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)

The potential role of nitric oxide in the diabetes-induced hypersensitive activation of glycogen phosphorylase by epinephrine was investigated in adult rat ventricular cardiomyocytes. Pretreatment of normal and diabetic-derived cells with 1 mM sodium nitroprusside significantly diminished the phosphorylase activation response by nearly 20% in both normal and diabetic myocytes but failed to alter the hypersensitivity of the diabetic cells. Nitroprusside increased cGMP levels in both normal and diabetic myocytes although the effect was more pronounced in the diabetic cells. Epinephrine did not alter cellular cGMP content and cGMP levels were consistently lower in diabetic myocytes when compared with normal myocytes. Preincubation of ventricular myocytes with the nitric oxide synthase inhibitor L-iminoethyl ornithine did not affect phosphorylase activation. These data indicate that nitric oxide plays a minor role in phosphorylase activation by epinephrine in rat cardiomyocytes and suggest that signal transduction via nitric oxide is not affected by the onset of diabetes.
 ...
PMID:Cyclic GMP accumulation in normal and diabetic primary culture adult rat ventricular cardiomyocytes: a minor role for nitric oxide in phosphorylase activation. 858 75

Aminoguanidine, which prevents formation of advanced glycation end products and is a relatively selective potent inhibitor of the inducible (versus constitutive) isoform(s) of nitric oxide synthase, has been reported to ameliorate structural and functional abnormalities in peripheral somatic nerves in rats with streptozocin (STZ)-induced diabetes. In the present studies, the effects of aminoguanidine treatment on ultrastructural changes in the autonomic nervous system of rats with STZ-induced diabetes were examined. The frequency of neuroaxonal dystrophy, the neuropathological hallmark of sympathetic autonomic neuropathy in diabetic rats, increased 9- to 11-fold in the superior mesenteric ganglia of 7- and 10-month STZ-diabetic rats compared with that in age-matched controls. Administration of aminoguanidine continuously from the time of induction of diabetes at a dose equal to or in excess of that providing a salutary effect in the diabetic somatic peripheral nervous system did not alter the severity of diabetes as assessed by plasma glucose level, 24-h urine volume, and levels of glycated hemoglobin. Chronic aminoguanidine therapy did not diminish the frequency or affect the ultrastructural appearance of neuroaxonal dystrophy in diabetic or age-matched control rat sympathetic ganglia after 7 or 10 months of continuous administration. Our findings (under these experimental conditions) do not support a role for aminoguanidine-sensitive processes in the development of sympathetic neuroaxonal dystrophy in diabetic rats. Glycation-linked aminoguanidine-insensitive processes, however, such as the formation of early glucose adducts (Schiff bases and Amadori products) with intracellular and/or extracellular proteins and amine-containing lipids, superoxide anion generation during subsequent autoxidation of these glucose adducts, and non-glycative processes, remain potential pathogenetic mechanisms for diabetic autonomic neuropathy.
Diabetes 1996 Mar
PMID:Effect of aminoguanidine on the frequency of neuroaxonal dystrophy in the superior mesenteric sympathetic autonomic ganglia of rats with streptozocin-induced diabetes. 859 31

Cytokines released by both T lymphocytes and activated macrophages, in particular interleukin-1 (IL-1), have been implicated as immunological effector molecules that both inhibit insulin secretion from the pancreatic beta cell and induce beta-cell destruction. Recent findings have demonstrated that production of the free radical nitric oxide (NO), resulting from the expression of the cytokine-inducible isoform of NO synthase (iNOS), mediates these deleterious effects. The cellular mechanism responsible for inhibition of beta-cell function and destruction by NO involves, in part, inactivation of enzymes specifically localized to the beta-cell mitochondria that contain iron- sulfur centers or clusters. Intraislet release of IL-1 also inhibits beta-cell function by this same cellular mechanism involving the overproduction of NO. In addition, the cytokine, IL-1, induces the co-expression of both iNOS and the cytokine-inducible isoform of cyclooxygenase, COX-2. The expression of COX-2 results in the overproduction of the proinflammatory prostaglandins and thromboxanes. Furthermore, NO produced by iNOS directly stimulates the activities of both constitutive and inducible isoforms of COX, further augmenting the overproduction of these proinflammatory mediators, NO and prostaglandins, which may be important in initiating or maintaining the inflammatory response and destruction of the beta cell associated with autoimmune diabetes.
 ...
PMID:Cytokines and nitric oxide in islet inflammation and diabetes. 859 15

Inflammatory cytokines may participate in the destruction of pancreatic islets during the pathogenesis of insulin-dependent diabetes mellitus, and the cytokine interleukin-1 (IL-1) strongly inhibits insulin secretion from rat pancreatic islets by a process which involves induction of expression of the inducible isoform of nitric oxide synthase and the overproduction of nitric oxide. The signaling events between IL-1 receptor occupancy and induction of nitric oxide synthase in rat islets involve activation of the transcriptional activator NFkappa B. Because sphingomyelin hydrolysis has been implicated as a signaling process both in NFkappa B activation and in IL-1 action in some cells, we have examined the potential involvement of sphingomyelin hydrolysis in the induction of islet nitric oxide overproduction by IL-1. Rat islet sphingomyelin pools were radiolabeled with [3H]choline, and sphingomyelin was then isolated by normal phase HPLC. Electrospray ionization-mass spectrometric analysis revealed islet sphingomyelin consists of at least 4 distinct molecular species, and the most abundant of them contained sphingosine as the long chain base and a residue of palmitic acid as the fatty acid substituent. Molecular species containing residues of stearic acid and arachidic acid were also observed. Neither interleukin-1 nor tumor necrosis factor-alpha was found to induce hydrolysis of islet sphingomyelin species, and neither an exogenous, cell-permeant ceramide species (N-acetyl-D-sphingosine) nor exogenous sphingomyelinase mimicked or potentiated the effect of IL-1 to increase rat islet nitric oxide generation, as reflected by nitrite production. Similar findings were obtained with RINm5F insulinoma cells and with mouse pancreatic islets. These findings provide the first information on the molecular species of sphingomyelin in pancreatic islets and suggest that sphingomyelin hydrolysis is not involved in the signaling pathway whereby IL-1 induces the overproduction of nitric oxide by pancreatic islets.
 ...
PMID:Characterization of the sphingomyelin content of isolated pancreatic islets. Evaluation of the role of sphingomyelin hydrolysis in the action of interleukin-1 to induce islet overproduction of nitric oxide. 860 64

Inflammatory cytokines and nitric oxide (NO) are candidate mediators of pancreatic islet beta-cell destruction in insulin-dependent diabetes mellitus. In this study, we used a semiquantitative PCR assay to measure levels of messenger RNA (mRNA) expression of the inflammatory cytokines, interleukin-1 alpha (IL-1 alpha), tumor necrosis factor-alpha, and interferon-gamma (IFN gamma), and of the inducible form of NO synthase (iNOS) in mononuclear leukocytes isolated from pancreatic islets of autoimmune diabetes-prone nonobese diabetic (NOD) female mice. We found that mRNA levels of iNOS, IL-1 alpha, and IFN gamma in islet mononuclear leukocytes increased from 5 weeks of age to onset of diabetes ( > 13 weeks of age). To determine whether increased iNOS, IL-1 alpha, and IFN gamma mRNA expressions were related to diabetes development, we compared mRNA levels of these molecules in mononuclear leukocytes from islets of 12 week-old diabetes-prone NOD female mice and three groups of 12-week-old mice with low diabetes risk: NOD female mice injected with complete Freund's adjuvant at 4 weeks of age, NOD male mice, and BALB/c female mice that do not develop diabetes. We found that iNOS, IL-1 alpha, and IFN gamma mRNA levels were higher in mononuclear leukocytes from islets of diabetes-prone NOD female mice than in those from mice correlated with IL-1 alpha and IFN gamma mRNA levels. By using specific antibodies and immunohistochemical methods, we localized iNOS in macrophages as well as in beta-cells of islets from diabetes-prone NOD female mice. These findings suggest that IL-1 alpha and IFN gamma may promote islet beta-cell destruction at least in part by up-regulating iNOS expression an No production by both macrophages and beta-cells in the islets of autoimmune diabetes-prone NOD mice.
 ...
PMID:Inducible nitric oxide synthase (iNOS) in pancreatic islets of nonobese diabetic mice: identification of iNOS- expressing cells and relationships to cytokines expressed in the islets. 861 52

The goal of this study was to test the hypothesis that administration of L-arginine, a substrate for the synthesis of nitric oxide, restores endothelium-dependent dilatation of the basilar artery during diabetes mellitus. We measured the diameter, of the basilar artery in vivo in nondiabetic and diabetic (streptozotocin; 50-60 mg/kg i.p.) rats in response to endothelium-dependent agonists (acetylcholine and bradykinin) and an endothelium-independent agonist (nitroglycerin) before and during application of L-arginine. Topical application of acetylcholine (1.0 and 10 muM) and bradykinin (1.0 and 10 microM) produced dilatation in nondiabetic rats of the basilar artery which was impaired in diabetic rats. Topical application of nitroglycerin (0.1 and 1.0 microM) produced similar dilatation of the basilar artery in nondiabetic and diabetic rats. Topical application of L-arginine (0.1 and 3 mM) did not enhance dilatation of the basilar artery in response to acetylcholine and bradykinin in diabetic rats. Thus, impairment of dilatation of the basilar artery in diabetic rats in response to acetylcholine and bradykinin appears to be related to a mechanism unrelated to the availability of L-arginine for nitric oxide synthase.
 ...
PMID:L-Arginine does not restore dilatation of the basilar artery during diabetes mellitus. 862 55

Impaired omega-6 essential fatty acid metabolism and exaggerated polyol pathway flux contribute to the neurovascular abnormalities in streptozotocin-diabetic rats. The potential interactions between these mechanisms were examined by comparing the effects of threshold doses of aldose reductase inhibitors and evening primrose oil, alone and in combination, on neurovascular deficits. In addition, high-dose aldose reductase inhibitor and evening primrose oil treatment effects were challenged by co-treatment with the cyclo-oxygenase inhibitor, flurbiprofen, or the nitric oxide synthase inhibitor, NG-nitro-L-arginine. Eight weeks of diabetes caused an 18.9% reduction in sciatic motor conduction velocity (p < 0.001). This was only modestly ameliorated by a 0.1% dietary supplement of evening primrose oil or the aldose reductase inhibitors ZD5522 (0.25 mg.kg-1.day-1 and WAY121 509 (0.2 mg.kg-1.day-1 for the final 2 weeks. However, joint treatment with primrose oil and ZD5522 or WAY121 509 caused marked 71.5 and 82.4% corrections, respectively, of the conduction deficit. Sciatic nutritive blood flow was 43.1% reduced by diabetes (p < 0.001) and this was corrected by 67.8% with joint ZD5522 and primrose oil treatment (p < 0.001). High-dose WAY121 509 (10 mg. kg-1.day-1 and primrose oil (10% dietary supplement) prevented sciatic conduction velocity and nutritive blood flow deficits in 1-month diabetic rats (p < 0.001). However, these effects were abolished by flurbiprofen (5 mg.kg(-1).day-1 and NG-nitro-L-arginine (10 mg.kg-1.day-1) co-treatment (p < 0.001). Thus, the data provide evidence for synergistic interactions between polyol pathway/nitric oxide and essential fatty acid/cyclo-oxygenase systems in the control of neurovascular function in diabetic rats, from which a potential therapeutic advantage could be derived.
 ...
PMID:Interactions between essential fatty acid, prostanoid, polyol pathway and nitric oxide mechanisms in the neurovascular deficit of diabetic rats. 863 69

Aminoguanidine, nucleophilic hydrazine derivative, has been shown to inhibit diamine oxidase, the formation of advanced glycation endproducts, nitric oxide synthase, and catalase. Prompted by the reports that aminoguanidine also inhibits aldose reductase (AR), we have investigated the effect of aminoguanidine, 1,3-diaminoguanidine, and methylguanidine on AR activity in vitro, and in vivo. In vitro, we have measured the inhibition of AR isolated from bovine lenses; in vivo, we have examined the effect on the galactitol levels in the red blood cells, sciatic nerve, retina, and lens of rats administered the test compounds for 11 days in the drinking water and, for the last 4 days, given access to a 20% galactose diet. Two known, structurally distinct AR inhibitors, tolrestat and compound WAY-121,509, were used as reference. In vitro, at concentrations up to 1.0 mmol/L, none of the tested guanidine derivatives had any effect on AR. As a corollary, in vivo, at doses ranging from 201 to 349 mg/kg/day, none of the guanidine derivatives affected tissular galactitol levels. We conclude that, in short-term galactose-fed rats, at the doses tested, aminoguanidine, 1,3-diaminoguanidine, and methylguanidine do not inhibit AR.
J Diabetes Complications
PMID:Aminoguanidine does not inhibit aldose reductase activity in galactose-fed rats. 863 71

Alterations in G-protein-controlled signalling pathways (primarily pathways controlled by Gs and Gi) have been reported to occur in animal models of diabetes mellitus. We have therefore studied the effect of a long-term exposure of human umbilical vein endothelial cells to elevated concentrations of glucose on expression and function of G-protein subunits and endothelial NO synthase. Long-term incubation in high glucose (30 mM for 15 days) did not affect the levels of Gialpha-2, Gqalpha, the splice variants (long and short form) of Gsalpha, and the G-protein beta-subunits or adenylate cyclase activity; basal, as well as isoprenaline-, forskolin- and guanosine 5'-[gamma-thio]triphosphate-stimulated enzyme activities were comparable in high- and low-glucose-treated cells, thus ruling out any functional changes in the stimulatory pathway. Pretreatment of endothelial cells with pertussis toxin blocked a substantial fraction (50%) of the mitogenic response to serum factor(s) which depend(s) of functional Gi2. The sensitivity of cells cultured in high glucose was comparable with that of the paired controls maintained in normal glucose (EC50 = 3.1 +/- 0.5 and 3.3 +/- 0.4 ng/ml respectively). Similarly, we failed to detect any differences in endothelial NO synthase expression, or intracellular distribution and basal activity of the enzyme in endothelial cells cultured in high glucose. Stimulation of NO synthase in intact cells revealed a comparable response to the calcium ionophore (A23187). In contrast, stimulation with histamine (which acts via H1-receptors predominantly coupled to Gq) resulted in a significantly increased response in the cells maintained in high glucose. These data are suggestive of an altered H1-histamine receptor-Gq-phospholipase C pathway in endothelial cells cultured in high glucose concentrations, but rule out any glucose-induced functional changes in Gs- and Gi-controlled signalling pathways.
 ...
PMID:High-glucose incubation of human umbilical-vein endothelial cells does not alter expression and function either of G-protein alpha-subunits or of endothelial NO synthase. 867 Jan 19

Aminoguanidine (AG; < or =0.5 mM) is a potent inhibitor of the inducible form of nitric oxide synthase (iNOS) and, at higher concentrations, is also able to prevent advanced glycosylation of proteins. Due to these properties, AG might be an interesting therapeutic compound for prevention of the development of diabetes and for prevention of diabetes complications. In the present study, we examined the effect of AG (0.1, 0.5, 1.0, 5.0, or 10 mM) on prolonged in vitro culture of isolated rat pancreatic islets. Furthermore, the acute effect of AG on pancreatic and islet blood flow in anaesthetized rats was studied with a microsphere technique. Culture for 6 days of pancreatic islets at either 11.1 mM or 28 mM glucose, in the presence of 0.1-1.0 mM AG, was not toxic to the islet cells or impaired insulin secretion. However, when islets were cultured for 8 days with the addition of 5 mM AG at 11.1 mM or 28 mM glucose, a 50% inhibition of glucose-stimulated insulin release was observed. Rats injected intravenously with AG (1, 10, or 50 mg/kg body weight) had a decreased pancreatic blood flow 30 min later. Glucose injection (1 g/kg body weight) increased the islet blood flow, and this effect was not attenuated by AG. The present data suggest that AG, when used in concentrations that inhibit iNOS, can affect pancreatic blood flow, but appears not to be directly harmful to beta-cell function.
 ...
PMID:Effects of aminoguanidine on rat pancreatic islets in culture and on the pancreatic islet blood flow of anaesthetized rats. 868 86


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