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)

Adenosine transport in cultured human umbilical vein endothelial cells (HUVEC) was characterized and shown to be mediated by a single facilitated diffusion mechanism. Initial rates of adenosine influx at 22 degrees C were saturable [apparent Michaelis constant, 69 +/- 10 microM; maximum velocity (Vmax), 600 +/- 70 pmol.10(6) cells-1.s-1] and inhibited by nitrobenzylthioinosine (NBMPR). Formycin B had an unusually high affinity [inhibitory constant (Ki), 18 +/- 4.3 microM], whereas inosine had a low affinity (Ki, 440 +/- 68 microM) and nucleobases were without effect on adenosine influx. The number of transporters (1.2 x 10(6) sites/cell) was estimated by NBMPR equilibrium binding (apparent dissociation constant, 0.11 +/- 0.01 nM; maximum binding, 2.0 +/- 0.15 pmol/10(6) cells). In addition, we compared these endothelial cells with those obtained from cords from pregnancies complicated by diabetes (HUVEC-D), since embriopathy may occur in these conditions. HUVEC-D exhibited a 2.3-fold reduction in both the Vmax for adenosine influx and the maximum number of NBMPR binding sites (260 +/- 40 pmol.10(6) cells-1.s-1 and 0.86 +/- 0.08 pmol/10(6) cells, respectively). However, the turnover number for each nucleoside transporter in normal and diabetic HUVEC was similar (approximately 300 adenosine molecules/s). Adenosine metabolism at 10 microM in HUVEC-D was modified compared with normal cells. Intracellular phosphorylation (> 90%) was the predominant pathway in normal HUVEC, whereas in HUVEC-D, substantial levels of adenine and adenosine were detected. The present results demonstrate therefore the downregulation of the NBMPR-sensitive nucleoside transporter and changes in adenosine metabolism in HUVEC from diabetic pregnancies.
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PMID:Adenosine transport in cultured human umbilical vein endothelial cells is reduced in diabetes. 804 91

Twenty-five newly diagnosed cases of noninsulin-dependent diabetes mellitus were studied at the time of diagnosis and again after metabolic control of diabetes was achieved (approximately 3 months later) for platelet aggregation abnormalities in whole blood by the impedance method. Adenosine diphosphate in 10 and 20 mumol/L final concentrations and arachidonic acid in 25 and 50 mmol/L final concentrations were used as agonists. Patients had a significant hyperaggregation of platelets (P < 0.01) at the time of diagnosis compared with age-matched healthy control subjects. After metabolic control of blood glucose was achieved using oral hypoglycemic agents (n = 20) and diet regulation alone (n = 5), there was a significant decrease in platelet aggregation (P < 0.01). There was a positive relationship between blood glucose levels and whole blood platelet aggregation with adenosine diphosphate (P < 0.02 and < 0.05, with 10 mumol/L and 20 mumol/L, respectively), but there was no relationship between aggregation and glycosylated hemoglobin levels. Thus, platelet hyperaggregation was present even at the time of diagnosis in patients with diabetes mellitus in the absence of any vascular complications, and there was significant improvement in platelet hyperaggregation after metabolic control of blood glucose levels was achieved.
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PMID:Hyperaggregation of platelets detected by whole blood platelet aggregometry in newly diagnosed noninsulin-dependent diabetes mellitus. 835 39

Nerve growth factor (NGF) is a potent neurotrophin signaling protein, the best-known member of a family of similar neurotrophins. Specific neuronal populations depend upon the neurotrophins for normal function and disturbances in NGF and neurotrophin supply have been implicated in neurodegenerative disease, diabetes, and hypertension. This report details experiments in which the hourly pattern of NGF secretion by cultured vascular smooth muscle cells is examined. Vascular smooth muscle cells are major innervation targets of the neuronal population first discovered to be NGF-dependent: the sympathetic principal neurons. The results show that arginine vasopressin (AVP), angiotensin II (AngII), and alpha-adrenergic receptor activation, all contractile stimuli, elevate NGF secretion. However, AVP dependably does so alone while AngII requires coactivation of adenosine receptors. Adenosine alone inhibits secretion and the alpha-adrenergic increase in NGF output can be antagonized by activation of beta-adrenergic receptors. A change to fresh culture medium is also a potent stimulus to increased NGF output.
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PMID:Receptor-mediated stimulation and inhibition of nerve growth factor secretion by vascular smooth muscle. 839 98

1. There is evidence to suggest that adenosine may regulate arterial smooth muscle cell (SMC) growth and proliferation, which is a key event in atherogenesis. This regulation may be mediated via adenylate cyclase. As diabetes is a known risk factor for atherosclerosis, we investigated the growth of aortic SMC from diabetic rats in primary culture and their sensitivity to adenosine and to adenylate cyclase activity. 2. Diabetes was induced with streptozotocin (STZ, 66 mg kg-1, i.p.) Aortic SMC primary cultures were prepared from STZ-diabetic and age-matched rats 5 weeks after the STZ injection. 3. SMC from STZ-diabetic rats grew faster and reached greater densities at confluence than those from non-diabetic animals. 4. Adenosine inhibited growth in both control and diabetic SMC. However, cells from STZ-diabetic rats were apparently more sensitive to adenosine. 5. Direct activation of adenylate cyclase by forskolin induced a dose-dependent growth inhibition, similar in both groups of cells. 6. Cholera toxin, an activator of stimulatory GTP-binding protein (Gs), induced a similar growth inhibitory response in non-diabetic and diabetic SMC. Pertussis toxin (PTX), an inactivator of inhibitory GTP-binding protein (Gi), did not itself affect SMC growth. However, PTX increased dose-dependently the growth inhibition induced by adenosine in SMC from non-diabetic rats but not in SMC from diabetic rats. 7. These findings suggest a functional abnormality in Gi activity in SMC from diabetic rats, that would explain the increased sensitivity to the nucleoside. This impaired inhibitory pathway may reflect changes in the growth regulation of SMC in experimental diabetic states.
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PMID:Adenosine inhibitory effect on enhanced growth of aortic smooth muscle cells from streptozotocin-induced diabetic rats. 876 8

Adenosine myocardial perfusion single-photon emission computed tomography (SPECT) is now increasingly used for risk stratification of patients with known or suspected coronary artery disease. However, the incremental prognostic value of this test over clinical and historical information in a large series of women has not been examined. Thus, we studied 923 consecutive women who underwent adenosine technetium (Tc)-99m sestamibi myocardial perfusion SPECT and were followed-up for a mean period of 26+/-8 months. During the follow-up period, 77 hard events (46 cardiac deaths and 31 nonfatal myocardial infarctions) occurred. The results of the perfusion scan significantly risk stratified the population; patients with normal scans had a low rate of nonfatal myocardial infarction and cardiac death (< 1%/year of follow up). Patients with mildly abnormal scans had low cardiac death rates (0.9%/year of follow up); these rates increased as a function of scan abnormality (4.1% and 7.5% mortality per year of follow up in moderate and severely abnormal scans). Cox proportional hazards analysis demonstrated that after adjusting for prior myocardial infarction and diabetes mellitus (the most predictive individual clinical variables [global chi-square=22.5, p <0.001]), as well as heart rate at rest (the most predictive physiologic variable [chi-square=3.8; p=0.05]), the most predictive nuclear variable (summed stress score [chi-square=48.5; p <0.0001]) added significant incremental prognostic information (global chi-square increased from 22.5 to 56.2 [p <0.0001]). In conclusion, adenosine myocardial perfusion SPECT added significant incremental prognostic information to clinical and physiologic variables in women. Normal scans were associated with an excellent prognosis. In contrast, patients with moderately to severely abnormal scans were at a higher risk for future cardiac events.
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PMID:Incremental prognostic value of adenosine myocardial perfusion single-photon emission computed tomography in women with suspected coronary artery disease. 976 Oct 81

Adenosine in the extracellular space modulates stimulated glucose transport in striated muscle. In the heart and in adipocytes, adenosine potentiates insulin-stimulated glucose transport. There is controversy regarding the effect of adenosine in skeletal muscle, with reports of both an inhibitory effect and no effect, on insulin-stimulated glucose transport. We found that, in rat epitrochlearis and soleus muscles, removing adenosine with adenosine deaminase or blocking its action with the adenosine receptor blocker CPDPX markedly reduces the responsiveness of glucose transport to stimulation by 1) insulin alone, 2) contractions alone, and 3) insulin and contractions in combination. Measurement of the increase in GLUT4 at the cell surface in response to a maximally effective insulin stimulus in the epitrochlearis muscle, using the exofacial label ATB-[3H]BMPA, showed that adenosine deaminase treatment markedly reduces cell-surface GLUT4 labeling. The reduction in cell-surface GLUT4 labeling was similar in magnitude to the decrease in maximally insulin-stimulated glucose transport activity in adenosine deaminase-treated muscles. These results show that adenosine potentiates insulin- and contraction-stimulated glucose transport in skeletal muscle by enhancing the increase in GLUT4 at the cell surface and raise the possibility that decreased adenosine production or action could play a causative role in insulin resistance.
Diabetes 1998 Nov
PMID:Removal of adenosine decreases the responsiveness of muscle glucose transport to insulin and contractions. 979 34

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.
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PMID:The purine nucleoside adenosine in retinal ischemia-reperfusion injury. 1039 21

Leptin, the ob gene product that can decrease caloric intake and increase energy expenditure, is functionally released by insulin from adipose tissue. Adenosine is thought to be an important regulator of the action of insulin in adipose tissue. The present study investigated the role of adenosine in the release of leptin by insulin in isolated rat white adipocytes. Release of leptin, measured by radioimmunoassay, from insulin-stimulated samples was seen after 30 min. Adenosine deaminase, at concentrations sufficient to metabolize endogenous adenosine, decreased insulin-stimulated leptin release. Also, the insulin-stimulated leptin release was completely blocked by the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). Mediation of endogenous adenosine in this action of insulin was further supported by the assay of adenosine released into the medium from adipocytes stimulated with insulin. In addition, activation of adenosine A1 receptors by N6-cyclopentyladenosine (CPA) induced an increase in leptin release in a concentration-dependent manner that could be blocked by antagonists, either DPCPX or 8-(p-sulfophenyl)theophylline (8-SPT). In the presence of U73312, a specific inhibitor of phospholipase C (PLC), CPA-stimulated leptin secretion from adipocytes was reduced in a concentration-dependent manner, but it was not affected by U73343, the negative control for U73312. Moreover, chelerythrine and GF 109203X diminished the CPA-stimulated leptin secretion at concentrations sufficient to inhibit protein kinase C (PKC). These results suggest that, in isolated white adipocytes, the released adenosine acts as a helper and/or a positive regulator for insulin in the release of leptin via an activation of adenosine A1 receptors that involves the PLC-PKC pathway.
Diabetes 2000 Jan
PMID:Role of adenosine in insulin-stimulated release of leptin from isolated white adipocytes of Wistar rats. 1061 45

The present study was aimed at investigating the effects of diabetes on the cavernosal smooth muscle relaxations mediated by adenosine and adenosine triphosphate (ATP) in tissues obtained from men and rats. Adenosine- and ATP-induced relaxant responses showed an enhanced sensitivity with an unaltered effectiveness in diabetic men. Adenosine-elicited relaxation in diabetic rat corporeal tissues exhibited enhanced effectiveness with unaltered sensitivity, whereas ATP-induced relaxations were decreased in diabetic animals when compared to control animals. Tetraethylammonium pretreatment, but not glibenclamide, L-NAME and 8-phenyltheophylline, normalized enhanced apparent affinity to adenosine in tissue from diabetic men and effectiveness (E(max)) to adenosine in diabetic rats. These results suggest that adenosine-elicited relaxation in diabetes is controlled at the receptor level events including K(+) channels in men whereas in rats postreceptor-related events including K(+) channels control the adenosine-induced relaxation. These relaxations to adenosine and ATP in men and rats with and without diabetes may be nitric oxide-independent mechanisms. Our results also suggest that ATP-induced relaxation did not involve K(ATP) channels and Ca-activated K(+) channels.
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PMID:Altered relaxant responses to adenosine and adenosine 5'-triphosphate in the corpus cavernosum from men and rats with diabetes. 1065 60

Adenosine has been implicated as an important endogenous regulator of various tissue functions. In diabetes, the responsiveness of several tissues to adenosine is altered. The aim of this study was to investigate the activities of enzymes metabolizing adenosine in tissues of diabetic rats. The cytosolic activity (V(max)) of adenosine kinase (AK) was decreased by 50% in the kidney and by 40% in the heart and liver of diabetic rats. A decrease in the V(max) of AK in diabetic tissues was not associated with a change in the K(m) for adenosine. Evaluation of AK gene transcript status showed significantly lower levels of AK mRNA in diabetic tissues as compared to normal tissues. In diabetic kidneys, the level of AK gene transcript was lowered by 50% on first day after streptozotocin administration, and these reduced levels were sustained declined during the next 10 days. Smaller changes in AK gene transcript levels were observed in the heart and liver than in the kidney. The cytosolic activities of 5'-nucleotidase, AMP deaminase, and adenosine deaminase were unchanged in kidney, heart, and liver of diabetic rats. These results suggest that the turnover of the AMP-adenosine metabolic cycle might be impaired in diabetic tissues due to the reduced activity of adenosine kinase.
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PMID:Decreased expression of adenosine kinase in streptozotocin-induced diabetes mellitus rats. 1068 43


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