Enhanced in vivo lipid peroxidation at elevated plasma total homocysteine levels. (41/5009)

An elevated plasma total homocysteine level (tHcy) is considered an independent risk factor for atherosclerosis. The mechanisms by which hyperhomocysteinemia induces atherosclerosis are only partially understood, but promotion of LDL oxidation and endothelial injury have been suggested. The purpose of this study was to test the hypothesis that a high plasma tHcy is associated in men with increased in vivo lipid peroxidation, as measured by plasma F2-isoprostane concentrations. We investigated this association in a subset of the participants in the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study. Of 256 male participants, a subsample of 100 consecutive men was selected for F2-isoprostane assays. The mean tHcy was 11.0 micromol/L, and the mean F2-isoprostanes was 29.6 ng/L. The simple correlation coefficient for association between tHcy and F2-isoprostane was 0.40 (P<0.001). In a linear regression model, the variables with the strongest associations with F2-isoprostane were tHcy (standardized coefficient 0.33, P<0.001), serum triglycerides (0.21, P=0.042), carbohydrate-deficient transferrin (0.15, P=0.132), and plasma lipid-standardized alpha-tocopherol (-0.11, P=0.252) (R2=0.24, P<0. 001 for model). Plasma F2-isoprostane levels increased linearly across quintiles of tHcy (P<0.001). The unadjusted mean (95% confidence interval) F2-isoprostanes was 47.5% greater in the highest tHcy quintile (37.4, 31.1 to 43.6 ng/L) than in the lowest quintile (25.3, 21.3 to 29.3 ng/L). Adjustment for the strongest other determinants of F2-isoprostane reduced this difference to 28. 2% (P=0.010). Our present data suggest that elevated fasting plasma tHcy is associated with enhanced in vivo lipid peroxidation in men.  (+info)

Determinants of fasting and post-methionine homocysteine levels in families predisposed to hyperhomocysteinemia and premature vascular disease. (42/5009)

Elevated plasma total homocysteine (tHcy) levels, either measured in the fasting state or after oral methionine loading, are associated with an increased risk of atherothrombotic disease. Fasting and post-methionine hyperhomocysteinemia (HHC) overlap to a limited extent; both can occur as familial traits. We investigated determinants of fasting, postmethionine and delta (ie, post-methionine minus fasting levels) tHcy levels in 510 subjects of 192 HHC-prone families including 161 patients with clinical vascular disease and 349 without vascular disease. We focused on tHcy levels in relation to levels of vitamin B12, B6 and folate and the methylenetetrahydrofolate reductase (MTHFR) C677T mutation. Multivariate linear analyses adjusted for the presence of vascular disease showed that fasting tHcy was significantly related to folate and vitamin B12, and the presence of the MTHFR TT genotype and the T allele, and to age, smoking habits, and serum levels of creatinine. Both post-methionine and delta tHcy levels were related to serum folate levels, and the presence of the MTHFR TT genotype and the T allele, and to postmenopausal status, and body mass index. An interaction was found between MTHFR TT genotype and serum folate levels for both fasting and post-methionine tHcy, ie, for a given decrease in serum folate, homocysteine levels increased more in subjects with the TT genotype than in those with the CC genotype. Fasting, post-methionine and delta tHcy were higher in patients with vascular disease than in their healthy siblings, but these levels were less dependent on serum folate levels (P<0.05), whereas the effect of MTHFR genotype was stronger (P=0.01). This study found evidence that post-methionine and delta tHcy levels are not only influenced by factors affecting homocysteine transsulfuration but also by factors that affect remethylation. The explained variances of fasting, post-methionine and delta tHcy were 49%, 62%, and 78%, respectively. We also found evidence, in patients with premature vascular disease but not in their healthy siblings, for a factor that increases tHcy levels but weakens the normal inverse relation between folate and tHcy and amplifies the effect of the MTHFR genotype.  (+info)

Substrate metabolism when subjects are fed carbohydrate during exercise. (43/5009)

This study determined the effect of carbohydrate ingestion during exercise on the lipolytic rate, glucose disappearance from plasma (Rd Glc), and fat oxidation. Six moderately trained men cycled for 2 h on four separate occasions. During two trials, they were fed a high-glycemic carbohydrate meal during exercise at 30 min (0.8 g/kg), 60 min (0.4 g/kg), and 90 min (0.4 g/kg); once during low-intensity exercise [25% peak oxygen consumption (VO2 peak)] and once during moderate-intensity exercise (68% VO2 peak). During two additional trials, the subjects remained fasted (12-14 h) throughout exercise at each intensity. After 55 min of low-intensity exercise in fed subjects, hyperglycemia (30% increase) and a threefold elevation in plasma insulin concentration (P < 0.05) were associated with a 22% suppression of lipolysis compared with when subjects were fasted (5.2 +/- 0.5 vs. 6.7 +/- 1.2 micromol. kg-1. min-1, P < 0.05), but fat oxidation was not different from fasted levels at this time. Fat oxidation when subjects were fed carbohydrate was not reduced below fasting levels until 80-90 min of exercise, and lipolysis was in excess of fat oxidation at this time. The reduction in fat oxidation corresponded in time with the increase in Rd Glc. During moderate-intensity exercise, the very small elevation in plasma insulin concentration (approximately 3 microU/ml; P < 0.05) during the second hour of exercise when subjects were fed vs. when they were fasted slightly attenuated lipolysis (P < 0.05) but did not increase Rd Glc or suppress fat oxidation. These findings indicate that despite a suppression of lipolysis after carbohydrate ingestion during exercise, the lipolytic rate remained in excess and thus did not limit fat oxidation. Under these conditions, a reduction in fat oxidation was associated in time with an increase in glucose uptake.  (+info)

Regional glycerol and free fatty acid metabolism before and after meal ingestion. (44/5009)

We measured splanchnic and leg glycerol [and free fatty acid (FFA)] uptake and release in 11 healthy volunteers before and after meal ingestion to assess whether regional FFA-to-glycerol release ratios mirror systemic release ratios. Basal splanchnic triglyceride release was also assessed. Although basal splanchnic glycerol uptake (111 +/- 18 micromol/min) accounted for most of systemic glycerol rate of appearance (156 +/- 20 micromol/min), leg glycerol uptake was also noted. The basal, systemic FFA-to-glycerol release ratio was less (2.6 +/- 0.2, P < 0.05) than the splanchnic ratio of 6.1 +/- 1.3, and the leg FFA-to-glycerol release ratio under fed conditions was less than the systemic ratio (0.9 +/- 0.1 vs. 1.6 +/- 0.2, respectively, P < 0.05). Basal splanchnic triglyceride production rates were 74 +/- 20 micromol/min, which could produce equimolar amounts of glycerol in the peripheral circulation via lipoprotein lipase action. In summary, 1) regional FFA-to-glycerol release ratios do not mirror systemic ratios, 2) leg glycerol uptake occurs in humans, and 3) splanchnic triglyceride production rates are substantial relative to systemic glycerol appearance. Glycerol appearance rates may not be a quantitative index of whole body lipolysis.  (+info)

Effect of protein intake and physical activity on 24-h pattern and rate of macronutrient utilization. (45/5009)

Effects of moderate physical activity (90 min at 45-50% of maximal O2 uptake 2 times daily) and "high" (2.5 g protein. kg-1. day-1, n = 6) or "normal" protein intake (1.0 g protein. kg-1. day-1, n = 8) on the pattern and rate of 24-h macronutrient utilization in healthy adult men were compared after a diet-exercise-adjustment period of 6 days. Energy turnover (ET) was determined by indirect and direct (suit) calorimetry, and "protein oxidation" was determined by a 24-h continuous intravenous infusion of [1-13C]leucine. Subjects were in slight positive energy balance during both studies. Protein contributed to a higher (22 vs. 10%) and carbohydrate (CHO) a lower (33 vs. 58%) proportion of total 24-h ET on the high- vs. normal-protein intake. The highest contribution of fat to ET was seen postexercise during fasting (73 and 61% of ET for high and normal, respectively). With the high-protein diet the subjects were in a positive protein (P < 0.001) and CHO balance (P < 0.05) and a negative fat balance (P < 0.05). The increased ET postexercise was not explained by increased rates of urea production and/or protein synthesis.  (+info)

Genetic differences in cholesterol absorption in 129/Sv and C57BL/6 mice: effect on cholesterol responsiveness. (46/5009)

This study compared the cholesterolemic response of two strains of mice with genetically determined differences in cholesterol absorption. When fed a basal low-cholesterol diet, 129/Sv mice absorbed cholesterol twice as efficiently as did C57BL/6 mice (44% vs. 20%). Total lipid absorption, in contrast, averaged 80-82% in both strains. The higher level of cholesterol absorption in the 129/Sv animals was reflected in an adaptive reduction in hepatic and intestinal sterol synthesis. When fed lipid-enriched diets, the 129/Sv mice became significantly more hypercholesterolemic and had twofold higher hepatic cholesterol concentrations than did the C57BL/6 animals even though the conversion of cholesterol to bile acids was stimulated equally in both strains. The difference in cholesterol absorption between these mouse strains was not the result of physicochemical factors relating to the size and composition of the intestinal bile acid pool but more likely reflects an inherited difference in one or more of the biochemical steps that facilitate the translocation of sterol across the epithelial cell.  (+info)

Isolated low HDL cholesterol: an insulin-resistant state only in the presence of fasting hypertriglyceridemia. (47/5009)

Individuals with isolated low HDL cholesterol are at increased risk of coronary artery disease. It has been reported previously that this is an insulin-resistant state. We analyzed data from the 1992 Singapore National Health Survey with the objective of defining the clinical and metabolic parameters associated with isolated low HDL cholesterol. A total of 3,568 individuals were selected by stratified random sampling. Subjects with low HDL cholesterol (<0.9 mmol/l) and "ideal" total cholesterol (<5.2 mmol/l) were identified. Data on anthropometry, blood pressure (BP), insulin resistance, glucose tolerance, sex, smoking habit, and ethnic group were examined. We found that this group was heterogeneous. Those with fasting triglyceride (TG) >1.7 mmol/l (low HDL/high TG) displayed features of the insulin resistance syndrome characterized by obesity, higher diastolic BP, greater insulin resistance, and a greater tendency to have diabetes or impaired glucose tolerance (IGT). If fasting TG was <1.7 mmol/l (isolated low HDL cholesterol), individuals were similar to the general population in terms of insulin resistance and obesity. Both groups were more commonly men and Asian Indian. The ethnic difference in prevalence could not be explained by differences in diet, exercise, alcohol ingestion, or smoking. Our data support the view that Asian Indians are genetically predisposed to isolated low HDL cholesterol as well as the insulin resistance syndrome. The higher prevalence of isolated low HDL cholesterol, the young age at which individuals exhibit this phenotype (mean age 32.5 years), along with the greater propensity for Asian Indians to develop insulin resistance and IGT contribute to the threefold increased incidence of myocardial infarction in those <65 years of age in this ethnic group.  (+info)

Tumor necrosis factor system activity is associated with insulin resistance and dyslipidemia in myotonic dystrophy. (48/5009)

Myotonic dystrophy (MyD) is a multisystem autosomal dominant disorder associated with progressive muscle wasting and weakness. The striking metabolic abnormality in MyD is insulin resistance. The mechanism by which target tissues are insensitive to insulin action remains uncertain. In a recent study, plasma soluble tumor necrosis factor receptor (sTNFR)2 levels were found to be associated with muscle tissue mass and insulin resistance. Given these associations, we speculated that disorders of the muscle cell membrane could lead simultaneously to insulin insensitivity and sTNFR2 leakage in MyD. To test this hypothesis, we measured the levels of circulating sTNFR1 and sTNFR2 and insulin resistance in MyD patients. We studied 22 MyD patients and 24 age-, BMI-, and fat mass-matched control subjects. Both MyD men and women showed higher plasma insulin levels in the presence of comparable glucose concentrations than did control subjects. sTNFR2, but not sTNFR1, levels were approximately 1.5-fold higher in MyD patients. In parallel with these findings, the fasting insulin resistance index (FIRI) was also higher in MyD patients. In fact, in the whole population, fasting insulin and FIRI strongly correlated with sTNFR2 in both men (r = 0.77 and r = 0.81, P<0.0001, respectively) and women (r = 0.67 and r = 0.64, P = 0.001, respectively). sTNFR2 levels were also associated with the insulin sensitivity index (S(I)), calculated from an oral glucose tolerance test (OGTT) according to the method by Cederholm and Wibell (r = -0.43, P = 0.006). We constructed a multiple linear regression to predict FIRI, with BMI, waist-to-hip ratio, and sTNFR2 as independent variables. In this model, both BMI (P = 0.0014) and sTNFR2 (P = 0.0048) levels contributed independently to 46% of the variance of FIRI. In another model, in which FIRI was substituted for S(I) from the OGTT, both BMI (P = 0.0001) and sTNFR2 (P = 0.04) levels contributed independently to 48% of the variance of S(I) from the OGTT. Plasma cholesterol and triglyceride concentrations were significantly increased in MyD patients. sTNFR1 and sTNFR2 levels were found to be strongly associated with plasma cholesterol, LDL cholesterol, and triglycerides. sTNFR1 and sTNFR2 also correlated with serum creatine kinase activity in MyD patients (r = 0.57, P = 0.006; r = 0.75, P<0.0001, respectively). In conclusion, here we describe, for the first time to our knowledge, a relationship between insulin action and plasma sTNFR2 concentration in MyD patients. We have also found increased concentrations of plasma triglycerides and cholesterol levels in parallel with sTNFR1 and sTNFR2 concentrations in MyD patients. We speculate that the latter associations are dependent on, and secondary to, increased tumor necrosis factor (TNF)-alpha action. Whether TNF action is implicated in the pathogenesis of MyD or is a simple marker of disease activity awaits further studies.  (+info)