnover, are frequently found in patients with cancer. Because platelets secrete angiogenic factors on activation, this study tested the hypothesis that platelets contribute to angiogenesis. Stimulation with vascular endothelial growth factor (VEGF, 25 ng/mL) of human umbilical vein endothelial cells (HUVECs) promoted adhesion of nonactivated platelets 2.5-fold. In contrast, stimulation of HUVECs with basic fibroblast growth factor (bFGF) did not promote platelet adhesion. By blocking tissue factor (TF) activity, platelet adhesion was prevented and antibodies against fibrin(ogen) and the platelet-specific integrin, alpha(IIb)beta(3), inhibited platelet adhesion for 70% to 90%. These results indicate that VEGF-induced platelet adhesion to endothelial cells is dependent on activation of TF. The involvement of fibrin(ogen) and the alpha(IIb)beta(3) integrin, which exposes a high-affinity binding site for fibrin(ogen) on platelet activation, indicates that these adhering platelets are activated. This was supported by the finding that the activity of thrombin, a product of TF-activated coagulation and a potent platelet activator, was required for platelet adhesion. Finally, platelets at physiologic concentrations stimulated proliferation of HUVECs, indicative of proangiogenic activity in vivo. These results support the hypothesis that platelets contribute to tumor-induced angiogenesis. In addition, they may explain the clinical observation of an increased platelet turnover in cancer patients. Platelets may also play an important role in other angiogenesis-dependent diseases in which VEGF is involved, such as diabetes and autoimmune diseases. (Blood. 2000;96:4216-4221)
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PMID:Vascular endothelial growth factor-stimulated endothelial cells promote adhesion and activation of platelets. 1111 Jun 94

Major congenital malformations, including those affecting the cardiovascular system, remain the leading cause of mortality and morbidity in infants of diabetic mothers. Interestingly, targeted mutations of several genes (including VEGF and VEGF receptors) and many teratogenic agents (including excess D-glucose) that give rise to embryonic lethal phenotypes during organogenesis are associated with a failure in the formation and/or maintenance of a functional vitelline circulation. Given the similarities in the pathology of the abnormal vitelline circulation in many of these conditions, we hypothesized that the hyperglycemic insult present in diabetes could cause the resultant abnormalities in the vitelline circulation by affecting VEGF/VEGF receptor signaling pathway(s). In this study we report that hyperglycemic insult results in reduced levels of VEGF-A in the conceptus, which in turn, leads to abnormal VEGF receptor signaling, ultimately resulting in embryonic (vitelline) vasculopathy. These findings and our observation that addition of exogenous rVEGF-A(165) within a defined concentration range blunts the hyperglycemia-induced vasculopathy in the conceptus support the concept that VEGF levels can be modulated by glucose levels. In addition, these findings may ultimately lead to novel therapeutic approaches for the treatment of selected congenital cardiovascular abnormalities associated with diabetes.
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PMID:Hyperglycemia-induced vasculopathy in the murine conceptus is mediated via reductions of VEGF-A expression and VEGF receptor activation. 1129 May 33

The pathogenetic basis for diabetic neuropathy has been enigmatic. Using two different animal models of diabetes, we have investigated the hypothesis that experimental diabetic neuropathy results from destruction of the vasa nervorum and can be reversed by administration of an angiogenic growth factor. Nerve blood flow, as measured by laser Doppler imaging or direct detection of a locally administered fluorescent lectin analogue, was markedly attenuated in rats with streptozotocin-induced diabetes, consistent with a profound reduction in the number of vessels observed. A severe peripheral neuropathy developed in parallel, characterized by significant slowing of motor and sensory nerve conduction velocities, compared with nondiabetic control animals. In contrast, 4 weeks after intramuscular gene transfer of plasmid DNA encoding VEGF-1 or VEGF-2, vascularity and blood flow in the nerves of treated animals were similar to those of nondiabetic control rats; constitutive overexpression of both transgenes resulted in restoration of large and small fiber peripheral nerve function. Similar experiments performed in a rabbit model of alloxan-induced diabetes produced comparable results. These findings support the notion that diabetic neuropathy results from microvascular ischemia involving the vasa nervorum and suggest the feasibility of a novel treatment strategy for patients in whom peripheral neuropathy constitutes a secondary complication of diabetes.
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PMID:Reversal of experimental diabetic neuropathy by VEGF gene transfer. 1137 8

LANGERHANS ISLET TRANSPLANTATION: Early results have been promising with insulin production in all cases two years after transplantation. These encouraging results have been obtained with a specifically designed protocol for islet harvesting, immunosuppression and transplantation of a large quantity of islets from several donors. EARLY IMMUNOSUPPRESSION: Since diabetes mellitus type 1 is an autoimmune disease, immunosuppression could be a most interesting etiopathological solution. Results obtained both in mouse models and in humans given monoclonal humanized anti-lymphocyte T antibodies (hOKT3 gamma 1) during the first 6 weeks following diagnosis have been quite encouraging. TWO APPROACHES TO GENE THERAPY: For the first, the goal is to improve the transplantation technique by isolating the islets in vitro in an attempt to improve their function via ex vivo transfection of different genes. The second approach aims at treatment of the complications of diabetes, particularly lower limb arteritis and coronary artery disease. Here the vector is an adenovirus carrying a gene coding for VEGF, a growth factor with proangiogenic action.
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PMID:[Prevention and treatment of type 1 diabetes]. 1157 80

Early induction of VEGF was studied in liver, kidney and lung of spontaneously diabetic rats. Western blot analysis, northern hybridization were applied to show the expression of VEGF in different organs. Radiolabelled hypoxia responsive element (HRE) and cAMP responsive element (CRE) oligonucleotides were assayed by electrophoretic mobility shift (EMSA) or supershift using anti ARNT and anti CREB-1 monoclonal antibodies. An increase in VEGF expression at the level of protein and mRNA was demonstrated at the beginning of the disease. EMSAs showed: a.) a binding of HIF-1 to HRE and/or CRE, b.) in the same time the binding of CREB- I was detected to both HRE and/or CRE sequences in the liver, kidney and lung of diabetic animals. Based on these in vivo observations it is supposed that HRE and CRE through the interaction between HIF-1 and CREB-1 are equally involved in the regulation of VEGF expression at the onset of diabetes.
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PMID:The regulation of the induction of vascular endothelial growth factor at the onset of diabetes in spontaneously diabetic rats. 1169 60


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