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)

Nitric oxide has recently been implicated as the effector molecule that mediates IL-1 beta-induced inhibition of glucose-stimulated insulin secretion and beta-cell specific destruction. The pancreatic islet represents a heterogeneous cell population containing both endocrine cells (beta-[insulin], alpha-]glucagon], gamma[somatostatin], and PP-[polypeptide] secreting cells) and non-endocrine cells (fibroblast, macrophage, endothelial, and dendritic cells). The purpose of this investigation was to determine if the beta-cell, which is selectively destroyed during insulin-dependent diabetes mellitus, is both a source of IL-1 beta-induced nitric oxide production and also a site of action of this free radical. Pretreatment of beta-cells, purified by FACS with IL-1 beta results in a 40% inhibition of glucose-stimulated insulin secretion that is prevented by the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (NMMA). IL-1 beta induces the formation of nitric oxide by purified beta-cells as evidenced by the accumulation of cGMP, which is blocked by NMMA. IL-1 beta also induces the accumulation of cGMP by the insulinoma cell line Rin-m5F, and both NMMA as well as the protein synthesis inhibitor cycloheximide prevent this cGMP accumulation. Iron-sulfur proteins appear to be intracellular targets of nitric oxide. IL-1 beta induces the formation of an iron-dinitrosyl complex by Rin-m5F cells indicating that nitric oxide mediates the destruction of iron-sulfur clusters of iron containing enzymes. This is further demonstrated by IL-1 beta-induced inhibition of glucose oxidation by purified beta-cells, mitochondrial aconitase activity of dispersed islet cells, and mitochondrial aconitase activity of Rin-m5F cells, all of which are prevented by NMMA. IL-1 beta does not appear to affect FACS-purified alpha-cell metabolic activity or intracellular cGMP levels, suggesting that IL-1 beta does not exert any effect on alpha-cells. These results demonstrate that the islet beta-cell is a source of IL-1 beta-induced nitric oxide production, and that beta-cell mitochondrial iron-sulfur containing enzymes are one site of action of nitric oxide.
 ...
PMID:Interleukin 1 beta induces the formation of nitric oxide by beta-cells purified from rodent islets of Langerhans. Evidence for the beta-cell as a source and site of action of nitric oxide. 133 75

Cytokines have been implicated as immunological effector molecules that induce dysfunction and destruction of the pancreatic beta-cell. The mechanisms of cytokine action on the beta-cell are unknown; however, nitric oxide, resulting from cytokine-induced expression of nitric oxide synthase, has been implicated as the cellular effector molecule mediating beta-cell dysfunction. Nitric oxide is a free radical that targets intracellular iron-containing enzymes, which results in the loss of their function. The cytokine IL-1 beta induces the formation of nitric oxide in isolated rat islets and the insulinoma cell line, Rin-m5F. NMMA and NAME, both inhibitors of nitric oxide synthase, completely protect islets from the deleterious effects of IL-1 beta. These inhibitors are competitive in nature and inhibit both the cytokine-inducible and constitutive isoforms of nitric oxide synthase with nearly identical kinetics. This may preclude their use as therapeutic agents because of increases in blood pressure which result from the inhibition of constitutive nitric oxide synthase activity. Aminoguanidine, an inhibitor of nonenzymatic glycosylation of cellular and extracellular constituents associated with diabetic complications, recently has been reported to inhibit nitric oxide synthase. Aminoguanidine is approximately 40-fold more effective in inhibiting the inducible isoform of nitric oxide synthase, suggesting that aminoguanidine or analogues may serve as potential therapeutic agents to block diseases associated with nitric oxide production by the inducible isoform of nitric oxide synthase. In vivo administration of TNF IL-1 has been shown to induce anti-diabetogenic effects in the NOD mouse. This anti-diabetogenic effect of cytokines appears to conflict with evidence suggesting that cytokines mediate beta-cell dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1992 Aug
PMID:Does nitric oxide mediate autoimmune destruction of beta-cells? Possible therapeutic interventions in IDDM. 137 15

1 We have determined the dermal microvascular effects of the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 100 nmol/site), endothelin-1 (ET-1, 0.1-10 pmol/site) and ET-3 (0.1-30 pmol/site) in rats with streptozotocin (STZ)-induced diabetes mellitus. Cutaneous blood flow changes as measured by a 133xenon (133Xe) clearance technique, were determined in diabetic rats four weeks after treatment with streptozotocin (STZ) and compared with responses measured in normal rats four weeks after treatment with saline. 2 Resting skin blood flow was similar in diabetic and in normal rats, as measured by 133Xe clearance and laser Doppler flowmetry. 3 Intradermal NG-nitro-L-arginine methyl ester (L-NAME) reduced skin blood flow in normal rats by 55.2 +/- 2.6% as measured by 133Xe clearance, (n = 9). L-NAME was significantly less effective in diabetic rats, inducing a 40.9 +/- 7.7% decrease in blood flow (n = 9, P less than 0.05). The enantiomer D-NAME had no effect in either group of rats. 4 Low doses of ET-1 and ET-3 injected intradermally induced dose-dependent decreases in blood flow, measured by 133Xe clearance, which were similar in both groups of rats. However, the responses to the highest doses of ET-1 (10 pmol/site) and ET-3 (10 and 30 pmol/site) were significantly reduced in the diabetic compared with the normal rats (P less than 0.05).In addition vasoconstriction to the highest doses of vasopressin (0.3 and 3 pmol/site) and vasodilatation to the neuropeptide calcitonin gene-related peptide (CGRP, 1O pmol/site) were similarly reduced in the diabetic rats (P <0.05).5. The decrease in blood flow induced by submaximal doses of ET-1 was enhanced by co-injection with L-NAME (100 nmol/site) in both diabetic and normal rats. However, this enhanced response was significantly reduced in the diabetic rats (P<0.05). A similar pattern of responses were observed to ET-3 in the presence and absence of L-NAME.6. These results indicate that the cutaneous microvasculature of rats with STZ-induced diabetes responds differently to intradermal ET-1 and ET-3 compared with normal rats; a similarly altered vascular reactivity was observed with vasopressin and CGRP. Hence, the diabetic microcirculation has impaired responses to several vasoconstrictors and a vasodilator. The effect of the nitric oxide synthase inhibitor L-NAME is also suppressed in the diabetics, suggesting that there may be decreased local production of, or response, to nitric oxide.
 ...
PMID:Altered microvascular reactivity to endothelin-1, endothelin-3 and NG-nitro-L-arginine methyl ester in streptozotocin-induced diabetes mellitus. 139 77

1. In addition to metabolic and neurohumoral factors endothelium-derived autacoids like the nitric oxide radical NO and prostacyclin are effective regulators of vascular tone and thus tissue perfusion. NO is produced in endothelial cells from L-arginine by a Ca2+/calmodulin-dependent enzyme NO synthase. In addition, the NO radical is ultimately cleaved from all nitrovasodilators and resembles their vasoactive and antiaggregatory principle, which is used under pathological conditions as substitution therapy for impaired endothelial function and autacoid production. Impaired endothelium-dependent vasomotor control has been documented in hypercholesterolaemia, atheromatosis, diabetes, hypertension, and in reperfusion damage. L-arginine supplementation is effective in a few instances.
 ...
PMID:Clinical relevance of endothelium-derived relaxing factor (EDRF). 163 78

Nitric oxide has recently been identified as the primary toxic effector molecule in the lysis of islet cells by inflammatory macrophages. We show here that N-nitro-L-arginine-methylester (NAME), an inhibitor of endothelial and macrophage NO synthase partially suppresses diabetes development in the low dose streptozotocin induced diabetes model in C57BL/6J mice. Mean blood glucose levels were lower in the group receiving NAME throughout the observation period of 30d (p less than 0.05-0.001). Similar concentrations of NAME as expected in vivo were tested in vitro in macrophage-islet cell cocultures and were found to partially suppress NO production and islet cell lysis. We conclude that NO synthase activity is a pathogenetic factor in diabetes development.
 ...
PMID:Suppression of low dose streptozotocin induced diabetes in mice by administration of a nitric oxide synthase inhibitor. 172 Aug 58

Arginine metabolism via nitric oxide (NO) synthase and other pathways was studied in coronary endothelial cells (EC) from the spontaneously diabetic BB rat, an animal model of human type I diabetes mellitus (IDDM). EC were prepared from insulin-treated diabetic BB (BBd) and non-diabetes-prone BB (BBn) rats. Basal NO synthesis was studied in EC cultured for 48 h in medium containing 0.4 mM L-arginine. At the end of the culture period, the medium was analyzed for nitrite and nitrate (two major end stable oxidation products of NO), and the cells were used to determine arginine uptake and metabolism and the activities of some arginine-degrading enzymes. For studies of arginine metabolism, cells were incubated at 37 degrees C for 1 h in Krebs-Henseleit bicarbonate buffer (pH 7.4) containing 1 mM L(-)[1-14C]arginine or L(-)[1-14C]ornithine. The rates of production of nitrite plus nitrate by BBd EC were only 15% of those of BBn cells. This impaired NO synthesis in BBd EC was not due to alterations in arginine uptake, NO synthase activity, or intracellular arginine concentrations but might have resulted from a limited intracellular availability of cofactors of NO synthase. In addition to the arginine-NO pathway, arginine was found to be metabolized to urea, ornithine, and, to a much lesser extent, CO2 via arginase and ornithine aminotransferase. The activities of arginase and the formation of ornithine and urea from arginine were decreased by 90% in BBd compared with BBn cells. These results, coupled with the reduced NO synthesis, indicate metabolic defects in arginine metabolism in BBd EC.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Impaired arginine metabolism and NO synthesis in coronary endothelial cells of the spontaneously diabetic BB rat. 748 63

Diabetic rats manifest abnormal renal hemodynamic responses, with persistent renal vasodilation at reduced renal perfusion pressures. We hypothesized that in diabetes, renal hemodynamics are modulated by increased activity of the endogenous vasodilator, NO. In anesthetized Munich-Wistar rats, after 6 wk of streptozotocin-induced, insulin-treated diabetes, and in age-matched, nondiabetic littermates (n = 7-8), basal renal hemodynamics and responses to graded reductions in renal perfusion pressure were determined before and after intrarenal arterial infusion of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). An identical protocol was followed in a second cohort of rats pretreated with indomethacin (4 mg/kg iv). Diabetic rats demonstrated hyperglycemia, renal enlargement, hyperfiltration, and increased urinary excretion of the stable NO metabolites, NO2 and NO3. L-NAME eliminated basal hyperfiltration in diabetic rats, and L-NAME, but not indomethacin, also eliminated persistent renal vasodilation at reduced renal perfusion pressure. We conclude that in a rat model of diabetes, increased endogenous NO activity may play a role in basal hyperfiltration and in the persistent renal vasodilatation manifested at reduced renal perfusion pressures.
 ...
PMID:Abnormal renal hemodynamic response to reduced renal perfusion pressure in diabetic rats: role of NO. 750 73

MRL-lpr/lpr mice spontaneously develop various manifestations of autoimmunity including an inflammatory arthropathy and immune complex glomerulonephritis. This study examines the role of nitric oxide, a molecule with proinflammatory actions, in the pathogenesis of MRL-lpr/lpr autoimmune disease. MRL-lpr/lpr mice excreted more urinary nitrite/nitrate (an in vivo marker of nitric oxide production) than did mice of normal strains and MRL-(+/+) and B6-lpr/lpr congenic strains. In addition, MRL-lpr/lpr peritoneal macrophages had an enhanced capacity to produce nitric oxide in vitro as well as increased nitric oxide synthase activity, and certain tissues from MRL-lpr/lpr mice had increased expression of inducible nitric oxide synthase (NOS) mRNA and increased amounts of material immunoreactive for inducible NOS. Oral administration of NG-monomethyl-L-arginine, a nitric oxide synthase inhibitor, prevented the development of glomerulonephritis and reduced the intensity of inflammatory arthritis in MRL-lpr/lpr mice. By using interspecific backcross mice, the gene for inducible NOS (Nosi) was mapped to mouse chromosome 11. This chromosomal localization was different from those loci that we have previously demonstrated to be linked to enhanced susceptibility to renal disease in an MRL-lpr/lpr cross. However, the chromosomal location of the NOS gene was consistent with an insulin-dependent diabetes locus identified in an analysis of nonobese diabetic (NOD) mice. These results suggest that elevated nitric oxide production could be important in the pathogenesis of autoimmunity, and that treatments to block the production of nitric oxide or block its effects might be valuable therapeutically.
 ...
PMID:The role of nitric oxide in the pathogenesis of spontaneous murine autoimmune disease: increased nitric oxide production and nitric oxide synthase expression in MRL-lpr/lpr mice, and reduction of spontaneous glomerulonephritis and arthritis by orally administered NG-monomethyl-L-arginine. 750 9

Complete loss of pancreatic insulin function in insulin-dependent diabetes is thought to be due to an autoimmune cytokine-mediated destruction of the beta-cell. The effects of several classes of agents on interleukin-1 beta (IL-1 beta)-induced suppression of insulin secretion, beta-cell NAD levels, and beta-cell viability were examined. After overnight incubation of isolated rat islets with 15 U/ml IL-1 beta and 11 mM glucose, sequential hourly insulin secretory responses to the same glucose concentration, 22 mM glucose, and 22 mM glucose plus forskolin were severely inhibited to 10-37% of the control value. Islet NAD levels were also sharply reduced to 43% of the control value after 24-h exposure to IL-1 beta, but not after 1 or 3 h, demonstrating the same time course as that for inhibition of insulin secretion. Exposure to IL-1 beta also decreased islet cell viability measured as trypan blue exclusion. Only 1 mM N-methyl arginine, an inhibitor of nitric oxide synthase, completely protected all three parameters of beta-cell function from damage by IL-1 beta. Nicotinamide and thymidine prevented the IL-1 beta-induced loss of cell viability and suppression of NAD, but had no effect on sustaining insulin secretion. Antioxidants, steroids, and several neuropeptides also did not prevent inhibition or restore the secretory response. Thus, the loss of the secretory response appears to be more narrowly restricted to nitric oxide radical damage induced by exposure to IL-1B.
 ...
PMID:Interrelationship of changes in islet nicotine adeninedinucleotide, insulin secretion, and cell viability induced by interleukin-1 beta. 750 26

Murine macrophages express high levels of nitric oxide synthase and produce large amounts of nitric oxide (NO) when stimulated with certain cytokines in the presence of a trace amount of lipopolysaccharide (LPS). The stimulatory cytokines include interleukin-1 (IL-1), interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and migration inhibitory factor. Activated macrophages are highly effective killers of intra- and extra-cellular pathogens. However, as excessive NO can lead to immunopathology (diabetes, graft-v.-host disease, EAE, liver cirrhosis, rheumatoid arthritis), NO production is necessarily under tight regulation. A number of cytokines, including IL-4, IL-10 and transforming growth factor-beta, can down regulate the induction of NO synthase in macrophages. In addition, macrophages exposed to LPS alone and then stimulated with a mix of IFN-gamma and LPS express significantly lower levels of NO synthase than cells stimulated without pre-exposure to LPS. Furthermore, NO can reduce the activity of NO synthase by feedback inhibition, and also inhibit the production of IFN-gamma by Th1 cells (thus turning off its own synthesis from upstream). The regulatory pathways involve tyrosine kinase and protein kinase C.
 ...
PMID:The role of nitric oxide in parasitic diseases. 751 Jan


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