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)

Evidence that nitric oxide (NO) is involved in cytokine-mediated islet beta-cell dysfunction and destruction in vitro has led to the hypothesis that increased production of NO may contribute to the pathogenesis of insulin-dependent diabetes mellitus (IDDM). This study demonstrates that oral administration of N omega-nitro-L-arginine methyl ester (an inhibitor of NO synthase) from 30 to 150 days of age significantly reduced (P < 0.05) the incidence of IDDM in diabetes-prone BB/E rats. This supports the idea that NO plays a significant role in the pathogenesis of IDDM in this animal model.
Diabetes 1995 Mar
PMID:N omega-nitro-L-arginine methyl ester reduces the incidence of IDDM in BB/E rats. 753 36

1. Diabetes mellitus is associated with changes in gastrointestinal motility. The effects of experimental diabetes, induced by streptozotocin administration to rats 3-4 weeks previously, on the nitric oxide (NO)-mediated (nitrergic) relaxation of the duodenum have now been investigated. 2. The non-adrenergic, non-cholinergic (NANC) relaxation of the isolated duodenum induced by nicotine (0.3-10 microM) or the nicotinic agonist, 1,1-dimethyl-4-phenylpiperazinium (DMPP; 10 microM) was inhibited by the NO synthase inhibitor, NG-nitro-L-arginine (3-100 microM). 3. This nitrergic relaxation induced by nicotine or DMPP of the duodenum from diabetic rats was substantially smaller than that of the tissue from control rats. 4. By contrast, the relaxation of the duodenum from diabetic rats to the NO donor, nitroprusside (0.3-10 microM) was similar to that of control tissue, whereas the relaxation to ATP (0.1-3 microM) was enhanced to a small but significant degree. 5. Incubation of duodenal tissue from control rats at 4 degrees C for 72 h, which leads to neuronal disruption, significantly attenuated the relaxation to nicotine or DMPP whereas the relaxation induced by nitroprusside or ATP was not affected. Comparable cold-storage did not affect the endothelium-dependent relaxation of rat aortic rings induced by acetylcholine (0.01-2 microM). 6. The calcium-dependent NO synthase activity in duodenal tissue, determined by the conversion of radiolabelled L-arginine to citrulline, was significantly reduced in cold-stored tissue and in tissue obtained from diabetic rats. 7. These findings in the rat duodenum indicate that a reduction in intestinal NO synthase activity is associated with an impairment of the NANC relaxation. A defect in the intestinal nitrergic innervation could thus contribute to the motility dysfunction observed in diabetes.
 ...
PMID:Impairment of nitrergic-mediated relaxation of rat isolated duodenum by experimental diabetes. 754 94

Nitric oxide (NO) may be a mediator of beta-cell damage in insulin-dependent diabetes mellitus. beta-Cells express the inducible form of NO synthase (iNOS) and produce large amounts of NO upon exposure to cytokines. iNOS requires the amino acid arginine for NO formation. It has been shown in other cell types that interferon-gamma (IFN gamma) and bacterial lipopolysaccharide induce the enzyme argininosuccinate synthetase (AS), enhancing the capacity of these cells to regenerate arginine from citrulline and maintain NO production in the presence of low arginine concentrations. To characterize the messenger RNA (mRNA) expression of AS in insulin-producing cells, RINm5F cells (RIN cells) were exposed to interleukin-1 beta (IL-1 beta) or to tumor necrosis factor-alpha plus IFN gamma. After 4-6 h, there was a significant and parallel induction of AS and iNOS mRNA. IL-1 beta-induced AS and iNOS mRNA expression was prevented by an inhibitor of the activation factor NF-kappa B pyrrolidine diaminoguanidine, an inhibitor of gene transcription (actinomycin D), and a blocker of protein synthesis (cycloheximide), suggesting coregulation of AS and iNOS by cytokines. RIN cells exposed to IL-1 beta in the presence of citrulline but the absence of arginine had increased AS enzyme activity and produced NO, demonstrating that cytokine-induced AS mRNA expression is accompanied by increased AS activity. Both adult rat islets exposed to IL-1 beta and human pancreatic islets cultured in the presence of IL-1 beta, tumor necrosis factor-alpha, and IFN gamma were able to use citrulline to regenerate arginine and produce NO. Taken as a whole, the present data suggest that regulation of AS activity may play a role in modulation of NO production in both rodent and human insulin-producing cells.
 ...
PMID:Expression of the citrulline-nitric oxide cycle in rodent and human pancreatic beta-cells: induction of argininosuccinate synthetase by cytokines. 762 52

This study was undertaken to compare the ability of two guanidine compounds (aminoguanidine and methylguanidine), with different in vitro effects on NO synthase activity and AGE formation, to inhibit diabetic vascular dysfunction developing early after the onset of diabetes. In rats with STZ-induced diabetes of 5-wk duration, regional vascular [125I]albumin permeation was increased about two- to threefold in ocular tissues, sciatic nerve, and aorta; in general, both guanidine compounds normalized albumin permeation in diabetic rats without affecting it in controls. Methylguanidine was only approximately 7% as effective as aminoguanidine as an inhibitor of AGE formation from L-lysine and G6P; both compounds were poor inhibitors of AR. Methylguanidine was approximately 1-5% as potent as aminoguanidine and L-NMMA as an inhibitor of the cytokine- and endotoxin-inducible isoform of NO synthase. In contrast, the potency of methylguanidine as an inhibitor of the constitutive isoform of NO synthase was comparable to that of aminoguanidine, and both guanidine compounds were much less effective than L-NMMA. These observations suggest a role for a relative or absolute increase in NO production in the pathogenesis of early diabetic vascular dysfunction and raise the possibility that inhibition of diabetic vascular functional changes by aminoguanidine may reflect inhibition of NO synthase activity rather than, or in addition to, prevention of AGE formation.
Diabetes 1993 Feb
PMID:Prevention of diabetic vascular dysfunction by guanidines. Inhibition of nitric oxide synthase versus advanced glycation end-product formation. 767 25

Overproduction of the free radical nitric oxide (NO) has been implicated in the pathogenesis of a variety of inflammatory and immunologically mediated diseases as well as complications of diabetes. In the present study we have demonstrated that aminoguanidine selectively inhibits the cytokine-inducible isoform of NO synthase which appears to be responsible for the excess production of NO linked to these disease states. By using organ, cell, and enzyme-based measurements we have shown that aminoguanidine is equipotent to NG-monomethyl-L-arginine (L-NMA) as an inhibitor of the cytokine-induced isoform of NO synthase but is 10 to 100-fold less potent as an inhibitor of the constitutive isoform. Thus, aminoguanidine may be useful as a selective inhibitor of the inducible NO synthase in the treatment of disease states characterized by the pathological overproduction of NO.
 ...
PMID:Selective inhibition of the inducible nitric oxide synthase by aminoguanidine. 768 10

The inducible NO synthase (iNOS) was found to be expressed in pancreatic lesions of adult diabetes-prone BB rats. Pancreatic iNOS mRNA was detected by reverse transcriptase PCR in pancreatic RNA of adult diabetes-prone BB rats but not in normal Wistar rats, young diabetes-prone BB rats without insulitis or in diabetes-resistant BB rats. Immunohistochemistry of pancreatic sections using an iNOS-specific antiserum labeled the pancreas of adult diabetes-prone BB rats but not Wistar rats. Parallel staining for ED1-positive macrophages showed restriction of iNOS expression to areas of islet infiltration by macrophages. In conclusion, the data provide direct evidence for enhanced expression of inducible NO synthase in tissue lesions during the development of autoimmune diabetes.
 ...
PMID:Transcription and translation of inducible nitric oxide synthase in the pancreas of prediabetic BB rats. 768 27

Nitric oxide (NO) generation may be a final common pathway for beta-cell damage in early insulin-dependent diabetes mellitus. Insulin-producing cells express an inducible form of NO synthase (iNOS), which is similar to that observed in activated macrophages. Induction of iNOS mRNA in these cells depends on protein synthesis. To further characterize the regulation of iNOS induction in insulin-producing cells, RINm5F cells (RIN cells) were exposed for 6 h to human recombinant interleukin-1 beta (rIL-1 beta; 1 ng/ml) alone or in combination with either nicotinamide (10, 20, or 50 mM) or dexamethasone (1 or 5 microM). These agents have been previously shown to prevent activation of iNOS in macrophages, fibroblasts, and hepatocytes. rIL-1 beta induced the expression of iNOS mRNA in RIN cells and a 12- to 13-fold increase in medium nitrite accumulation, the latter indicating NO production. Nicotinamide decreased nitrite production in a dose-dependent way. Thus, 10 mM nicotinamide decreased rIL-1 beta-induced nitrite formation by 30%, 20 mM by 60%, and 50 mM by 90%. The highest concentration of nicotinamide also prevented rIL-1 beta-induced iNOS mRNA, an effect associated with inhibition of total protein biosynthesis. However, 10 or 20 mM nicotinamide did not modify rIL-1 beta-induced iNOS mRNA expression or inhibit protein biosynthesis. Dexamethasone also decreased rIL-1 beta-induced nitrite production without affecting iNOS mRNA expression. As a whole, these data suggest that both nicotinamide and dexamethasone may prevent NO accumulation in insulin-producing cells by posttranscriptional mechanisms. It is also possible that these drugs induce direct inhibition of iNOS enzymatic activity and/or scavenge NO. Higher concentrations of nicotinamide might also inhibit iNOS mRNA expression, possibly by blocking protein biosynthesis.
 ...
PMID:Nicotinamide and dexamethasone inhibit interleukin-1-induced nitric oxide production by RINm5F cells without decreasing messenger ribonucleic acid expression for nitric oxide synthase. 769 79

Experiments were performed to determine the influence of endogenous nitric oxide (NO) on basal arteriolar diameter in kidneys from diabetic rats and to evaluate the role of superoxide anions as modulators of NO activity under these conditions. Male Sprague-Dawley rats were injected with streptozotocin (STZ, 65 mg/kg i.v.) and received insulin via ip osmotic minipumps (3 U/kg per day). Sham rats received vehicle treatments. Videomicroscopy was used, in conjunction with the in vitro blood-perfused juxtamedullary nephron technique, to visualize renal afferent and efferent arterioles 2 wk after the onset of diabetes. Baseline afferent arteriolar inside diameter was greater in STZ (32 +/- 2 microns) than in sham rats (24 +/- 2 microns). Efferent arteriolar diameter did not differ between STZ (24 +/- 2 microns) and sham rats (21 +/- 1 microns). In kidneys from sham rats, N omega-nitro-L-arginine (L-NNA, an NO synthase inhibitor) decreased arteriolar diameters in a concentration-dependent manner, with 100 microM L-NNA significantly reducing both afferent (13 +/- 2%) and efferent (11 +/- 1%) diameters. In kidneys from STZ rats, 100 microM L-NNA reduced afferent and efferent diameters by only 3 +/- 1 and 4 +/- 1%, respectively, indicating a suppressed arteriolar influence of NO. In STZ kidneys treated with superoxide dismutase (SOD, 150 U/mL), afferent and efferent arteriolar L-NNA responses were restored to levels comparable to those of SOD-treated and untreated sham kidneys. These observations suggest that suppressed SOD activity reduces the tonic influence of NO on renal arterioles during the early stage of diabetes mellitus, perhaps through allowing the accumulation of NO-scavenging superoxide anions.
 ...
PMID:Superoxide dismutase restores the influence of nitric oxide on renal arterioles in diabetes mellitus. 775 88

Defective endothelium-dependent relaxation in diabetic blood vessels may be regulated at the site of synthesis. We tested the hypothesis that acute administration of L-arginine (L-Arg) as substrate for endothelium-derived relaxing factor (EDRF) would normalize defective relaxation to acetylcholine (ACh) in streptozotocin-induced diabetic rat aortic rings. Plasma concentrations of basic amino acids (e.g., arginine, lysine, and histidine) were significantly reduced by diabetes, but variable results (increased, decreased, or no change) were observed in plasma concentrations of neutral amino acids. Endothelium-dependent relaxation to ACh (but not calcium ionophore A23187) was impaired in diabetic rings. Relaxation to nitroglycerin (NTG) was not altered. Pretreatment with L-nitroarginine methyl ester (L-NAME), a nitric oxide (NO) synthase inhibitor, blocked the relaxation to ACh and A23187 but not relaxation to NTG in both control and diabetic rings. Pretreatment with 3 mM L-Arg (but not D-Arg) potentiated the relaxation to ACh in diabetic rings. L-Arg had no effect on ACh-induced relaxation in control rings or on relaxation to NTG in control or diabetic rings. A mechanism for impaired endothelium-dependent relaxation to ACh in diabetic aorta may arise from a defect in utilization of L-Arg by NO synthase for production of EDRF/NO.
 ...
PMID:Amelioration by L-arginine of a dysfunctional arginine/nitric oxide pathway in diabetic endothelium. 776 4

Splenic cells from the diabetes-prone BB rat show reduced proliferative responses to concanavalin A (ConA) and other mitogens. This study was undertaken to test whether this reduced lymphoproliferation in the BB rat is mediated by an increased production of nitric oxide (NO) by macrophages. Splenic leukocytes from diabetes-prone BB rats and five strains of control rats (BB-R, Wistar-Furth, Sprague-Dawley, Wistar, and Lewis) were cultured in RPMI-1640 media containing ConA. The leukocytes from BB rats showed reduced [3H]thymidine uptake and increased release of NO compared with the control rats. Partial depletion of macrophages from the culture or incubation with -NG-monomethylarginine (NGMMA), a specific NO synthase inhibitor, markedly augmented ConA-induced proliferation of the splenic leukocytes from BB but not the control rats. Enrichment of BB rat macrophages suppressed the proliferation of BB-R rat spleen cells. Excess L-arginine added to the culture reversed the NGMMA effect. These results suggest that increased production of NO by macrophages is partly responsible for the reduced proliferative responses of splenic leukocytes in the BB rat.
Diabetes 1994 Oct
PMID:Nitric oxide produced by macrophages mediates suppression of ConA-induced proliferative responses of splenic leukocytes in the diabetes-prone BB rat. 792 91


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