Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have shown that nitric oxide synthase (NOS), the enzyme that catalyzes the formation of nitric oxide (NO), is expressed in skeletal muscle. The aim of the present study was to test the hypothesis that NO can modulate glucose metabolism in slow- and fast-twitch skeletal muscles. Calcium-dependent NOS was detected in skeletal muscle, and the enzyme activity was greater in fast-type extensor digitorum longus (EDL) muscles than in slow-type soleus muscles. Both the neuronal-type (nNOS) and endothelial-type (eNOS) enzymes are expressed in resting skeletal muscles. However, nNOS protein was only detected in EDL muscles, whereas eNOS protein contents were comparable in soleus and EDL muscles. NOS expression in muscle cryosections (diaphorase histochemistry) was located in vascular endothelium and in muscle fibers, and the staining was greater in type IIb than in type I and IIa fibers. The macrophage-type inducible NOS (iNOS) was not detected in resting muscle, but endotoxin treatment induced its expression, concomitant with elevated NO production. iNOS induction was associated with impaired insulin-stimulated glucose uptake in isolated rat muscles. In vitro, NOS blockade with specific inhibitors did not affect basal or insulin-stimulated glucose transport in EDL or soleus muscles. In contrast, the NO donors GEA 5024 and sodium nitroprusside induced dose-dependent inhibition (up to 50%) of maximal insulin-stimulated glucose transport in both muscles with minor effects on basal uptake values. GEA 5024 also blunted insulin-stimulated glucose transport and amino acid uptake in cultured L6 muscle cells without affecting insulin binding to its receptor. On the other hand, the permeable cGMP analogue dibutyryl cGMP did not affect muscle glucose transport. These results strongly suggest that NO modulates insulin action in both slow- and fast-type skeletal muscles. This novel autocrine action of NO in muscle appears to be mediated by cGMP-independent pathways.
Diabetes 1997 Nov
PMID:Expression of nitric oxide synthase in skeletal muscle: a novel role for nitric oxide as a modulator of insulin action. 935 14

Erectile dysfunction occurs frequently in humans with diabetes mellitus; the molecular basis of this phenomenon is not known. We investigated the effects of diabetes on penile erection, nitric oxide synthase and growth factors expression in an animal model. Forty male rats were divided into two groups: the experimental group (n = 30) received intraperitoneal injection of Streptozotocin (STZ) dissolved in citrate buffer to induce diabetes; ten age-matched control rats received injection of citrate buffer vehicle only. Before euthanization at eight weeks, erectile function was assessed by electrostimulation of the cavernous nerves. NADPH diaphorase staining was used to identify NOS and immunostaining technique was used to identify nNOS in the penile nerve fibers. RT-PCR was used to identify mRNA expression of nNOS, eNOS, iNOS, ER-beta, ER-alpha, NGF, IGF-I, TGF-beta 1, and AR. Western blot was used to identify nNOS, IGF-I, NGF, and TFG-beta protein expressions. In the diabetic group, there was: (1) a significant decrease in NOS containing nerve fibers in the dorsal and intracavernosal nerves; (2) a significant lower maximal intracavernosal pressure. RT-PCR showed down-regulation of nNOS (large form), iNOS and ER-beta mRNA expression, Immunoblot showed down-regulation of nNOS protein expression and nNOS immunostaining showed less positive staining in the dorsal and intracavernous nerves in the diabetic group. These molecular changes may provide the basis for further studies to explore the association between diabetes and impotence.
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PMID:Effects of diabetes on nitric oxide synthase and growth factor genes and protein expression in an animal model. 1040 80

Decreased availability of arginine and impaired production of NO (nitric oxide) have been implicated in the development of endothelial dysfunction. Citrulline formed by the NOS reaction is recycled to arginine by the citrulline-NO cycle, which is composed of NOS, argininosuccinate synthetase (AS), and argininosuccinate lyase. Therefore, we investigated the alterations of these enzymes in the aorta of streptozotocin (STZ)-induced diabetic rats. eNOS and AS mRNAs were increased by three- to fourfold 1-2 weeks after STZ treatment and decreased at 4 weeks. AL mRNA was weakly induced. Induction of eNOS and AS proteins was also observed. Cationic amino acid transporter (CAT)-1 mRNA remained little changed, and CAT-2 mRNA was not detected. The plasma nitrogen oxide levels were increased 1-2 weeks after STZ treatment and decreased at 4 weeks. Transforming growth factor-beta1 (TGF-beta1) mRNA in the aorta was also induced. TGF-beta1 induced eNOS and AS mRNAs in human umbilical vein endothelial cells but inhibited the proliferation of HUVEC. These results indicate that eNOS and AS are coinduced in the aorta in early stages of STZ-induced diabetic rats and that the induction is mediated by TGF-beta1. The results also suggest that TGF-beta1 works antiatherogenically at early stages of diabetes by increasing NO production, whereas prolonged elevation of TGF-beta1 functions atherogenically by inhibiting endothelial cell growth.
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PMID:Coinduction of endothelial nitric oxide synthase and arginine recycling enzymes in aorta of diabetic rats. 1138 98

It has been shown that BH(4) ameliorates endothelial dysfunction associated with conditions such as hypertension, cigarette smoking, and diabetes. This effect has been proposed to be due to a superoxide scavenging activity of BH(4). To examine this possibility we determined the rate constant for the reaction between BH(4) and superoxide using electron paramagnetic resonance (EPR) spin trapping competition experiments with 5-diethoxyphosphoryl-5-methyl-1-pyrroline N-oxide (DEPMPO). We calculated a rate constant for the reaction between BH(4) and superoxide of 3.9 +/- 0.2 x 10(5) M(-1)s(-1) at pH 7.4 and room temperature. This result suggests that superoxide scavenging by BH(4) is not a major reaction in vivo. HPLC product analysis showed that 7,8-BH(2) and pterin are the stable products generated from the reaction. The formation of BH(4) cation radical (BH(4)(*+)) was demonstrated by direct EPR only under acidic conditions. Isotopic substitution experiments demonstrated that the BH(4)(*+) is mainly delocalized on the pyrazine ring of BH(4). In parallel experiments, we investigated the effect of ascorbate on 7,8-BH(2) reduction and eNOS activity. We demonstrated that ascorbate does not reduce 7,8-BH(2) to BH(4), nor does it stimulate nitric oxide release from eNOS incubated with 7,8-BH(2). In conclusion, it is likely that BH(4)-dependent inhibition of superoxide formation from eNOS is the mechanism that better explains the antioxidant effects of BH(4) in the vasculature.
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PMID:Reaction of tetrahydrobiopterin with superoxide: EPR-kinetic analysis and characterization of the pteridine radical. 1159 82

An arteriograph was used to assess myogenic tone, smooth muscle contractility and the influence of endothelial function on mesenteric resistance artery reactivity in insulin-resistant mice (C57BL/KsJ-db/db) and age- and gender-matched wild-type mice. Increases in transmural pressure induced myogenic tone in arteries from both control and db/db mice. At 12 and 16 weeks of age, greater tone developed in diabetic than in control mice. In control, but not in db/db mice, pretreatment of arteries with L-NAME potentiated myogenic tone. Indomethacin and SQ29548 (PGH2/TXA2 receptor antagonist) had no efffect in control, but inhibited myogenic tone in db/db mice. Endothelium-dependent vasodilation induced by acetylcholine and bradykinin, was depressed in db/db mice and potentiated by SQ29548 and LY333531 (protein kinase C(beta) inhibitor). Messenger RNA expression levels for PKC(beta) were over-expressed 2.5-fold in db/db relative to those in control mice. However, expression levels of mRNA for eNOS, PKC(alpha), and PKC(xi) were similar in the db/db and control mice. Collectively, these results suggest that the greater myogenic tone in resistance arteries from diabetic mice may be attributable, to greater amounts of one or more vasoconstricting prostanoids. Our data indicate that in diabetic mice, basal and agonist-stimulated NO releases are depressed and NO-mediated vasorelaxation in these mice may be countered by an endogenous vasoconstrictive prostanoid. This prostanoid-induced vasoconstriction is mediated by a PKC(beta)-dependent mechanism. Therefore, heightened activation of PKC(beta) and release of a vasoconstrictor prostanoid could play a role in endothelial dysfunction associated with type II diabetes.
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PMID:Influence of type II diabetes on arterial tone and endothelial function in murine mesenteric resistance arteries. 1174 Jan 57

This study assessed whether the in vivo production of nitric oxide (NO) in the penis is impaired in experimental diabetes and whether this phenomenon can be explained by abnormal levels of NO synthase isoenzymes and/or plasma androgens. Adult male Sprague-Dawley rats were injected with streptozotocin (STZ) (40 mg/kg, i.p.) or vehicle. One half of the STZ-treated animals received daily insulin replacement. Twelve weeks later, the animals were tested for mating behavior and erectile reflexes. They were then anesthetized with urethane (1 g/kg), and the NO levels in their corpora cavernosa were monitored electrochemically with porphyrin microsensors before and after electrostimulation of the cavernous nerve. The intracavernous pressure (ICP) was measured simultaneously. The diabetic animals had substantial impairment in the mating and erectile reflexes tests, decreased basal and stimulated NO levels in the corpora, and a reduced ICP response to cavernous nerve stimulation. Insulin replacement fully reversed the effects of diabetes on the mating reflexes, the basal NO signals, and the ICP responses to electrical field stimulation and partially restored the stimulated NO release. Neither diabetes nor diabetes with insulin treatment had significant effects on serum testosterone levels or NOS isoform (nNOS, eNOS, and iNOS) protein content in penile homogenates, indicating that the changes found in erectile function were independent of such variables. These results also suggest that the diabetes-induced reduction in corporeal NO levels could be mainly due to the lack of some essential cofactors for NOS activity rather than to changes in the amount of enzyme proteins.
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PMID:Changes in mating behavior, erectile function, and nitric oxide levels in penile corpora cavernosa in streptozotocin-diabetic rats. 1175 Dec 81

Nitric oxide (NO) is a multifunctional mediator that has been implicated in the short-term hemodynamic alterations that occur in acute streptozocin (STZ)-induced diabetes. We investigated the role of NO produced by inducible nitric oxide synthase (iNOS) in chronic STZ diabetic nephropathy. Diabetes was induced in C57BL/6 and iNOS knockout (KO) mice with two intraperitoneal injections of STZ, 100 mg/kg. Animals were maintained without insulin treatment for 40 weeks. There were no significant differences between the strains in blood urea nitrogen (BUN), serum creatinine or glucose concentration, or urinary protein excretion during the entire observation period. Urinary nitrite + nitrate excretion was significantly lower in iNOS KO mice compared to control animals at all time points; in C57 mice, urinary nitrite declined progressively with more prolonged duration of diabetes. Renal hypertrophy (kidney weight/body weight) was noted in both strains of mice. However, histopathological assessment of renal tissue specimens at 16 and 40 weeks demonstrated increased mesangial hypercellularity and expansion as well as more prominent tubulointerstitial fibrosis in iNOS KO versus C57 mice. These changes were accompanied by increased interstitial deposition of type I collagen at 16 and 40 weeks in iNOS KO mice. Glomerular basement membrane staining for type IV collagen was also increased at 40 weeks in diabetic iNOS KO mice. While iNOS protein was undetectable in any of the kidney specimens obtained from either strain, eNOS was present throughout the course of chronic STZ diabetes. Moreover, eNOS expression was significantly increased by approximately 40% at 16 and 40 weeks of observation in iNOS KO versus C57 mice. There was no difference in renal cortical malondialdehyde content between the strains early or late in the disease course. In time control animals, there was no evidence of renal histopathological damage in iNOS KO or C57 mice after 40 weeks. We conclude that iNOS-derived NO modulates glomerulosclerosis and tubulointerstitial fibrosis in chronic STZ nephropathy. This action is probably a result of the direct actions of NO on the synthesis and degradation of extracellular matrix proteins.
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PMID:Chronic diabetic nephropathy: role of inducible nitric oxide synthase. 1179 30

Leukocyte adhesion to the diabetic retinal vasculature results in blood-retinal barrier breakdown, capillary nonperfusion, and endothelial cell injury and death. Intercellular adhesion molecule-1 (ICAM-1) and the leukocyte integrin CD18 are required for these processes. Diabetes was induced in Long Evans rats, resulting in a two- to threefold increase in retinal leukocyte adhesion. Following one week of diabetes, neutrophil CD11a, CD11b, and CD18 expression was increased significantly, as were retinal ICAM-1 levels. Animals were treated with aspirin, a cyclooxygenase 2 (COX-2) inhibitor (meloxicam), or a soluble tumor necrosis factor alpha (TNF-alpha) receptor/Fc construct (TNFR-Fc, etanercept). High-dose aspirin, etanercept, and high-dose meloxicam each reduced leukocyte adhesion and suppressed blood-retinal barrier breakdown. High-dose aspirin also reduced the expression of CD11a, CD11b, and CD18, whereas meloxicam and etanercept did not. High-dose aspirin, etanercept, and high-dose meloxicam each reduced retinal ICAM-1 expression. Aspirin and meloxicam both lowered retinal TNF-alpha levels. Notably, aspirin, meloxicam, and etanercept did not change retinal vascular endothelial growth factor levels. High-dose aspirin, etanercept and high-dose meloxicam, each suppressed the retinal expression of eNOS and the DNA-binding capacity of retinal nuclear factor-kappaB. High-dose aspirin also suppressed Erk kinase activity, which is involved in CD18 up-regulation. Taken together, these data identify COX-2 and TNF-alpha as operative in the early signature pathologies of diabetic retinopathy, a newly recognized inflammatory disease.
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PMID:Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression. 1182 Dec 58

Endothelial dysfunction, considered as a defective vascular dilatation after certain stimuli, is characteristic of different pathological conditions, such as hypertension, atherosclerosis, or diabetes. A decreased synthesis or an increased degradation of nitric oxide (NO) has been postulated as the mechanism responsible for this alteration. The present experiments were designed to test the hypothesis that the presence of an abnormal extracellular matrix in vessel walls could be responsible for the decreased NO synthesis observed in these pathological conditions. Experiments were performed in cultured human umbilical vein endothelial cells (HUVECs) grown on type IV (Col. IV) or type I (Col. I) collagen. Cells seeded on Col. I showed decreased nitrite synthesis, nitric oxide synthase activity, eNOS protein content, and eNOS mRNA expression when compared with cells grown on Col. IV. Moreover, cells grown on Col. I failed to respond to glucose oxidase activation of the eNOS system. In both cases, the changes in the eNOS mRNA expression seemed to depend on the modulation of eNOS promoter activity. The downregulation of eNOS induced by Col. I was blocked by D6Y, a peptide that interferes with the Col. I-dependent signals through integrins, as well as by specific anti-integrin antibodies. Moreover, a decreased activation of integrin-linked kinase (ILK) may explain the effects observed in Col. I-cultured cells because the activity of this kinase was decreased in these cells and ILK modulation prevented the Col. I-induced changes in HUVECs. Taken together, these findings may contribute to explaining the basis of endothelial dysfunction in some vascular diseases.
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PMID:Decreased nitric oxide synthesis in human endothelial cells cultured on type I collagen. 1190 17

This study investigated coronary perfusion pressure, nitric oxide (NO) and superoxide production, nitrotyrosine (NT) formation, and cardiac cell apoptosis in isolated hearts perfused with high glucose concentration. Coronary perfusion pressure; NO and superoxide anion generation; immunostaining for NT, inducible NO synthase (iNOS), and the constitutive type of NO synthase (NOS) eNOS; iNOS and eNOS mRNA expression by Western blot and RT-PCR; and apoptosis of cardiac cells were studied in hearts perfused for 2 h with solutions containing D-glucose at a concentration of 11.1 mmol/l (control), D-glucose at the concentration of 33.3 mmol/l (high glucose), or D-glucose (33.3 mmol/l) plus glutathione (0.3 mmol/l). Perfusion of isolated hearts in conditions of high glucose concentration caused a significant increase of coronary perfusion pressure (P < 0.001) and an increase of both NO and superoxide generation. However, superoxide production was 300% higher than baseline, whereas NO production was 40% higher (P < 0.001 for both). This effect was accompanied by the formation of NT, and an increase of iNOS expression. eNOS remained unchanged. At the end of the experiments, cardiac cell apoptosis was evident in hearts perfused with high glucose. The effects of high glucose were significantly prevented by glutathione. This study demonstrates that high glucose for 2 h is enough to increase iNOS gene expression and NO release in working rat hearts. Upregulation of iNOS and raised NO generation are accompanied by a marked concomitant increase of superoxide production, a condition favoring the production of peroxynitrite, a powerful pro-oxidant that can mediate the toxic effects of high glucose on heart by itself and/or via the formation of nitrotyrosine, as suggested by the detection of cell apoptosis.
Diabetes 2002 Apr
PMID:Acute hyperglycemia induces nitrotyrosine formation and apoptosis in perfused heart from rat. 1191 28


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