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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although hyperglycemia has been shown to cause peripheral nerve dysfunction in patients with diabetes, the biochemical mechanisms for this effect are poorly understood. The excessive production of reactive oxygen species and reactive nitrogen species has been proven to be detrimental in experimental diabetes, but there is little evidence that these metabolic events take place clinically and are physiologically important in man. To assess this we measured nitrite and nitrate (indices of nitric oxide production), nitrotyrosine (an index of peroxynitrite), 8-isoprostaglandin F-2 alpha, an isoprostane reflective of oxidative stress and lipid peroxidation, and uric acid, an index of antioxidant defense in patients with recently diagnosed Type 1 diabetes and aged-matched controls. The diabetic patients were followed for three years. We documented the overproduction of nitric oxide and increased lipid peroxidation in early diabetes and showed these changes had detectable adverse effects on peripheral nerve function especially sympathetic sudomotor nerves. We documented the suppression of uric acid and showed this was associated with multiple abnormalities in autonomic function. In addition, we present indirect evidence that overproduction of reactive oxygen species and reactive nitrogen species have adverse effects on beta cell function and blood pressure.
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PMID:Nitrosative stress in early Type 1 diabetes. David H. P. Streeten Memorial Lecture. 1760 44

We used the partial protection exerted by suitable dosages of nicotinamide against the beta-cytotoxic effect of streptozotocin (STZ) to create an experimental diabetic syndrome in adult rats that appears closer to type II diabetes mellitus than other available animal models. The dosage of 230 mg/kg of nicotinamide given intraperitoneally 15 min before STZ administration (65 mg/kg i.v.) yielded animals with hyperglycemia (187.8 +/- 17.8 vs. 103.8 +/- 2.8 mg/dL in controls; P < 0.001) and preservation of plasma insulin levels. This study assessed the relationship between endothelial dysfunction and agonist-induced contractile responses in such rats. In the thoracic aorta, the acetylcholine (ACh) induced relaxation was significantly reduced and the noradrenaline (NA) induced contractile response was significantly increased in diabetic rats compared with age-matched control rats. In the superior mesenteric artery, the ACh-induced relaxation was similar in magnitude between diabetic and age-matched control rats; however, the ACh-induced endothelium-derived hyperpolarizing factor (EDHF) type relaxation was significantly weaker in diabetic rats than in the controls. The phenylephrine (PE) induced contractile response was not different between the two groups. The plasma concentration of NOx (NO2- + NO3-) was significantly lower in diabetic rats than in control rats. We conclude that vasomotor activities in conduit arteries are impaired in this type II diabetes model.
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PMID:Alterations in vascular endothelial function in the aorta and mesenteric artery in type II diabetic rats. 1505 83

Keishi-bukuryo-gan (Gui-zhi-fu-ling-wan) is a formula used for the improvement of blood circulation. Recently it has often also been used for arteriosclerosis. One of the mechanisms involved is thought to be the improvement of endothelial dysfunction, but the details are still unclear. In this study, the effect of Keishi-bukuryo-gan on vascular function and hemorheological factors in spontaneously diabetic (WBN/kob) rats was studied. Rats were given Keishi-bukuryo-gan in chow for 30 weeks. Body weight, blood glucose, endothelium-dependent/-independent relaxation, vasocontraction by free radical-induced and contractive prostanoids, triglyceride, advanced glycation endproduct, lipid peroxides, serum NO2-/NO3- and blood viscosity were measured. The results indicated that Keishi-bukuryo-gan caused a decrease in endothelium-dependent relaxation by acetylcholine to become significantly increased, and vasocontraction induced by free radicals and contractive prostanoids was significantly decreased. Furthermore, serum NO2-/NO3- and blood viscosity were significantly decreased. From these results, it was supposed that Keishi-bukuryo-gan exerted a protective effect on the endothelium. The WBN/kob rat is a useful study model for the complications of human diabetes, and Keishi-bukuryo-gan showed a protective effect against vascular injury in the susceptible rat.
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PMID:Effects of Keishi-bukuryo-gan on vascular function and hemorheological factors in spontaneously diabetic (WBN/kob) rats. 1507 Jan 71

Impairment of erectile function compromises quality of life in millions of men and their partners, many of whom prefer to suffer in silence. It is important to maintain an elevated index of clinical suspicion in patients with erectile dysfunction (ED) risk factors (e.g. hypertension, diabetes, coronary heart disease). There remains a high rate of voluntary discontinuation of therapy associated with most treatment modalities. Since the introduction of sildenafil, a greater awareness and openness regarding the epidemiology and treatment of male erectile dysfunction has emerged. The development of newer and potentially more efficacious phosphodiesterase type 5 (PDE5) inhibitors will serve to treat an even greater number of patients, allowing once daily and more convenient dosing. An increased understanding of the physiological principles of penile erection has allowed the development of novel oral pharmacological therapies. The new agents offer a potential benefit in a broader range of patients and clinical situations. They may provide a more acceptable alternative than other more invasive options (intracavernosal/urethral injection, implant surgery). The dopamine agonist apomorphine acts on the central control of penile erection to allow a sublingual preparation to produce a prompt response. It is not contraindicated in patients on nitrate medication for coronary artery disease, or in patients with depression or on antidepressants. As with any other treatment, the clinician's responsibility in the care of ED patients does not end with the writing of a prescription. Adequate education and follow-up are needed to optimize the efficacy and safety of oral ED therapy. Furthermore, patients and their partners need to be advised that the agents are not effective in the absence of sexual stimulation. Communicating with both the patient and his partner in a discreet, non-judgmental manner that fosters the physician-patient alliance can facilitate the recognition and treatment of ED.
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PMID:Update on oral treatments for male erectile dysfunction. 1509 34

Erectile dysfunction (ED) is often a marker for serious underlying cardiovascular disease (CVD), and cardiologists are increasingly involved in the care of men with ED. It is important to ask specifically about ED when evaluating men with CVD, since they may be embarrassed to volunteer this information. During the clinical workup, it is also important to check for contributing factors to ED such as diabetes, depression, stress, alcohol abuse, and cardiovascular risk factors. Patients should be advised that many treatment options are available for ED, including the phosphodiesterase type 5 (PDE5) inhibitors. The PDE5 inhibitors are safe and effective in most patients with CVD, including those taking multiple antihypertensive drugs. Furthermore, they have no deleterious effect on exercise capacity, heart rate, or extent of exercise-induced ischemia. In the future, the PDE5 inhibitors may have a role in reducing pulmonary hypertension in persons with primary pulmonary arterial hypertension (PAH) or congestive heart failure. The one major precaution for men taking PDE5 inhibitors is to avoid concomitant administration of therapeutic and recreational nitrate preparations. Patients with chest pain suggestive of a heart attack need to inform emergency room (ER) personnel if they are taking a PDE5 inhibitor. Similarly, before giving nitrates, ER personnel need to ask patients if they have used PDE5 inhibitors. Nitrates should not be given for at least 24 h after a patient uses sildenafil or vardenafil and at least 48 h after a patient uses tadalafil.
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PMID:Role of the cardiologist: clinical aspects of managing erectile dysfunction. 1511 89

The aim of the present study was to compare vascular dysfunction between the early (12 wk old) and later (36 wk old) stages of spontaneous diabetes in Goto-Kakizaki (GK) rats. We also evaluated the aortic expression of the alpha(2D)-adrenoceptor and endothelial nitric oxide synthase (eNOS). Vascular reactivity was assessed in thoracic aortas from age-matched control rats and 12- and 36-wk GK rats. Using RT-PCR and immunoblots, we also examined the changes in expression of the alpha(2D-)adrenoceptor and eNOS. In aortas from GK rats (vs. those from age-matched control rats): 1) the relaxation response to ACh was enhanced at 12 wk but decreased at 36 wk; 2) the relaxation response to sodium nitroprusside was decreased at both 12 and 36 wk, 3) norepinephrine (NE)-induced contractility was decreased at 12 wk but not at 36 wk, 4) the expressions of alpha(1B)- and alpha(1D)-adrenoceptors were unaffected, whereas those of alpha(2D)-adrenoceptor and eNOS mRNAs were increased at both 12 and 36 wk; and 5) NE- and ACh-stimulated NO(x) (nitrite and nitrate) levels were increased at 12 wk, although at 36 wk ACh-stimulated NO(x) was lower, whereas NE-stimulated NO(x) showed no change. These results clearly demonstrate that enhanced ACh-induced relaxation and impaired NE-induced contraction, due to NO overproduction via eNOS and increased alpha(2D)-adrenoceptor expression, occur in early-stage GK rats and that the impaired ACh-induced relaxation in later-stage GK rats is due to reductions in both NO production and NO responsiveness (but not in eNOS expression).
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PMID:Differential expression of alpha2D-adrenoceptor and eNOS in aortas from early and later stages of diabetes in Goto-Kakizaki rats. 1513 Aug 81

The assessment of the postprandial state in diabetes mellitus has gained importance due to postprandial hyperglycemia being considered as an independent risk factor for cardiovascular disease. Hyperglycemia may contribute to vascular dysfunction through the alteration of the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway. The authors assessed the NO/cGMP pathway in the fasting and postprandial state in 20 type 1 diabetic patients (age: 34.1 +/- 2.6 years, body mass index (BMI): 24.1 +/- 1.3 kg/m (2), duration of diabetes: 16 +/- 2.2 years, HbA (1C): 8.3 +/- 0.4 %, [x +/- SEM], 10 without, 10 with late complications) and 20 matched control subjects (age: 39.7 +/- 1.9 years, BMI: 25.3 +/- 1.1 kg/m (2)). In the fasting state NO end product (nitrite/nitrate) levels did not differ between the diabetic and control group, cGMP levels were found to be significantly lower in the diabetic group (2.5 +/- 0.2 vs. 4.6 +/- 0.6 nmol/l, p = 0.01). A higher level of lipid peroxidation end products (TBARS) was found in diabetic subjects (6.7 +/- 0.4 vs. 5.0 +/- 0.3 micro mol/l, p = 0.004). The diabetic subgroup without late complications had significantly higher nitrite/nitrate levels compared to the patients with complications (57.8 +/- 6.6 vs. 30.4 +/- 4.3 micro mol/l, p = 0.006), their TBARS and cGMP levels were similar. The control subjects responded to the test meal with an increase in the cGMP levels (4.6 +/- 0.6 to 5.5 +/- 0.6 nmol/l, p = 0.02), while in the diabetic group no change was detected. Postprandial nitrite/nitrate levels decreased in both groups, they were significantly lower in the diabetic group. There was no difference between postprandial nitrite/nitrate, cGMP, or glucose levels in the diabetic subgroups. Postprandial glucose levels showed a significant negative correlation with cGMP levels in the diabetic group (r = - 0.50, p = 0.02). The results suggest that in subjects with type 1 diabetes mellitus NO might have an impaired ability to induce cGMP production in the fasting state prior to the development of late specific complications or microalbuminuria under hyperglycemic conditions. Postprandial hyperglycemia is suggested to interfere with endothelial NO action, as shown by the decreased nitrite/nitrate and unchanged cGMP plasma levels in the diabetic group. The impairment of the NO/cGMP pathway both in the fasting and postprandial state that was shown in patients without diabetic complications may be an early sign of hyperglycemia induced vascular damage in type 1 diabetes mellitus.
Exp Clin Endocrinol Diabetes 2004 May
PMID:Impairment of the NO/cGMP pathway in the fasting and postprandial state in type 1 diabetes mellitus. 1514 72

The precise mechanisms of vascular diseases in patients with insulin-dependent diabetes mellitus (IDDM) are not clearly understood. There are evidences of alteration in mechanisms involved in regulating vascular tone including increased ACE activity and decreased NO production in STZ diabetic rats. Insulin treatment may reverse these changes by an unknown mechanism. This study sought to examine the interaction of ACE activity and NO and how insulin treatment affected these mechanisms. Four groups of eight male Sprauge-Dawely rats including control (C) and three diabetic groups (D, IT and LIT) were used in this study. Diabetes induced by injection of 60 mg kg(-1) STZ i.p. After induction of diabetes IT group treated with insulin (10 units kg(-1) daily s.c.) for 4 weeks. LIT group received the same amount of insulin and N(omega)-nitro-l-arginine methyl ester (L-NAME; 20 mg kg(-1) i.p.) for the same period. The D group was diabetic control that treated with saline. ACE activity was determined by HPLC method. At the end of study in D group ACE activity was increased in aorta, heart, lung and serum but Serum NO(x) (nitrate and nitrite) concentration decreased compared to C group. These values were reversed to normal by insulin treatment in IT group. In LIT group the ACE activity remained elevated only in aorta and heart while the serum NO(x) was lower than control group. It is concluded that ACE reducing activity of insulin in aorta and heart of STZ-induced diabetic rats may be mediated by elevation of NO by insulin treatment.
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PMID:Study of interaction between nitric oxide and ACE activity in STZ-induced diabetic rats: role of insulin. 1522 68

Different types of ATP-sensitive K+ (K(ATP)) channels have been identified in cardiomyocytes, vascular smooth muscle cells, pancreatic beta-cells, neurons and mitochondria. Years before the discovery of the K(ATP) channel in cardiomyocytes, pharmacological openers of this channel had been developed for the treatment of angina pectoris and hypertension. The K(ATP) channel plays an important role not only in coronary blood flow regulation but also in protection of cardiovascular cells from ischemia/reperfusion injury. In animal models of myocardial ischemia/reperfusion, activation of the mitochondrial K(ATP) channels by their pharmacological openers has been shown to attenuate endothelial dysfunction and to reduce myocardial necrosis. Conversely, blockade of the K(ATP) channel aggravates microvascular necrosis and the no-reflow phenomenon after ischemia/reperfusion, resulting in augmentation of post-infarct ventricular dysfunction. Recent clinical studies have shown that a combination of coronary reperfusion therapy and infusion of nicorandil, a hybrid of K(ATP) channel opener and nitrate, improved left ventricular function in patients with acute myocardial infarction. Furthermore, chronic treatment with nicorandil has been shown to significantly improve prognosis of patients with high-risk stable angina pectoris. Both of these clinical benefits cannot be attributed to the nitrate property of nicorandil. However, a recent basic investigation has suggested that the protective function of K(ATP) channel openers is compromised by concurrent hypercholesterolemia and administration of sulfonylureas for diabetes mellitus. These interferences in the beneficial action of K(ATP) channel openers by concurrent illness and pharmacological agents need to be further investigated to allow a more effective use of K(ATP) channel openers in patients with coronary artery diseases.
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PMID:ATP-sensitive K+ channel openers: old drugs with new clinical benefits for the heart. 1532 Apr 72

Macro and microvascular diseases are the principal causes of morbidity and mortality in patients with type I and II diabetes mellitus. Growing evidence implicates reactive nitrogen species (RNS), such as peroxynitrite (ONOO-), derived from nitric oxide (NO) and superoxide anion (O2*-), are important in diabetes. The mechanisms by which diabetes increases RNS, and those by which RNS modifies vascular function, are poorly understood. The authors recently discovered that physiologically relevant concentrations of ONOO- oxidize the zinc thiolate center in endothelial nitric oxide synthase (eNOS). In active eNOS dimers, a tetracoordinated zinc ion is held by four thiols, two from each 135-kDa monomer. Because it remains partially positively charged, the zinc thiolate center is subject to attack by the ONOO-. This oxidant disrupts the zinc thiolate center, releasing zinc, and oxidizing the thiols. Upon thiol reduction, eNOS dimers dissociate into monomers. This modification of eNOS results in reduced NO bioactivity and enhanced endothelial O2*- production, which reacts with NO, further generating ONOO- (eNOS uncoupling). In addition, the authors' studies also demonstrate that low concentrations of ONOO- selectively nitrate and inactivate prostacyclin synthase (PGIS), which not only eliminates the vasodilatory, growth-inhibiting, antithrombotic, and antiadhesive effects of prostacyclin (PGI2), but also increases release of the potent vasoconstrictor, prothrombotic, growth- and adhesion-promoting agents, prostaglandin H2 (PGH2) and thromboxane A2 (TxA2). In diabetic mice and rats, eNOS is uncoupled resulting in an increased tyrosine nitration of PGIS. The authors' studies indicate that in diabetes the synthetic enzymes of the two major endogenous vasodilators undergo oxidative inactivation by different mechanisms, which are, however, tightly interdependent.
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PMID:Peroxynitrite and vascular endothelial dysfunction in diabetes mellitus. 1537 68


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