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

Autoimmune diabetes is characterized by an early infiltration of lymphocytes into and around islets, which is followed by selective destruction of the insulin-secreting beta-cell. Cytokines released during this inflammatory reaction have been implicated as effector molecules which mediate beta-cell destruction. In vitro treatment of rat islets with the cytokine IL-1 beta results in an inhibition of glucose-stimulated insulin secretion that is mediated by the overproduction of nitric oxide. IL-1 beta also stimulates the production of the cyclooxygenase (COX) product prostaglandin E2 (PGE2). In this study we have examined the effects of IL-1 beta on both inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (iCOX) expression, and the direct effects of nitric oxide on the activity of COX. Treatment of rat islets with 5 units/mL IL-1 beta induces a similar time-dependent production of both nitrite and PGE2. IL-1 beta-induced nitrite and PGE2 production is attenuated by the NOS inhibitor NG-monomethyl-L-arginine (NMMA), but NMMA has no inhibitory effect on the expression of either iCOX or iNOS as determined by immunoprecipitation. Actinomycin D prevents IL-1 beta-induced iCOX and iNOS expression and the production of both nitrite and PGE2 by islets, suggesting that mRNA transcription is required for IL-1 beta-induced expression of both iNOS and iCOX. The effects of exogenous arachidonic acid on both constitutive COX (cCOX) and iCOX activity were also investigated.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:IL-1 beta induces the coexpression of both nitric oxide synthase and cyclooxygenase by islets of Langerhans: activation of cyclooxygenase by nitric oxide. 750 13

Increased blood flow and vascular permeability of early diabetes have been associated with increased nitric oxide formation in diabetic rats, but the specific nitric oxide synthase responsible is unknown. We examined the modulation of the induction and activity of the inducible NOS isoform by high glucose concentration in a murine macrophage cell line, RAW 264.7, and murine glomerular mesangial cells. Culturing both cell types in high glucose concentration led to significant increases in nitrite production and the mRNA encoding iNOS upon stimulation with LPS plus interferon-gamma, as compared with normal glucose concentration. High glucose also modestly enhanced LPS/IFN-gamma-induced stimulation of the iNOS promoter in transient transfection experiments in mesangial cells. Protein kinase C activation led to enhanced mRNA expression of iNOS, and inhibitors of protein kinase C blocked nitrite accumulation in mesangial cells. These findings suggest that high glucose in combination with stimulation by LPS plus IFN-gamma enhances iNOS expression, and protein kinase C activation may be playing a role in this enhancement.
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PMID:Enhanced expression of inducible nitric oxide synthase in murine macrophages and glomerular mesangial cells by elevated glucose levels: possible mediation via protein kinase C. 753 75

1. There is evidence that endothelial dysfunction is associated with diabetes mellitus. The purpose of the present study was to assess local cerebral blood flow (LCBF) and cerebrovascular responsiveness to the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) in spontaneously diabetic insulin-dependent BioBred (BB) rats. 2. Diabetic rats, and non-diabetic controls, were treated with L-NAME (30 mg kg-1, i.v.) or saline, 20 min prior to the measurement of LCBF by the fully quantitative [14C]-iodoantipyrine autoradiographic technique. 3. There were no significant differences in physiological parameters (blood pH, PCO2, and PO2, rectal temperature, arterial blood pressure, or plasma glucose) between any of the groups of rats, and no difference in either the extent or the temporal characteristics of the hypertensive response to L-NAME between diabetic and non-diabetic rats. 4. In diabetic rats, a global reduction in basal LCBF was observed, although significant reductions (between -20 and -30%) were found in only 5 (mainly subcortical) out of the 13 brain regions measured. Following L-NAME injection, significant reductions in LCBF (between -20 and -40%) were found in the non-diabetic animals. In diabetic animals treated with L-NAME, a significant reduction in LCBF was measured only in the hypothalamus (-33%). 5. The cerebrovascular response to acute L-NAME is attenuated in spontaneously diabetic insulin-dependent BB rats. This would be consistent with the endothelial dysfunction in cerebral vessels, known to be associated with diabetes mellitus and it is possible that a loss of NO-induced dilator tone, amongst other factors, may underlie the observed reductions of basal LCBF in these animals.
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PMID:Cerebrovascular responsiveness to NG-nitro-L-arginine methyl ester in spontaneously diabetic rats. 873 22

The activity of nitric oxide (NO) has been implicated as an important mediator in ovarian function, including the regulation of the blood-follicle barrier and ovulation. Both clinical and experimental diabetes have been found to impair endothelial-dependent vascular activity through the inactivation of NO. It has also been shown that diabetes-induced inactivation of NO can be rescued with administration of insulin as well as with free radical scavengers such as superoxide dismutase (SOD). In this study, we report decreases in both ovulation and the activity of the blood-follicle barrier in insulin-dependent diabetic prepubertal mice treated with exogenous gonadotropic hormones. Moreover, these ovarian defects are rescued with administration of insulin, nitroprusside, L-arginine, and the free radical scavengers citiolone and 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron). We found that the activity of Cu/Zn SOD in the ovaries of diabetic mice used in this study is decreased by 48% compared to that in nondiabetic mice. In contrast, inhibition of SOD activity in nondiabetic mice induces defects in the blood-follicle barrier and ovulation similar to those observed in diabetic mice. Lastly, we report the localization of endothelial nitric oxide synthase, inducible NOS, Cu/Zn SOD, and the LH receptor to the same population of endothelial cells surrounding the preovulatory follicle, supporting our hypothesis that the signaling of ovarian NO within the ovarian microvasculature at the time of ovulation may be compromised in these diabetic mice as a consequence of the loss of the protective activity of Cu/Zn SOD.
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PMID:Diabetes-mediated decreases in ovarian superoxide dismutase activity are related to blood-follicle barrier and ovulation defects. 877 Sep 36

Insulin-dependent diabetes mellitus is an autoimmune disease characterized by the selective destruction of insulin-secreting beta cells found in islets of Langerhans. The biochemical mechanisms associated with beta-cell destruction have remained elusive. Cytokines, released from T lymphocytes, macrophages, and monocytes during islet insulitis, have been implicated as effector molecules that participate in beta-cell death. Recently, cytokine-induced expression of inducible nitric oxide synthase (iNOS) and production of nitric oxide by beta cells has been suggested as one potential mechanism associated with beta-cell destruction. Treatment of rat islets with interleukin 1 (IL-1) results in a potent inhibition of insulin secretion followed by islet destruction. The inhibitory and destructive effects of this cytokine on islet function are completely prevented by the inhibition of iNOS enzymatic activity. Islets contain a heterogeneous population of both endocrine and nonendocrine cells including a low level of resident tissue macrophages ( approximately0.5% of all islet cells). The intraislet macrophage appears to one cellular source of IL-1. Activation of resident islet macrophages results in both the expression of iNOS and the release of IL-1. Intraislet macrophage production of nitric oxide (in the absence of IL-1) does not modulate beta-cell function; however, macrophage release of IL-1 and IL-1-induced iNOS expression by beta cells results in a potent inhibition of beta-cell function. These findings support a role for nitric oxide as a potential mediator of cytokine-induced inhibition of beta-cell function and implicate the intraislet macrophage as one cellular source of IL-1. Direct support for a role of nitric oxide in the development of diabetes includes the ability of inhibitors of iNOS to prevent or delay the development of this disease condition in animal models. Important to these studies has been the identification of selective inhibitors of iNOS. Many inhibitors of nitric oxide synthase have been developed; however, few selective inhibitors for the individual isoforms of NOS (inducible, endothelial, neuronal) have been described. Aminoguanidine has been identified as one of the first iNOS selective inhibitors. Aminoguanidine is over 50-fold more effective at inhibiting the enzymatic activity of iNOS than endothelial or neuronal NOS. The effects of aminoguanidine on the development of diabetes in the nonobese diabetic mouse using an adoptive transfer protocol has been evaluated. Aminoguanidine delays the onset of diabetes in this animal model by 7-10 days. These studies, which provide in vivo evidence implicating a role for nitric oxide in the development of autoimmune diabetes, also support the use of selective inhibitors of iNOS for the attenuation of disease conditions associated with the expression of iNOS and an increased production of nitric oxide.
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PMID:The Use of Aminoguanidine, a Selective iNOS Inhibitor, to Evaluate the Role of Nitric Oxide in the Development of Autoimmune Diabetes 881 41

Interleukin-1 (IL-1) may be a mediator of beta-cell damage in insulin-dependent diabetes mellitus (IDDM). The IL-1 mechanism of action on insulin-producing cells probably includes activation of the transcription nuclear factor kappa B (NF-kappa B), increased transcription of the inducible form of nitric oxide synthase (iNOS) and the subsequent production of nitric oxide (NO). Reactive oxygen intermediates, particularly H2O2, have been proposed as second messengers for NF-kappa B activation. In the present study, we tested whether ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), a glutathione peroxidase mimicking compound, could counteract the effects of IL-1 beta, H2O2 and alloxan in rat pancreatic islets and in the rat insulinoma cell line RINm5F (RIN cells). Some of these experiments were also reproduced in human pancreatic islets. Ebselen (20 microM) prevented the increase in nitrite production by rat islets exposed to IL-1 beta for 6 hr and induced significant protection against the acute inhibitory effects of alloxan or H2O2 exposure, as judged by the preserved glucose oxidation rates. However, ebselen failed to prevent the increase in nitrite production and the decrease in glucose oxidation and insulin release by rat islets exposed to IL-1 beta for 24 hr. Ebselen prevented the increase in nitrite production by human islets exposed for 14 hr to a combination of cytokines (IL-1 beta, tumor necrosis factor-alpha and interferon-gamma). In RIN cells, ebselen counteracted both the expression of iNOS mRNA and the increase in nitrite production induced by 6 hr exposure to IL-beta but failed to block IL-1 beta-induced iNOS expression following 24 hr exposure to the cytokine. Moreover, ebselen did not prevent IL-1 beta-induced NF-kappa B activation. As a whole, these data indicate that ebselen partially counteracts cytokine-induced NOS activation in pancreatic beta-cells, an effect not associated with inhibition of NF-kappa B activation.
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PMID:Ebselen and cytokine-induced nitric oxide synthase expression in insulin-producing cells. 898 32

A close association of neuronal nitric oxide synthase-immunoreactive (nNOS-IR) neurons with the retinal vasculature has been reported and it is proposed that activation of these neurons could be the mechanism by which retinal blood flow and metabolism are linked. Further, advanced glycation end products (AGEs) have previously been shown to be increased in the diabetic retina and aminoguanidine (AG), an inhibitor of advanced glycation, has been shown to attenuate the development of AGE accumulation as well as the progression of experimental diabetic retinopathy. This study examined the effects of short (1 and 3 weeks) and long term (32 weeks) diabetes on nNOS-containing neurons of the retina using NADPH diaphorase (NADPHd) histochemistry. In addition, the effect of aminoguanidine (an inhibitor of advanced glycation and NOS) and NG-nitro-L-arginine methyl ester (L-NAME) (a non-selective NOS inhibitor) on retinal nNOS-containing neurons was examined in short and long term control and diabetic rats. In a separate study, the effect of 2,3 diamino-phenazine (NN0028) (an inhibitor of advanced glycation, but not NOS) was examined in short term (3 weeks) diabetic rats. The number of NADPHd-positive neurons per retina was reduced after one week of diabetes and remained decreased in long term diabetic rats, an effect not observed in diabetic rats rendered euglycaemic by intensified insulin treatment. Treatment of diabetic animals with aminoguanidine or NN0028 prevented the depletion in the nNOS-containing neuron number, an effect not reproduced by L-NAME. These studies suggest that the action of AG in restoring the number of nNOS-containing retinal neurons is mediated by the inhibition of AGE formation. The depletion of nNOS-containing neurons may contribute to alterations in the autoregulation of blood flow which occurs in diabetes.
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PMID:Depletion of nitric oxide synthase-containing neurons in the diabetic retina: reversal by aminoguanidine. 986 8

Ovulation, recurring every reproductive cycle of the mammalian female and triggered by a surge of luteinizing hormone (LH) released from the pituitary is an essential prerequisite for fertilization and subsequent embryonic development. Here we shall review two of the biological responses leading to follicle rupture -- vascular changes and proteolysis. Naturally, our present knowledge is based mainly on work in a few species, such as the rat, the mouse and, to lesser extent the pig and monkeys and observations in the human. Therefore any generalizations to other mammals, should be considered as a working hypothesis yet to be confirmed. The LH surge stimulates, in the preovulatory follicles, a cascade of proteolytic enzymes, including plasminogen activator (PA), plasmin and matrix metalloproteinases (MMPs). These enzymes bring about the degradation of perifollicular matrix and, most notably, the decomposition of the meshwork of collagen fibers which provides the strength to follicular wall. Pharmacological blockage of any of these enzymes resulted in the reduction of ovulation rate. The increased ovarian proteolytic activity associated with ovulation is controlled by locally produced specific inhibitors, plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of metalloproteases-1 (TIMP-1). The increased synthesis of these two specific proteinase inhibitors in the theca of growing follicles ensures their development by protecting them from enzymes diffusing from ovulatory follicles. The stimulation of ovulation by the gonadotropin results in an increase in follicular blood flow, hyperemia, increase in vascular permeability and a marked increase in follicular volume. These vascular changes and the proteolytic activity are triggered either directly by LH or by local mediators and factors produced in response to the gonadotropic stimulus. These mediators allow the tight coordination of these two cascades culminating in the rupture of follicle wall. We shall review here, briefly, the various mediatory systems that have been implicated in follicle rupture. These include steroids, vascular endothelial growth factor (VEGF), cytokines, eicosanoids, platelet activating factor (PAF), nitric oxide and nitric oxide synthase (NO/NOS), kinins and oxygen radicals.
Exp Clin Endocrinol Diabetes 1999
PMID:Molecular aspects of mammalian ovulation. 1007 49

Chronic diabetes in man and animal models develops cardiomyopathic alterations which cannot be absolutely avoided by insuline therapy. Since diabetic damage is partly attributed to oxidative stress antioxidative treatment could be able to reduce the alterations. Aim of this study was to investigate the cardioprotective effects of EGb 761, known as a radical scavenger, against diabetic alterations in rats. The diabetes was induced by i.p. injection of 60 mg/kg body weight streptozotocin. Duration of diabetes was 4 months, the protected group received 100 mg/kg body weight EGb 761 with the drinking water over 3 months. Electron and light microscopic morphometry of left-ventricular samples revealed typical diabetic alterations consisting in decrease of volume fraction of myofibrils, SR and t-tubules and diminishing of cardiomyocyte diameter, increase of interstitial volume, mitochondrial size and volume fraction, and of vacuoles and of lipid drops. EGb treatment could gradually prevent the loss of myofibrils and reduction of myocyte diameter but has only little influence on interstitial and mitochondria volume. The diabetic-induced increase of lipid and vacuoles and the decrease of SR and t-tubules were not influenced. Biochemical parameters of oxidative stress: malondialdehyde (MDA) was only insignificantly altered by diabetes and EGb. The superoxide dismutase (SOD) activity was increased by diabetes and more increased by EGb treatment. Creatine kinase (CK) activity was diminished by diabetes but slightly increased by EGb. The polymerase chain reaction (PCR) of i-NOS was not different between the diabetic and protected diabetic groups.
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PMID:Protective effects of Gingko biloba extract EGb 761 on myocardium of experimentally diabetic rats. I: ultrastructural and biochemical investigation on cardiomyocytes. 1033 57

We have investigated the expression and localization of endothelium-derived nitric oxide synthase (eNOS) and the effect of eNOS on placental human chorionic gonadotrophin (HCG) release. eNOS mRNA was found to be expressed in all tissues, with its expression significantly (P<0.05) increased across gestation. Compared to normal term gestation, placentae from term pregnancies with fetal retardation, or maternal diabetes, but not with maternal hypertension, displayed significantly more (P<0.05) eNOS mRNA. By immunocytochemistry, we found staining for eNOS in both the cyto- and syncytiotrophoblasts of first trimester and a loss of cytotrophoblast eNOS staining in term placentae, while syncytiotrophoblasts at term were strongly eNOS positive. Additional staining was found in endothelium surrounding the vascular tree. HCG was found to colocalize with eNOS in trophoblasts, but not in endothelia. When placental explants were perifused, exposure to the NOS substrate, the NO donor, I-arginine and trinitroglycerol evoked a prompt, albeit transient, increase of HCG release. The NOS inhibitor delayed, but did not block arginine-induced HCG release. Thus, eNOS is expressed in the human placenta at increasing levels during gestation with further increases during some pathological conditions. A role for NO in the acute endocrine modulation of the placenta is suggested by the colocalization of eNOS with HCG in human trophoblasts and the prompt secretion of HCG in response to agents which increase NO concentrations.
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PMID:Expression and functional analysis of endothelial nitric oxide synthase (eNOS) in human placenta. 1033 73


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