Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

L-arginine, a substrate of nitric oxide synthase, was infused (30 g/300 ml/30 min) to patients with or without type 2 diabetes to examine whether or not endothelial dysfunction expressed as attenuated depressor response to the substrate in diabetic patients may accompany attenuated plasma NOx (NO2- and NO3-; an index of NO formation) elevation. Decrease in blood pressure by L-arginine was significantly smaller in diabetic patients than that in non-diabetic patients, and increase in plasma cGMP level in diabetic patients tended to be smaller and retarded than non-diabetic patients. However, plasma NOx decreased in both groups in a similar degree without changes in urinary NOx excretion, implying that NOx in plasma moved to other compartments. These results indicate that plasma NOx could not be solely used as an index of NO formation by L-arginine load and that this paradoxical decrease in plasma NOx would require further examination extending to other NOx compartments.
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PMID:Paradoxical decrease in plasma NOx by L-arginine load in diabetic and non-diabetic subjects. 1188 90

The renin-angiotensin system plays an important role in the elevation of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, in hypertensive patients, so the present study was designed to examine whether angiotensin-converting enzyme (ACE) activity is also involved in the mechanism of ADMA elevation in type 2 diabetes mellitus (NIDDM). A crossover study was performed to determine if ACE inhibition with perindopril (4 mg/day) for 4 weeks decreases serum ADMA concentration and plasma von Willebrand factor (vWF) level (a marker of endothelial injury) in 11 patients with NIDDM. None of the patients was treated with insulin or oral hypoglycemic drugs, and none had major diabetic complications. Before the protocol began, serum ADMA and plasma vWF were significantly higher in the 11 NIDDM patients, when compared with 8 control subjects without diabetes. Perindopril did not affect blood pressure or glucose metabolism, but did significantly decrease serum ADMA and plasma vWF. These results suggest that endothelial injury associated with ADMA elevation may be present even in patients with non-complicated NIDDM, and that increased activity of ACE may be involved in such endothelial dysfunction.
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PMID:Angiotensin-converting enzyme activity is involved in the mechanism of increased endogenous nitric oxide synthase inhibitor in patients with type 2 diabetes mellitus. 1222 17

Nitric oxide (NO) derived from endothelial cells is profoundly related to the maintenance of physiological vascular tone. Impairment of endothelial NO generation brought about by gene polymorphism is considered the major deterioration factor for progressive renal disease, including diabetic nephropathy. The present study aimed to elucidate the Glu298Asp polymorphism of endothelial NO synthase (eNOS) in patients with end-stage renal disease (ESRD) and its role as a predisposing factor for cardiovascular complications. Glu298Asp in exon 7 of the eNOS gene was determined by polymerase chain reaction, followed by restriction fragment length polymorphism analysis, in ESRD patients (n=185) and compared with that of unrelated healthy individuals (n=304). The occurrence of 298Asp was significantly higher in the ESRD group (P=0.0020; odds ratio [OR] 1.65; 95% confidential interval [CI]: 1.21 to 2.25). In this group, 72 patients had type 2 diabetes mellitus (DM). Although 298Asp did not reach a significant level in the non-DM ESRD subgroup, the occurrence of 298Asp was significantly higher in DM-derived ESRD patients (P=0.0010; OR 2.02; 95% CI: 1.37 to 3.07). The functional effect of the Glu298Asp was examined using Chinese hamster ovary (CHO) cells stably overexpressing either 1917G or 1917T. NO-selective electrode measurements and fluorometric nitrite assay revealed a statistically significant difference in NO production or nitrite accumulation between CHO 1917G and 1917T (P<0.01). These data indicated that Glu298Asp is the predisposing factor in ESRD, especially DM-derived ESRD. The functional difference in NO generation depending on eNOS with either glutamate or aspartate at position 298 was also confirmed in vitro.
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PMID:Association of eNOS Glu298Asp polymorphism with end-stage renal disease. 1269 20

Injection of insulin causes release of HISS (hepatic insulin sensitizing substance) from the liver in the fed state. HISS action accounts for 50-60% of the glucose disposal produced by a wide range of insulin doses (5-100 mU/kg). Although the chemical nature of HISS is unknown, precluding pharmacokinetic studies, the pharmacodynamics of HISS has advanced because of the use of the rapid insulin sensitivity test (RIST) which is a transient euglycemic clamp used following a bolus of insulin. HISS action can be blocked by hepatic denervation and restored by intraportal but not intravenous infusion of acetylcholine or a nitric oxide donor. HISS release is prevented by blockade of hepatic muscarinic receptors, nitric oxide synthase blockers, indomethacin, and animal models of insulin resistance, including chronic liver disease, sucrose feeding, hypertension, aging, obesity, and fetal alcohol exposure. HISS acts on skeletal muscle but not liver, gut, or adipose tissue. HISS is released by insulin in the fed state but decreases to insignificance after 24-hr fasting in rats. Cats and dogs appear to require a longer period of fasting to prevent HISS action. Lack of HISS action is suggested to be the cause of post-meal hyperglycemia and hyperlipidemia in type 2 diabetes and other disease states with similar metabolic dysfunction. The RIST can be carried out up to six times in the same animal, is not affected by pentobarbital anesthesia, and can readily differentiate HISS-dependent and HISS-independent insulin action.
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PMID:Practice and principles of pharmacodynamic determination of HISS-dependent and HISS-independent insulin action: methods to quantitate mechanisms of insulin resistance. 1242 50

Increased nitric oxide (NO) synthesis has been proposed to participate in the generation of insulin resistance in adipose and muscle tissues. Therefore, we examined the potential rate-limiting role of tetrahydrobiopterin (BH4) in cytokine-induced NO synthesis, and the effect of peroxisome proliferator activated receptor-gamma (PPARgamma) activation using the insulin-sensitizer rosiglitazone on cytokine-induced BH4 synthesis in 3T3-L1 adipocytes. Our data indicate that modulated availability of the mandatory nitric oxide synthase (NOS) cofactor BH4 affected cytokine-induced NO generation. Semiquantitative linear range reverse transcription polymerase chain reaction (RT-PCR) analysis demonstrated that rosiglitazone not only reduced inducible nitric oxide synthase (iNOS) mRNA transcription, but also guanosine triphosphate cyclohydrolase (GTPCH), the rate-limiting and controlling step of BH4 synthesis. Accordingly, intracellular BH4 concentration was reduced by 45% following rosiglitazone treatment. Furthermore, we observed a transient inhibitory effect of natural PPARgamma ligand 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PJ2) on cytokine-mediated iNOS and GTPCH induction. Thus, the inhibition of cytokine-induced NO synthesis by rosiglitazone is at least in part attributable to reduced availability of BH4, the synthesis of which might represent a potential new target in the treatment of type 2 diabetes and insulin resistance.
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PMID:Diminished production of nitric oxide synthase cofactor tetrahydrobiopterin by rosiglitazone in adipocytes. 1256 86

The thiazolidinedione class of antidiabetic drugs, including troglitazone, has an insulin-sensitizing effect for patients with type 2 diabetes. However, in some tissues, studies have shown that troglitazone also has an acute insulin-independent effect on glucose uptake. To determine the extent of this acute action of troglitazone, the effect of troglitazone on 2-deoxyglucose (2DG) uptake in L929 fibroblast cells was measured. Troglitazone stimulated 2DG uptake in a dose dependent manner with a maximum stimulation of >300% at 5-10 microM. In addition, nitric oxide has been shown to stimulate glucose uptake in peripheral muscle tissue. Therefore, the effect of nitric oxide on 2DG uptake in L929 cells was also investigated using the nitric oxide donor, sodium nitroprusside (SNP). SNP stimulated 2DG uptake by >200% with a maximally effective concentration of 5 mM. The combined effect of maximally effective concentrations of both stimulants (10 microM troglitazone + 5 mM SNP) was not additive suggesting a shared pathway for 2DG uptake. However, the nitric oxide synthase inhibitor, N(G)-monomethyl-L-arginine (L-NMMA, 50 microM) had no effect on troglitazone stimulated 2DG uptake, indicating that the troglitazone and nitric oxide pathways converge after nitric oxide production. In addition, 12.5 microM dantrolene was shown to have no effect on either troglitazone or SNP stimulated 2DG uptake suggesting that these stimulatory effects are independent of changes in calcium ion concentrations. These data provide important evidence for the acute regulation of glucose transport through GLUT 1 transporters.
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PMID:Acute effects of troglitazone and nitric oxide on glucose uptake in L929 fibroblast cells. 1263 98

This study was aimed to characterize the vascular production of superoxide in Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of type 2 diabetes. The nitroblue tetrazolium staining in the aorta from old (30 weeks) OLETF rat was more prominent than that of age-matched control (LETO) rat, which was significantly inhibited by diphenyleneiodonium (10 micromol/l), but not by inhibitors for other oxidases such as xanthine oxidase, mitochondrial oxidase, nitric oxide synthase, and cyclooxygenase. In the aorta from old OLETF rat with hyperglycemia, the enhanced NADH oxidase activity in association with upregulated expression of p22phox and gp91phox was observed, but not in both LETO and young (10 weeks) OLETF rats without hyperglycemia. Furthermore, there was a positive correlation (P<0.01) between elevation of blood glucose level and increase in vascular NADH oxidase activity. Based on these results, it was suggested that the enhanced NADH oxidase activity in the aorta from OLETF rat occurred after the onset of hyperglycemia, thereby resulting in the increased vascular production of superoxide.
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PMID:Enhanced vascular production of superoxide in OLETF rat after the onset of hyperglycemia. 1263 60

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS). Increased plasma levels of ADMA may indicate endothelial dysfunction and increased risk of angiopathy. The relation of ADMA to diabetes, glycemic control, and renal function, especially early diabetic hyperfiltration, remains unknown. We tried to evaluate whether there is an association between ADMA and glycosylated hemoglobin (GHbA(1c)) on the one hand and glomerular filtration rate (GFR) on the other hand in diabetic subjects with normal or slightly increased GFR. We also studied whether plasma ADMA is associated with some risk factors of vasculopathy (hypercholesterolemia and hypertension). The study subjects consisted of 86 patients with type 2 diabetes and 65 control subjects. Plasma ADMA levels were measured by high-pressure liquid chromatography as o-pthalaldehyde (OPA) derivatives and GFR was determined by the plasma clearance of chromium 51-EDTA. The diabetic patients had lower plasma ADMA levels than the nondiabetic control subjects (0.29 +/- 0.15 v 0.34 +/- 0.16 micromol/L, P <.03). In the diabetic subjects, plasma ADMA concentrations were inversely correlated with GHbA(1c) (R = -0.28, P =.01). In a multivariate linear model, significant predictors of ADMA were GFR (R = -0.32, P =.008) in diabetic subjects and GHbA(1c) (R = -0.19, P =.03) and GFR (R = -0.19, P =.02) in all subjects. Plasma ADMA was not associated with risk factors of vasculopathy. We conclude that diabetic patients with a normal or slightly increased GFR have lower circulating ADMA concentrations than nondiabetic control subjects. In type 2 diabetic patients high GFR and poor glycemic control were related to low plasma ADMA concentrations.
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PMID:Plasma concentrations of asymmetric-dimethyl-arginine in type 2 diabetes associate with glycemic control and glomerular filtration rate but not with risk factors of vasculopathy. 1264 67

Type 2 diabetes mellitus (T2-DM) markedly increases the incidence of ischemic heart disease (IHD) and, consequently, mortality. However, the underlying mechanisms leading to IHD in T2-DM are not completely understood. We hypothesized that in T2-DM the regulation of coronary microvascular resistance by local mechanisms is altered. Thus, in coronary arterioles (diameter: approximately 80 microm) isolated from male mice with T2-DM (C57BL/KsJ-db/db) and control littermates, responses to changes in intraluminal pressure, flow, and agonists with known mechanisms of action were studied. Increases in pressure (from 20 to 120 mmHg) resulted in similar myogenic responses of coronary arterioles of control and db/db mice, whereas dilations in response to cumulative concentrations of ACh and the nitric oxide (NO) donor NONOate were significantly decreased compared with those of control vessels. On the other hand, responses to adenosine were not different between vessels of control and db/db mice. Increases in flow (0-20 microl/min) resulted in dilations of control vessels (maximum: 38 +/- 4%) that were inhibited by the NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME). In contrast, arterioles of db/db mice exhibited greatly reduced dilations to flow (maximum: 4 +/- 6%) that were unaffected by L-NAME. In carotid arteries of db/db mice, superoxide dismutase (SOD)-sensitive, enhanced superoxide production was detected by dihydroethydine staining and lucigenin enhanced chemiluminescence. Correspondingly, intraluminal administration of SOD significantly augmented flow-, ACh-, and NONOate-induced dilations of diabetic arterioles, and then flow- and ACh-induced responses could be inhibited by L-NAME. Collectively, these findings suggest that in T2-DM, due to an enhanced superoxide production, NO mediation of agonist- and flow-induced dilations of coronary arterioles is reduced. This alteration in the regulation of coronary microvascular resistance may contribute to the development of IHD in T2-DM.
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PMID:Superoxide-NO interaction decreases flow- and agonist-induced dilations of coronary arterioles in Type 2 diabetes mellitus. 1280 26

We tested the hypothesis that short-term treatment of mice with Type 2 diabetes mellitus (DM) with rosiglitazone (ROSI), an agonist of peroxisome proliferator-activated receptor-gamma, ameliorates the impaired coronary arteriolar dilation by reducing oxidative stress via a mechanism unrelated to its effect on hyperglycemia and hyperinsulinemia. Control and Type 2 DM (db/db) mice were treated with ROSI (3 mg x kg(-1) x day(-1)) for 7 days, which did not significantly affect their serum concentration of glucose and insulin. Compared with controls, in db/db mice serum levels of 8-isoprostane and dihydroethydine-detectable superoxide production in carotid arteries were significantly elevated and were reduced by ROSI treatment. In coronary arterioles (diameter, approximately 80 microm) isolated from db/db mice, the reduced dilations to ACh, the nitric oxide (NO) donor NONOate, and increases in flow were significantly augmented either by in vitro administration of apocynin, an inhibitor of NAD(P)H-oxidase, or by in vivo ROSI treatment, responses that were then significantly reduced by the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester. In aortas of db/db mice, activity of SOD and catalase was reduced, whereas NAD(P)H oxidase activity was enhanced. ROSI treatment enhanced catalase and reduced NAD(P)H oxidase activity but did not affect the activity of SOD. These findings suggest that ROSI treatment enhances NO mediation of coronary arteriolar dilations due to the reduction of vascular NAD(P)H oxidase-derived superoxide production and enhancement of catalase activity. Thus, in addition to the previously revealed beneficial metabolic effects, the antioxidant action of rosiglitazone may protect coronary arteriolar function in Type 2 DM.
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PMID:PPARgamma activation, by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with Type 2 diabetes. 1455 Oct 45


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