dimethylarginine and Hyperglycemia

The endothelium is a thin layer of cells at the internal surface of blood vessels in continuous contact with the circulating fluids. The endothelial cells represent the primary barrier for the transport of glucose from the vascular conduits into the interstitial space. Insulin and nitric oxide have an important role in the regulation of glucose transport and metabolism. Hyperglycaemia is the main criteria for the diagnosis of diabetes and is responsible for the micro- and macro-vascular pathology seen in diabetic patients. Recent evidence suggests that post-challenge hyperglycaemia is a better predictor of cardiovascular risk than fasting glucose. Acute glucose elevations have been associated with a reduced endothelial-dependent flow mediated dilation indicating a decrease in nitric oxide production. Post-prandial hyperglycaemic peaks have been directly associated with increased intima media thickness in type 2 diabetic patients indicative of an increased atherosclerotic risk. The increase in intra-cellular glucose concentrations in the endothelial cells induces a hyper-generation of reactive oxygen species via the activation of different pathways (polyol-sorbitol, hexosamine, advanced glycated end products, activation of PKC, asymmetric dimethylarginine (ADMA)). These mechanisms influence the expression of genes and release of signalling and structural molecules involved in several functions (inflammation, angiogenesis, coagulation, vascular tone and permeability, cellular migration, nutrient metabolism). ADMA is considered as a biomarker of endothelial dysfunction and it has been associated with an increased risk of atherosclerosis and cardiovascular diseases. The increased generation of ADMA and reactive oxygen species in subjects with persistent hyperglycaemia could lead to an impairment of nitric oxide synthesis.

Topics: Animals; Arginine; Diabetes Mellitus, Type 2; Endothelium, Vascular; Glucose; Glucose Tolerance Test; Heart Diseases; Humans; Hyperglycemia; Metabolic Diseases; Nitric Oxide; Oxidative Stress

We investigated whether preventing hyperglycemia in septic patients affected the plasma concentration of asymmetric-dimethylarginine and if this was associated with clinical benefit.. A prospective, multicenter, randomized, controlled, clinical study.. Intensive care units (ICU) in three university hospitals.. A total of 72 patients admitted for severe sepsis or septic shock, who stayed at least 3 days in the ICU. At admission the patients were assigned to receive either tight or conventional glycemic control.. Determination of circulating levels of asymmetric-dimethylarginine, arginine, interleukin-6, C-reactive-protein and tumor-necrosis-factor-alpha.. Blood was sampled at admission (no differences between groups), and on the 3rd, 6th, 9th, and 12th (T12) days. Sequential organ failure assessment was scored at each sampling time. All the data were analyzed on an intention-to-treat basis. The control and treatment groups received the same energy intake, glycemia (110.4 +/- 17.3 vs. 163.0 +/- 28.9 mg/dL, P < 0.001) and insulin (P = 0.02) supply differed. No differences were found in high plasma levels of asymmetric-dimethylarginine (P = 0.812) at any time during the ICU stay. The clinical course, as indicated by markers of inflammation, average and maximum organ failure score, ICU stay and ICU and 90-day mortality, was the same.. Intensive insulin treatment, while achieving glucose control, did not reduce asymmetric-dimethylarginine in high-risk septic patients fed with no more than 25 kcal/kg per day to limit ventilatory demand and to simplify glucose control.. 45 (SIRS/sepsis: clinical studies).

Topics: Aged; Arginine; Female; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Intensive Care Units; Male; Middle Aged; Sepsis; Treatment Outcome

Cancer and surgical stress interact to aggravate insulin resistance, protein catabolism, and glutamine depletion in skeletal muscle. We compared the effects of insulin-mediated euglycemia and moderate hyperglycemia on kinetics of protein and selected amino acids in skeletal muscle of female cancer patients after major surgery.. In each patient, a 24-hr period of insulin-mediated tight euglycemia (mean blood glucose, 5.8 +/- 0.4 mmol/L) preceded or followed a 24-hr control period of moderate hyperglycemia (mean blood glucose, 9.6 +/- 0.6 mmol/L) on the first and second day after surgery, in randomized order, according to a crossover experimental design.. Intensive care unit, cancer hospital.. Cancer patients after abdominal radical surgery combined with intraoperative radiation therapy.. Intensive (57 +/- 11 units/24 hrs) and conventional (25 +/- 5 units/24 hrs) insulin treatment during total parenteral nutrition.. Muscle metabolism was assessed at the end of each 24-hr period of euglycemia and of hyperglycemia by leg arteriovenous catheterization with stable isotopic tracers. We found that euglycemia as compared with hyperglycemia was associated with higher (p < .05) fractional glucose uptake (16% +/- 4% vs. 9% +/- 3%); higher (p < .05) muscle protein synthesis and neutral net protein balance (-3 +/- 3 vs. -11 +/- 3 nmol phenylalanine x 100 mL(-1) x min(-1), respectively); lower (-52% +/- 12%, p < .01) muscle nonprotein leucine disposal (an index of leucine oxidation) and higher (p < .05) plasma leucine concentrations; and higher (3.6 +/- 1.7 times, p < .01) net de novo muscle glutamine synthesis and plasma glutamine concentrations (p < .05). Euglycemia was associated with higher (23% +/- 7%, p < .05) plasma concentrations of arginine but did not affect either arginine release from muscle or plasma concentration and muscle flux of asymmetrical dimethylarginine. Rate of muscle proteolysis correlated (p < .05) with muscle release of asymmetrical dimethylarginine.. Treating hyperglycemia improves skeletal muscle protein and amino acid metabolism in cancer patients after major surgery.

Topics: Abdominal Neoplasms; Amino Acids; Arginine; Blood Glucose; Cancer Care Facilities; Combined Modality Therapy; Critical Care; Cross-Over Studies; Energy Metabolism; Female; Glutamine; Humans; Hyperglycemia; Insulin; Insulin Resistance; Leucine; Middle Aged; Muscle Proteins; Muscle, Skeletal; Overweight; Parenteral Nutrition, Total; Phenylalanine; Postoperative Complications; Radiotherapy, Adjuvant

We investigated whether preventing hyperglycemia in septic patients affected the plasma concentration of asymmetric-dimethylarginine and if this was associated with clinical benefit.. A prospective, multicenter, randomized, controlled, clinical study.. Intensive care units (ICU) in three university hospitals.. A total of 72 patients admitted for severe sepsis or septic shock, who stayed at least 3 days in the ICU. At admission the patients were assigned to receive either tight or conventional glycemic control.. Determination of circulating levels of asymmetric-dimethylarginine, arginine, interleukin-6, C-reactive-protein and tumor-necrosis-factor-alpha.. Blood was sampled at admission (no differences between groups), and on the 3rd, 6th, 9th, and 12th (T12) days. Sequential organ failure assessment was scored at each sampling time. All the data were analyzed on an intention-to-treat basis. The control and treatment groups received the same energy intake, glycemia (110.4 +/- 17.3 vs. 163.0 +/- 28.9 mg/dL, P < 0.001) and insulin (P = 0.02) supply differed. No differences were found in high plasma levels of asymmetric-dimethylarginine (P = 0.812) at any time during the ICU stay. The clinical course, as indicated by markers of inflammation, average and maximum organ failure score, ICU stay and ICU and 90-day mortality, was the same.. Intensive insulin treatment, while achieving glucose control, did not reduce asymmetric-dimethylarginine in high-risk septic patients fed with no more than 25 kcal/kg per day to limit ventilatory demand and to simplify glucose control.. 45 (SIRS/sepsis: clinical studies).

Topics: Aged; Arginine; Female; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Intensive Care Units; Male; Middle Aged; Sepsis; Treatment Outcome

To investigate whether selective reduction of postchallenge hyperglycaemia influences acute endothelial dysfunction, a very early manifestation of vascular disease, in patients with impaired glucose tolerance.. In a randomized, double-blind, placebo-controlled, cross-over study the acute effect of 200-mg acarbose was investigated in 28 subjects with diagnosed impaired glucose tolerance. Flow-mediated dilation (FMD) of the brachial artery was determined as a measure of endothelial function before and 2 and 3 h after ingestion of 100-g saccharose. Asymmetrical dimethylarginine (ADMA) was measured by high-performance liquid chromatography.. A negative correlation was observed between the changes of glucose and FMD (r = 0.416, P = 0.0018) 2 h after ingestion of saccharose. At 3 h, neither blood glucose nor FMD were different from baseline. Changes of both blood glucose (P = 0.0007) and FMD (P = 0.046) were significantly lower after administration of acarbose. Subgroup analysis revealed that the effect of acarbose was restricted to those subjects with an increase of blood glucose above the median increase of glycaemia. No changes of plasma ADMA were observed.. Our data clearly demonstrate that the postchallenge alteration of vascular function in patients with impaired glucose tolerance is caused by the acute elevation of glycaemia but not mediated by ADMA.

Topics: Acarbose; Administration, Oral; Arginine; Blood Glucose; Brachial Artery; Cross-Over Studies; Dilatation, Pathologic; Double-Blind Method; Endothelium, Vascular; Female; Glucose Intolerance; Humans; Hyperglycemia; Insulin; Male; Middle Aged; Prospective Studies; Sucrose

The vascular complications of diabetes are the most serious manifestations of the disease. The hyperglycemia can directly promote an inflammatory state where the increase C-reactive (CRP) and cytokines, such as interleukins (IL-1 and IL-6), which contribute to the development of cardiovascular diseases. The current study was aimed to evaluate the role of environmentally-synthesized zinc oxide nanocrystals (ZnO-NPs) in augmentation of hyperglycemia and its complications, as well as the preservation of asymmetrical dimethylarginine (ADMA) level as a specific marker for endothelial dysfunction in streptozotocin (STZ)-induced diabetic rats. ZnO-NPs was chemically-synthesized using environmental benign biodegradable hydroxyl ethyl cellulose (HES) as both a stabilizing and directing agent in the presence of potassium hydroxide. HES is a biomaterial compound used in many biomedical applications due to its biodegradability and biocompatibility in nature. Particle size, morphological structure, purity, and crystallinity of the as-prepared ZnO-NPs were evaluated through different techniques, such as transmission electron microscopy (TEM), X-ray diffraction (XRD), and scanning electron microscopy connected to energy-dispersive X-ray spectra (SEM-EDS). Sixty male albino rats were used in this study and divided into four groups: control, ZnO-NPs, diabetic and treated groups; after the experimental period, CRP and interleukin-1 (IL-1α) were determined by ELISA. ADMA was estimated by RP-HPLC using a fluorescence detector. The results obtained indicate that CRP, IL-1α, and ADMA levels increased significantly concomitant with a reduction in NO level in the diabetic group, whereas ZnO-NPs supplementation significantly attenuated these parameters. Based on these encouraging results, the reported approach of environmental synthesis and application has the potential of leading to a new generation of nanometerials for treatment of diabetic complications with considerably enhanced selectively towards atherosclerosis.

Topics: Animals; Arginine; Biocompatible Materials; Cardiovascular Diseases; Cellulose; Diabetes Mellitus, Experimental; Humans; Hyperglycemia; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Nanoparticles; Particle Size; Rats; Zinc Oxide

Glucose-induced oxidative stress is involved in endothelial dysfunction. Dimethylarginine dimethylaminohydrolase (DDAH) and arginase are regulators of the endothelial NO synthase (eNOS). This study aimed to compare the effect of two polyphenolic antioxidants, resveratrol and piceatannol, on DDAH and arginase pathways in bovine aortic endothelial cells under 25 mM glucose for 24 h. DDAH activity and expression were decreased in these cells as compared to control cells, whereas arginase activity was unchanged. DDAH inhibition led to intracellular accumulation of asymmetric dimethylarginine (ADMA), a natural inhibitor of eNOS. Under these conditions, cell pre-treatment with resveratrol (0.1-10 μM) restored basal DDAH activity and ADMA level with a dose-dependent effect. Piceatannol acted as resveratrol on DDAH pathway but at 10-fold lower concentrations. Resveratrol and piceatannol restored DDAH activity even in the presence of splitomicin, a specific inhibitor of Sirtuin 1. These results suggest potential therapeutic intervention targeting resveratrol or piceatannol administration to improve endothelial dysfunction.

Topics: Amidohydrolases; Animals; Antioxidants; Aorta; Arginase; Arginine; Blotting, Western; Cattle; Cell Line; Endothelial Cells; Glucose; Hyperglycemia; Immunoprecipitation; Naphthalenes; Nitric Oxide Synthase; Oxidative Stress; Pyrones; Resveratrol; Sirtuin 1; Stilbenes