dimethylarginine and Insulin-Resistance

In this study, we examined the association between chronic kidney disease (CKD) and insulin resistance. In a patient cohort with nondiabetic stages 2-5 CKD, estimated glomerular filtration rate (eGFR) was negatively correlated and the plasma aldosterone concentration was independently associated with the homeostasis model assessment of insulin resistance. Treatment with the mineralocorticoid receptor blocker spironolactone ameliorated insulin resistance in patients, and impaired glucose tolerance was partially reversed in fifth/sixth nephrectomized rats. In these rats, insulin-induced signal transduction was attenuated, especially in the adipose tissue. In the adipose tissue of nephrectomized rats, nuclear mineralocorticoid receptor expression, expression of the mineralocorticoid receptor target molecule SGK-1, tissue aldosterone content, and expression of the aldosterone-producing enzyme CYP11B2 increased. Mineralocorticoid receptor activation in the adipose tissue was reversed by spironolactone. In the adipose tissue of nephrectomized rats, asymmetric dimethylarginine (ADMA; an uremic substance linking uremia and insulin resistance) increased, the expression of the ADMA-degrading enzymes DDAH1 and DDAH2 decreased, and the oxidative stress increased. All of these changes were reversed by spironolactone. In mature adipocytes, aldosterone downregulated both DDAH1 and DDAH2 expression, and ADMA inhibited the insulin-induced cellular signaling. Thus, activation of mineralocorticoid receptor and resultant ADMA accumulation in adipose tissue has, in part, a relevant role in the development of insulin resistance in CKD.

Topics: Adipose Tissue; Aged; Aldosterone; Amidohydrolases; Animals; Arginine; Cell Nucleus; Cytochrome P-450 CYP11B2; Female; Glomerular Filtration Rate; Glucose Tolerance Test; Homeostasis; Humans; Immediate-Early Proteins; Insulin Resistance; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Nephrectomy; Oxidative Stress; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; Receptors, Mineralocorticoid; Renal Insufficiency, Chronic; Renin; Signal Transduction; Spironolactone

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

Plasma asymmetric dimethylarginine (ADMA) concentrations are higher in apparently healthy, insulin-resistant (IR) individuals and decrease in response to thiazolidenedione treatment.. The objective of the study was to determine whether ADMA concentrations would also fall when insulin sensitivity is enhanced with weight loss in obese individuals. DESIGN/SETTING/PATIENTS/INTERVENTION: Twenty obese women classified as IR or insulin sensitive (IS) on the basis of their steady-state plasma glucose (SSPG) concentration during the insulin suppression test underwent 12 wk of dietary weight loss.. Plasma glucose, insulin, and ADMA were measured at baseline and after weight loss; change in insulin resistance was quantified by repeating the SSPG after the dietary intervention.. Although weight loss was similar in the two groups, significant improvements in SSPG, glucose, and insulin concentrations were confined to the IR group. Baseline plasma ADMA concentrations (mean +/- sd) were higher in IR subjects (1.69 +/- 0.44 vs. 1.18 +/- 0.45 micromol/liter, P = 0.02) and decreased to 1.20 +/- 0.22 micromol/liter (P < 0.001) with weight loss. In contrast, ADMA levels did not change with a similar extent of weight loss in the IS group.. Plasma ADMA levels are higher in obese, IR women than in equally obese, IS women and decrease in response to weight loss when associated with enhancement of insulin sensitivity.

Topics: Adult; Arginine; Blood Glucose; Diet, Reducing; Female; Humans; Insulin; Insulin Resistance; Middle Aged; Obesity; Weight Loss

Endoplasmic reticulum stress (ERS) as an emerging factor is involved in insulin resistance (IR), which is the pathological basis of diabetes mellitus. Accumulation of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase is associated with IR, but the underlying mechanisms have not been elucidated. This study was to reveal the important role of ADMA in IR and determine whether endogenous ADMA accumulation contributes to hepatic IR via ERS in diabetic rats and hepatocytes.. Diabetic rat model was induced by a single intraperitoneal injection of streptozotocin (50 mg/kg). Phosphorylation of insulin receptor substrate 1 (IRS1) and protein kinase B (Akt) was detected to evaluate IR. The protein kinase PKR-like ER kinase (PERK) and eukaryotic initiation factor 2α kinase (eIF2α) phosphorylation, x-box binding protein-1 (XBP-1) splicing, glucose-regulated protein 78 (GRP78) and C/EBP homologues protein (CHOP) expressions were measured to assess ERS.. Endogenous ADMA content was significantly increased and positively correlated with either IR as evidenced by increased IRS1 at serine and reduced Akt phosphorylation or ERS as indicated by upregulations of PERK and eIF2α phosphorylation, XBP-1 splicing, GRP78 and CHOP expressions in the liver of diabetic rats compared with control rats. Exogenous ADMA directly caused IR and ERS in dose- and time-dependent manners in primary mouse hepatocytes. Pretreatment with ERS inhibitor 4-phenylbutyrate or ADMA antagonist L-arginine not only improved ADMA-associated or -induced hepatic IR but also attenuated ADMA-associated or -induced ERS in diabetic rats or hepatocytes.. These findings indicate that endogenous ADMA accumulation contributes to hepatic IR via ERS in diabetic rats.

Topics: Animals; Apoptosis; Arginine; Diabetes Mellitus, Experimental; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Glucose Intolerance; Hepatocytes; Insulin; Insulin Resistance; Liver; Male; Rats; Rats, Sprague-Dawley; Signal Transduction

Asymmetric dimethylarginine (ADMA) plays a vital role in the regulation of insulin sensitivity and has been shown as a potential marker for various disease, including type 2 diabetes mellitus (DM2). However, the correlation between ADMA and impaired glucose tolerance (IGT) and obesity has not been studied. A total of 195 subjects were involved in our study. The characteristics of the subjects in the study cohort were measured and analyzed. We found that the serum ADMA and C-reactive protein levels were significantly increased in IGT and diabetic patients, whereas the levels of lipoprotein A and adiponectin were decreased, especially in diabetic patients with obesity. The serum ADMA level was positively correlated to a homeostatic model assessment for insulin resistance, and multivariate regression analysis further indicated that ADMA was an independent factor for DM patients with obesity. Our study expands the understanding of the complicated relationship between obesity, insulin resistance, IGT, and ADMA. In addition, we demonstrated that the serum ADMA level could serve as a diagnositic biomarker of the early signs for IGT patients with obesity.

Topics: Aged; Arginine; Biomarkers; Blood Glucose; C-Reactive Protein; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin Resistance; Male; Middle Aged; Obesity

In adult liver transplant recipients, coronary artery disease and congestive heart failure are significant cause of morbidity and mortality. This may be attributed to the long-term immunosuppressive treatment, mostly with calcineurin inhibitors and steroids, which in long-term may be associated with hyperlipidemia, oxidative stress and cardiovascular complications. Since such data for children is sparse, the aim of this study was to assess the lipid and oxidative stress markers after pediatric liver transplantation (LTx).. We performed prospective analysis of 74 children, at the median age of 7.9 (2.8-11.6) years, 3.2 (1.2-4.3) years after LTx. We assessed the BMI Z-scores, cholesterol fractions (LDLc, HDLc, VLDLc), triglicerides, apolipoproteins (ApoAI, ApoB, ApoE), LCAT, insulin resistance by HOMA-IR and markers of oxidative stress and atherosclerosis: glutathione (GSH), glutathione peroxidase (GPx), asymmetrical dimethyl arginine (ADMA) and oxidized low-density lipoprotein (oxyLDL). At baseline, the results were compared with a healthy age-and-sex matched control group. After 3.1±0.3 year follow-up we repeated all investigations and compared them with the baseline results.. At the baseline, we investigated 74 patients 3.2 (1.2-4.3) years after LTx, at the median age of 7.9 (2.8-11.6) years. The prevalence of overweight or obesity (BMI >85. Children after LTx had normal lipid profiles when compared to controls, however there is a tendency for hypercholesterolemia and obesity, which may play a role in cardiovascular complications in the future. Some markers of oxidative stress were increased after LTx, however further investigations are required to establish its clinical significance.

Topics: Apolipoproteins; Arginine; Biomarkers; Body Mass Index; Case-Control Studies; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Hypercholesterolemia; Insulin Resistance; Lipids; Liver Transplantation; Male; Obesity; Oxidative Stress; Triglycerides

Estimated glomerular filtration rate (eGFR) based on either cystatin C or creatinine performs similarly in estimating measured GFR, but associate differently with cardiovascular disease (CVD) and mortality. This could be due to confounding by non-GFR-related traits associated with cystatin C and creatinine levels. We investigated non-GFR-related associations between eGFR and two types of nontraditional risk factors for CVD and death: L-arginine/dimethylarginine metabolism and insulin resistance.. GFR was measured via iohexol clearance in a cross-sectional study of 1,624 middle-aged persons from the general population without CVD, diabetes or chronic kidney disease. The dimethylarginines were measured using liquid chromatography tandem mass spectrometry (LC-MSMS). Insulin resistance was determined by the homeostasis model assessment (HOMA-IR).. Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), the L-arginine/ADMA ratio and insulin resistance were associated with creatinine-based eGFR after accounting for measured GFR in multivariable adjusted analyses. The cystatin C-based eGFR showed a similar residual association with SDMA; an oppositely directed, borderline significant association with ADMA; and a stronger residual association with insulin resistance compared with eGFR based on creatinine.. Both creatinine- and cystatin C-based eGFR are influenced by nontraditional risk factors, which may bias risk prediction by eGFR in longitudinal studies.

Topics: Arginine; Bias; Creatinine; Cross-Sectional Studies; Cystatin C; Female; Glomerular Filtration Rate; Homeostasis; Humans; Insulin Resistance; Male; Middle Aged; Risk Factors

To define the clinical significance of asymmetric dimethylarginine (ADMA) and that of methylenetetrahydrofolate reductase (MTHFR) gene polymorphism as factors of endothelial dysfunction (ED) in the development of early kidney injury in obese patients.. The investigation included 86 patients (64 men and 22 women aged 44 +/- 11 years) with abdominal obesity. Along with physical examination, the authors determined albuminuria, calculated glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease (MDRD) formula, estimated insulin resistance markers (fasting plasma insulin and C-peptide concentrations and homeostatic model assessment (HOMA) index), as well as serum ADMA levels by enzyme immunoassay in all the patients. C677T polymorphism in the MTHFR gene was studied by allele-specific polymerase chain reaction and restriction fragment length polymorphism analysis. Kidney injury (chronic kidney disease (CKD)) was diagnosed using the Kidney Disease Outcomes Quality Initiative (KDOQI) criteria. Early vascular remodeling was determined from the increased intima-media thickness (IMT) of the common carotid artery (CCA).. CKD was diagnosed in 27(31%) patients. The latter, unlike the patients with CKD, were observed to have more pronounced obesity (body mass index (BMI) 36.8 +/- 8.0 and 32.0 +/- 4.7 kg/m2, respectively (p < 0.001)), waist circumference (119 +/- 18 and 109 +/- 11 cm (p = 0.002)), higher levels of C-peptide (1348 +/- 363 and 1028 +/- 363 pmol/I; p < 0.001), insulin (16.9 +/- 7.3 and 11.7 +/- 5.5 microU/ ml; p < 0.001), and HOMA index (4.3 +/- 1.7 and 2.9 +/- 1.5; p < 0.001). In the patients with Stage IIIa CKD, ADMA concentrations (0.77 +/- 0.19 micromol/l) was higher than in those with Stages I (0.58 +/- 0.11 micromol/l; p = 0.048) and II (0.61 +/- 0.13 micromol/l; p = 0.071). An association between ADMA concentrations, CCA IMT, and estimated GFR was revealed in the patients with CKD. The predictors of an estimated GFR reduction in obesity were elevated serum concentrations of ADMA, uric acid, insulin, and HOMA index. The combination of obstructive sleep apnea syndrome and metabolic syndrome increased the risk of CKD by 2.1-fold (95% confidence interval, 1.06-3.14). Evaluation of the impact of MTHFR gene polymorphism on kidney injury in obesity disclosed that the patients with homozygous carriage of the abnormal T allele of the MTHFR gene had a higher risk for Stages I-IIIa CKD (2.60 with 95% confidence interval, 1.32-3.88), more marked obesity and hyperinsulinemia, and increased serum ADMA concentrations.. Insulin resistance and ED hold a central position in the pathogenesis of CKD in obese patients. The mechanisms of the atherosclerotic vascular remodeling associated with elevated serum ADMA concentrations are of paramount importance in the progression of early-stage CKD. The homozygous carriage of the abnormal T allele of the MTHFR gene increases the risk of Stages I-IIIa by more than twice.

Topics: Adult; Arginine; Carotid Artery, Common; Data Interpretation, Statistical; Endothelium, Vascular; Female; Glomerular Filtration Rate; Humans; Hypoxia; Insulin Resistance; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Obesity; Polymorphism, Genetic; Renal Insufficiency, Chronic; Risk Factors; Severity of Illness Index; Tunica Media; Ultrasonography

Dimethylarginine dimethyl-aminohydrolase 1 (DDAH1) is a metabolic enzyme for asymmetric dimethylarginine (ADMA), both of which are closely related to endothelial function. Endothelial dysfunction, a main risk factor of cardiovascular diseases, can be attributed to insulin resistance. We aimed to determine the effects of atorvastatin, an endothelium-protective drug, on DDAH1/ADMA in insulin-resistant rats. Insulin resistance in male Sprague-Dawley rats was induced with a high-fat diet for 8 weeks. Some rats received atorvastatin (30 mg/kg/day) for an additional 8 weeks. Insulin-resistant rats exhibited not only decreases in the DDAH activity and aortic expression of DDAH1 and sterol regulatory element-binding protein 1 (SREBP1) but also increases in plasma ADMA levels, all of which were inhibited by atorvastatin. Insulin sensitivity and DDAH activity showed a significant positive correlation. In conclusion, our results suggest that atorvastatin may modulate DDAH1/ADMA to improve endothelial function in insulin-resistant rats; SREBP1 may also play a role in this.

Topics: Amidohydrolases; Animals; Arginine; Atorvastatin; Diet, High-Fat; Endothelial Cells; Endothelium, Vascular; Heptanoic Acids; Insulin; Insulin Resistance; Pyrroles; Rats; Rats, Sprague-Dawley

Topics: Arginine; Female; Humans; Insulin Resistance; Polycystic Ovary Syndrome; Reference Values; Tunica Intima; Tunica Media

We tested if asymmetric dimethylarginine (ADMA) contributes to the simultaneous evolution of atherosclerosis and insulin resistance. We investigated the significant predictors of insulin resistance in the context of atherosclerosis, focusing on the role ADMA, symmetric dimethylarginine (SDMA), and l-arginine play in a cohort of young atherosclerotic patients and their age-matched controls. In a case-control study, 60 patients younger than 55 years having at least 30% stenosis of the internal carotid artery and 30 age- and sex-matched controls were recruited at a community-based neurosonologic laboratory. We found a strong positive association between the homeostasis model assessment of beta-cell function and insulin resistance and the ADMA/SDMA ratio that remained statistically significant even after adjusting for all significant and a priori identified determinants (beta = 6.76; 95% confidence interval [CI], 2.13-11.39; P = .005). Interestingly, this relationship was even more pronounced in the atherosclerotic stratum (beta = 8.29; 95% CI, 1.43-15.15; P = .019), whereas, on multiple linear regression, lack of association was seen in subjects free of carotid atherosclerosis (beta = 1.39; 95% CI, -5.46 to 8.26; P = .671). We conclude that ADMA/SDMA ratio is a significant determinant of insulin resistance and may be a better parameter to monitor than ADMA alone. By accounting for the competition at the y+ transporters, ADMA/SDMA ratio could be an indicator of intracellular ADMA level.

Topics: Adult; Arginine; Atherosclerosis; Female; Humans; Insulin Resistance; Male; Middle Aged

Functional changes of the vessel wall--specifically dysfunction of endothelial cells--may precede the formation of frank plaques at the initiation of atherosclerosis. Clinically endothelial function and dysfunction can be measured by angiography or ultrasound techniques. Another possibility is the measurement of circulating markers of endothelial dysfunction in human plasma, such as the endogenous NOS inhibitor ADMA (asymmetric dimethylarginine). In our recent studies we were able to show that ADMA accumulates in the presence of metabolic changes such as hyperhomocysteinemia, insulin resistance and type-2 diabetes, and that these elevations of plasma ADMA correlate well with the amount of endothelial dysfunction and with NO bioavailability. Furthermore ADMA was shown to be dynamically regulated and to play an important patho-physiologic role in myocardial ischemia and reperfusion. Thus, measurements of plasma ADMA in patients could help to screen for manifestations of atherosclerosis. Moreover attempts to reduce plasma and tissue ADMA could potentially play an important role in the treatment of endothelial dysfunction, atherosclerosis, but also of ischemia reperfusion injury.

Topics: Arginine; Coronary Artery Disease; Diabetes Mellitus, Type 2; Endothelium, Vascular; Homocysteine; Humans; Insulin Resistance; Myocardial Reperfusion Injury; Nitric Oxide; Nitric Oxide Synthase; Statistics as Topic

Increased circulating methylarginines (MA) have been linked to the metabolic syndrome to explain endothelial dysfunction and cardiovascular disease risk. Proteins that contain MA are regulatory and release them during catabolism. We hypothesised that increased protein turnover in insulin-resistant states contributes to an increase in circulating MA. MATWERIALS AND METHODS: We performed hyperinsulinaemic, euglycaemic, and isoaminoacidaemic experiments on 49 lean, obese and elderly subjects, with measurements of the kinetics of glucose and protein metabolism. Plasma MA, i.e. asymmetrical dimethylarginine (ADMA), symmetrical dimethylarginine (SDMA), and N -monomethyl-L-arginine (NMMA), lipids and body composition were measured.. Insulin resistance of glucose and protein metabolism occurred in obese and elderly subjects. ADMA concentrations were 29 to 120% higher in obese and 34% higher in elderly than in lean subjects. SDMA were 34 and 20% higher in obese than in lean and than in elderly subjects, respectively. NMMA were 32% higher in obese than in lean subjects. ADMA differed by sex, being higher in men, namely by 1.75x in obese men and by 1.27x in elderly men. Postabsorptive ADMA (r=0.71), SDMA (r=0.46), and NMMA (r=0.31) correlated (all p<0.05) with rates of protein flux. All three MA correlated negatively with clamp glucose infusion rates and uptake (p<0.001). ADMA and SDMA correlated negatively with net protein synthesis and clamp amino acid infusion rates (p<0.05). All MA also correlated with adiposity indices and fasting insulin and triglycerides (p<0.05).. Obesity, sex and ageing affect MA. Elevations of the three MA in obese, and of ADMA in elderly men, are related to increased protein turnover and to lesser insulin sensitivity of protein metabolism. These interrelationships might amplify insulin resistance and endothelial dysfunction.

Topics: Adult; Aged; Aged, 80 and over; Aging; Arginine; Blood Glucose; Body Composition; Female; Glucose; Glucose Clamp Technique; Humans; Insulin; Insulin Resistance; Lipids; Male; Metabolic Syndrome; Middle Aged; Obesity; omega-N-Methylarginine; Proteins; Regression Analysis; Sex Characteristics