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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IL-1 and TNF alpha are assumed to be major mediators of islet cell destruction during the pathogenesis of type 1 diabetes. Here we show by neutralization of the two cytokines with excess antibody that IL-1 and TNF alpha do not contribute to the cytotoxic activity of activated macrophages towards isolated islet cells. However, islet cells can be protected from lysis by depleting the culture medium of L-arginine or by adding the antagonist NG-monomethyl-L-arginine, both of which inhibit the generation of nitric oxide by activated macrophages. These results indicate a role of nitric oxide or its equivalent, the endothelium-derived relaxing factor in the development of type 1 diabetes. This is the first report showing that nitric oxide may damage normal cells and thus may be a hitherto unrecognized pathogenetic factor in tissue inflammation and autoimmune disence.
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PMID:Activated macrophages kill pancreatic syngeneic islet cells via arginine-dependent nitric oxide generation. 202 50

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)
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PMID:Impaired arginine metabolism and NO synthesis in coronary endothelial cells of the spontaneously diabetic BB rat. 748 63

Nitric oxide produced by inducible nitric oxide synthase in islets exerts inhibitory and cytotoxic effects on pancreatic beta cells and is therefore thought to be a potent mediator in the pathogenesis of Type I diabetes mellitus. Here, using isolated rat pancreatic islets, we show that high-concentration nicotinamide (20 mM), but not low-concentration nicotinamide (5 mM), attenuates the interleukin-1 beta-evoked inhibition of glucose-induced insulin secretion by preventing the induction of interferon regulatory factor-1, a transcriptional factor which plays an essential role in inducible nitric oxide synthase gene expression, and the interleukin-1 beta-induced nitric oxide formation. High-concentration nicotinamide also restored an interleukin-1 beta-induced decrease in ATP content in pancreatic beta cells, suggesting that interleukin-1 beta-induced nitric oxide inhibits the mitochondrial function. The present results show the molecular basis of the preventive effect of high-dose nicotinamide on Type I diabetes mellitus.
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PMID:Nicotinamide inhibits IRF-1 mRNA induction and prevents IL-1 beta-induced nitric oxide synthase expression in pancreatic beta cells. 748 87

The mechanism by which angiotensin-converting enzyme (ACE) inhibition influences renal perfusion and function has assumed growing importance as alternatives for blocking the system have emerged. Neither renin inhibitors nor angiotensin II (Ang II) antagonists are likely to trigger responses similar to ACE inhibitor-induced involvement of kinins, prostaglandins, or nitric oxide. Several observations suggest species variation in the contribution of these pathways to the renal response to ACE inhibition. In humans, recent investigation suggests that virtually all of the renal response is due to a fall in Ang II formation. Perhaps most persuasive is the surprising observation that the renal hemodynamic response to renin inhibitors exceeds by more than 50% the response to ACE inhibition in healthy humans. To the extent that kinins or prostaglandins contribute to the renal response to ACE inhibition, one would anticipate a smaller response to renin inhibition. Possible explanations include an unanticipated additional action of renin inhibitors, better tissue penetration of these highly lipophilic agents, or more effective blockade of Ang II formation through an action at the rate-limiting step or non-ACE-dependent Ang II generation. Substantial evidence favors the latter two possibilities. Whatever the explanation, these observations raise the intriguing possibility that the undoubted therapeutic efficacy of ACE inhibition in renal injury, documented most rigorously for type I diabetes mellitus, might be exceeded with the newer classes of agent.
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PMID:Renal circulation and blockade of the renin-angiotensin system. Is angiotensin-converting enzyme inhibition the last word? 755 19

It has been recently reported that human pancreatic islets in tissue culture produce nitric oxide (NO) and show a decreased function when exposed for 6 days to combinations of cytokines (interleukin-1 beta (IL-1 beta) + tumor necrosis factor-alpha (TNF-alpha) + interferon-gamma (IFN-gamma). Here we study the effects of nicotinamide (Nic; 10 or 20 mmol/l) on these deleterious effects of cytokines (50 U/ml IL-1 beta + 1000 U/ml TNF-alpha + 1000 U/ml IFN-gamma). Islets were isolated from 8 human pancreata at the Central Unit of the beta-Cell Transplant, Brussels, sent to Uppsala and, after 3-5 days in culture, exposed for 6 additional days to the cytokines and/or Nic. The cytokines induced a 6-fold increase in islet NO production (P < 0.001), and this effect was partially counteracted by Nic (50-60% decrease in NO production; P < 0.001). The cytokines severely decreased the islet insulin content and glucose-induced insulin release (16.7 mmol/l glucose; 90% decrease; P < 0.001). Both these effects of cytokines were partially counteracted by Nic, especially at the highest concentration (20 mmol/l; 2-4-fold increase compared to islets exposed to cytokines alone; P < 0.01). Nic by itself did not affect the insulin content or insulin release by control islets. In conclusion, the present data indicate that Nic counteracts the deleterious effects of cytokines on human pancreatic islets. This effect of Nic may be relevant for the beneficial effects of the drug in early IDDM.
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PMID:Nicotinamide decreases nitric oxide production and partially protects human pancreatic islets against the suppressive effects of combinations of cytokines. 760 71

1. Diabetes mellitus type I was induced in 3-month old male C57 BL/KS-mdb mice (N = 24) by ip injection of streptozotocin (STZ, 45 mg/kg body weight) for 5 days. 2. To determine the possible protective effects of nitric oxide inhibition against hyperglycemia, the STZ-diabetic rats received two doses of NG-nitro-L-arginine- methyl ester (L-NAME) (10 mg/kg body weight and 10 mg/mouse) dissolved in PBS for 45 consecutive days. Another group of STZ-treated rats was similarly treated with L-arginine (5 mg/mouse). 3. Blood glucose levels were 118 +/- 37 mg/dl after 8 days of L-NAME administration (10 mg/kg body weight, N = 12) and 186 +/- 22 mg/dl (N = 12) after 5 days of L-NAME administration at the 5 mg/mouse dose. Treatment with L-arginine (5 mg/mouse, N = 12) caused a significant increase in blood glucose level to 151 +/- 17.5 mg/dl, showing the relevance of nitric oxide formation in this type of diabetes. 4. In STZ-diabetic mice treated with L-NAME (N = 12), diuresis was reduced by approximately 58% compared to STZ animals, whereas in L-arginine-treated animals (N = 12) diuresis returned to STZ levels. Urinary protein excretion, which was significantly affected by STZ (123% compared to control) was significantly reduced by 66% after treatment with L-NAME for 45 days, whereas treatment with L-arginine caused a return to STZ values. 5. Urinary kallikrein excretion, which was reduced by 80% in STZ mice compared to control, returned to control levels after L-NAME treatment. 6. The present results suggest a relationship between nitric oxide levels and the reduction of diabetic state and improved renal function by L-NAME.
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PMID:Streptozotocin-induced hyperglycemia is decreased by nitric oxide inhibition. 774 93

IDDM is caused by an immune-mediated destruction of the insulin-producing beta cells. Beta cells are destroyed by induction of oxygen-derived free radicals (FR) and nitric oxide (NO), which results in perturbation of the mitochondrial respiratory system and DNA strand breaks. As a result of beta cell destruction, islet cell antibodies (ICA) can be demonstrated in the circulation. These antibodies can be detected up to eight years prior to overt IDDM. Nicotinamide, a vitamin B3 derivative, interferes with the immune mediated beta-cell destruction by reducing the content of FR and NO and thereby reducing their deleterious effects. At the same time, nicotinamide increases the intracellular NAD pool, thus increasing the energy supply of the cell. Nicotinamide protects against chemically induced as well as spontaneous diabetes in animal models of the disease. Recently, open clinical studies have suggested that nicotinamide when administered to humans can prevent or delay clinical onset of IDDM. To test the possible preventive effect of nicotinamide in IDDM, a prospective, randomized, placebo-controlled study is needed. A multicentre study including 18 European countries, Israel and Canada is planned to start during 1993.
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PMID:[Nicotinamide and prevention of insulin-dependent diabetes mellitus. Rationale, effects, toxicology and clinical experiences. ENDIT Group]. 814 Jun 61

Endothelial dysfunction is known to occur in chemically-induced animal models of diabetes. The BB diabetic rat is a genetic diabetes-prone model which more closely resembles Type I diabetes mellitus. In this study, we examined the role of superoxide anion radical and cyclooxygenase activity on endothelial dysfunction in aorta of the spontaneous diabetic BB rat. Vascular endothelial function was studied in vitro in aortic rings from 8-wk diabetic rats and age-matched nondiabetic littermates. There was no alteration in reactivity to norepinephrine as a result of diabetes. Relaxation to acetylcholine (but not nitroglycerin) was impaired in diabetic rings. Relaxation to acetylcholine was abolished by 100 microM L-nitroarginine but unaltered by an equimolar concentration of aminoguanidine (an inducible nitric oxide synthase inhibitor) in both control and diabetic rings. Incubation with 10 microM indomethacin did not alter relaxation to acetylcholine in either control or diabetic rings. In contrast, addition of 20 U/ml superoxide dismutase enhanced relaxation to acetylcholine in diabetic rings but had no effect on relaxation to acetylcholine in control rings. Thus, nitric oxide-mediated, endothelium-dependent relaxation is diminished in aortic rings of the genetic diabetic BB rat. Furthermore, superoxide anion radicals but not cyclooxygenase products play an important role in endothelial dysfunction in this genetic diabetic model.
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PMID:Evaluation of the mechanism of endothelial dysfunction in the genetically-diabetic BB rat. 863 17

The role of free radicals as well as cytokines (IL-1, tumor necrosis factor alpha, interferon gamma) and nitric oxide in the immune-mediated processes leading to the beta-cell destruction during IDDM is described. It is also pointed that the excess of IL-1ra in relation to IL-1 prevents IL-1 toxicity to beta-cells.
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PMID:[The role of free radicals in pathogenesis of insulin dependent diabetes mellitus]. 870 Aug 8

Nitric oxide (NO) has been proposed as a possible mediator of beta-cell damage in human IDDM. This hypothesis is based on in vitro studies with rodent pancreatic islets. In the present study we examined whether human beta-cells are affected by NO. In view of species differences in beta-cell sensitivity to damaging agents, rat islets were investigated in parallel. Isolated islets were exposed for 90 min to different concentrations of three chemically unrelated NO donors, SIN-1, GSNO or RBS. At the end of this incubation, human insulin release was mostly similar in control and NO-treated islets but, 48 h later, islet retrieval, islet DNA and insulin content, and glucose-induced insulin release were markedly lower in islets exposed to NO donors. Rat islets were already inhibited during the initial 90 min; 48 h later their loss in beta-cell function was similar to that in human islets. Nicotinamide or succinic acid monomethyl ester partially protected against SIN-1 induced islet cell loss, but not against the functional inhibition of human pancreatic islets. Exposure of human or rat islets to RBS was associated with significant DNA strand breakage, as judged by the comet assay (single cell gel electrophoresis) and by ultrastructural signs of cell damage. DNA damage was more severe in rat islet cells exposed to similar amounts of RBS. It is concluded that NO donors can damage human pancreatic islets, an effect paralleled by induction of nuclear DNA strand breaks.
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PMID:Nitric oxide donors decrease the function and survival of human pancreatic islets. 873 93


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