Fasting Serum Triglyceride Concentrations Research Articles

Effect of dyslipidemia, obesity, and atopic status on exhaled and alveolar nitric oxide in asthmatic children.

Dyslipidemia and obesity contribute to a pro-inflammatory state. Eosinophilic airway inflammation can be indirectly measured by fractional exhaled nitric oxide (FeNO) produced in the airways of asthmatic subjects. To compare exhaled nitric oxide (NO) and alveolar NO in asthmatic children with and without dyslipidemia. Asthmatic children (5-18 years old) had fasting serum low-density lipoprotein cholesterol, triglyceride, and high-density lipoprotein cholesterol (HDL-C) concentrations, and C-reactive protein (CRP) concentrations measured. FeNO was measured at constant flow rates of 20, 50, 100, and 300 ml/s by the chemiluminescence method. NO concentrations in tissue of the upper airways (CawNO) and the total flux of NO in the conducting airways (JawNO) were determined through FeNO at 20, 100, and 300 ml/s using a mathematical model. The atopic status was assessed using the skin prick test for aero-allergens. One hundred forty-one asthmatic children were enrolled with a mean (standard deviation) age of 11.82 (3.38) years. Sixty-four (45.4%) children had dyslipidemia and 20 (14.2%) were obese. Children with low HDL-C concentrations had significantly higher CawNO and JawNO than those with normal HDL-C concentrations (both p = 0.03). Asthmatic children with obesity had higher CRP concentrations than those with a normal weight (p < 0.001). Atopic children had a significantly higher FeNO, CawNO, and JawNO than non-atopic children (all p < 0.05). This study suggests an effect of HDL-C on CawNO and JawNO in asthmatic children. An intervention that normalizes HDL-C concentrations may be beneficial for airway inflammation in asthmatic children.

Effects of pemafibrate on lipid metabolism in patients with type 2 diabetes and hypertriglyceridemia: A multi-center prospective observational study, the PARM-T2D study

AimsPemafibrate, a novel selective peroxisome proliferator-activated receptor modulator, was shown to ameliorate lipid abnormalities in a phase III clinical trial of patients with type 2 diabetes mellitus (T2DM). However, its efficacy has not been demonstrated in real-world clinical practice in patients with T2DM. MethodsWe performed a multi-center prospective observational study of the use of pemafibrate in patients with T2DM and hypertriglyceridemia versus conventional therapy, with or without a fibrate. The primary outcomes were the changes from baseline in fasting serum triglyceride (TG) and high-density lipoprotein-cholesterol (HDL-C) concentrations at week 52. ResultsWe recruited 650 patients, and data from 504 (252 per group) were analyzed after propensity score matching. In the pemafibrate group, both TG and HDL-C showed significant improvements (p < 0.001), and several indices reflecting TG-rich lipoproteins, low-density lipoprotein-cholesterol particle size, and liver enzyme elevations were significantly ameliorated compared with the control group, but there was no difference in glycemic control markers. One of the key secondary endpoints showed that switching from conventional fibrates to pemafibrate improved eGFR but increased uric acid concentration. ConclusionsIn patients with T2DM, pemafibrate has superior effects on lipid profile as well as liver and renal dysfunction to conventional fibrates.

Influence of high-protein and high-carbohydrate diets on serum lipid and fructosamine concentrations in healthy cats.

The aim of this study was to determine whether high-protein and high-carbohydrate diets exert differential effects on serum cholesterol, triglyceride and fructosamine concentrations in healthy cats. A randomised, crossover diet trial was performed in 35 healthy shelter cats. Following baseline health assessments, cats were randomised into groups receiving either a high-protein or high-carbohydrate diet for 4 weeks. The cats were then fed a washout diet for 4 weeks before being transitioned to whichever of the two studied diets they had not yet received. Fasting serum cholesterol, triglyceride and fructosamine concentrations were determined at the end of each 4-week diet period. Cats on the high-carbohydrate diet had significantly lower serum cholesterol (P <0.001) concentrations compared with baseline measurements. Cats on the high-protein diet had significantly higher serum cholesterol (P <0.001) and triglyceride (P <0.001) concentrations, yet lower fructosamine (P <0.001) concentrations compared with baseline measurements. In contrast, overweight cats (body condition score [BCS] >5) had lower cholesterol (P = 0.007) and triglyceride (P = 0.032) concentrations on the high-protein diet than cats within other BCS groups. Diets higher in protein and lower in carbohydrates appear beneficial for short-term glucose control in healthy cats. A high-protein diet was associated with significantly elevated cholesterol and triglyceride concentrations in healthy cats, even though the increase was significantly less pronounced in cats with a BCS >5. This finding suggests that overweight cats process high-protein diets, cholesterol and triglycerides differently than leaner cats.

Leptin Concentration Predicts Future Metabolic Syndrome Risk in Japanese Americans Independent of Body Composition

Aims: Leptin has been shown to predict risk of metabolic syndrome (MetS), but it is not known whether this association is independent of body composition. Thus, we examined whether plasma leptin concentration predicted risk of MetS after adjustment for body composition measured using imaging. Methods: We used the modified ATP III MetS criteria for an Asian population to classify participants in the longitudinal Japanese-American Community Diabetes Study as to presence of MetS. Participants without MetS at baseline (n=283) were followed for its development over 5 years. CT-measured adipose depots included baseline and 5-year intra-abdominal and abdominal subcutaneous fat areas at the level of the umbilicus, subcutaneous mid-thigh fat area, and subcutaneous thorax fat area at the nipple level. Other measurements included fasting plasma leptin and serum HDL-cholesterol and triglyceride concentrations, fasting and 2 hour glucose from a 75 g OGTT, systolic blood pressure (SBP), and medication use. Logistic regression analysis was used to estimate the odds of incident MetS by leptin concentration, body composition, and baseline MetS features. Results: 65 participants developed MetS at 5-year follow-up. Multivariable logistic regression models showed a lower odds of incident MetS with 1-SD greater leptin concentration (OR = 0.45; 95% CI = 0.25-0.79; p = 0.006) adjusting for age, sex, CT-fat areas at baseline, and 5-year change in CT-fat areas. Additional adjustment for other MetS features at baseline (fasting and 2 hour glucose, triglycerides, HDL-cholesterol, SBP) yielded similar results (OR = 0.38; 95% CI = 0.20-0.71; p = 0.002). Conclusions: Leptin concentration predicts MetS risk in Japanese Americans independent of body composition. Further research is needed to confirm this association in other populations and to understand potential underlying biologic mechanisms. Disclosure C. Liao: None. W.Y. Fujimoto: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim GmbH, Elcelyx Therapeutics, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Research &amp; Development, Merck &amp; Co., Inc., Novo Nordisk A/S. D.L. Leonetti: None. E.J. Boyko: None.

Meal-derived glucagon responses are related to lower hepatic phosphate concentrations in obesity and type 2 diabetes

AimType 2 diabetes (T2D) alters glucagon, glucagon-like peptide (GLP)-1, glucose-dependent insulinotropic polypeptide (GIP) and hepatic energy metabolism, yet the possible relationships remain unclear. MethodsIn this observational study, lean insulin-sensitive control subjects (BMI: 23.2±1.5kg/m2), age-matched insulin-resistant obese subjects (BMI: 34.3±1.7kg/m2) and similarly obese elderly T2D patients (BMI: 32.0±2.4kg/m2) underwent mixed-meal tolerance tests (MMTTs), and assessment of hepatic γATP, inorganic phosphate (Pi) and lipids using 31P/1H magnetic resonance spectroscopy. Meal-induced secretion of glucagon and incretins was calculated from incremental areas under the concentration–time curves (iAUCs). Peripheral and adipose tissue insulin sensitivity were assessed from time courses of circulating glucose, insulin and free fatty acids. ResultsMMTT-derived peripheral insulin sensitivity was lowest in T2D patients (P<0.001), while glucagon concentrations were comparable across all three groups. At 260min, GLP-1 was lower in T2D patients than in controls, whereas GIP was lowest in obese individuals. Fasting glucagon concentrations correlated positively with fasting (r=0.60) and postprandial hepatocellular lipid levels (160min: r=0.51, 240min: r=0.59), and negatively with adipose tissue insulin sensitivity (r=−0.73). Higher meal-induced glucagon release (iAUC0–260min) correlated with lower fasting (r=−0.62) and postprandial Pi levels (160min: r=−0.43, 240min: r=−0.42; all P<0.05). Higher meal-induced release of GIP (iAUC0–260min) correlated positively with fasting (r=0.54) and postprandial serum triglyceride concentrations (iAUC0–260min, r=0.54; all P<0.01). ConclusionCorrelations between fasting glucagon and hepatic lipids and between meal-induced glucagon and hepatic Pi suggest a role for glucagon in hepatic energy metabolism.

Impact of the triglyceride level on coronary plaque components in female patients with coronary artery disease treated with statins.

Several studies have reported that elevated triglyceride (TG) levels may be more strongly associated with an increased risk of coronary artery disease (CAD) in females than in males. We examined gender differences in the relationship between TG levels and coronary atherosclerosis using integrated backscatter intravascular ultrasound (IB IVUS) in CAD patients treated with statins. Three hundred seventy-eight CAD patients (105 females and 273 males) who underwent percutaneous coronary intervention using IB IVUS, and who were already receiving statin treatment, were included. Gray-scale and IB IVUS examinations were performed for the non-culprit segment of a coronary artery and fasting serum TG concentrations were measured. We found that TG levels were significantly correlated with increased lipid (r = 0.40, p < 0.001) and decreased fibrous (r = -0.37, p < 0.001) plaque components in females, but not in males. Low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels were not related to either the gray-scale or IB IVUS parameters in both genders. After adjustment for conventional coronary risk factors by a multivariate stepwise regression analysis, higher TG levels in females were independently associated with increased lipid (β = 0.31, p<0.001) contents in coronary plaques. In conclusion, among CAD patients treated with statins, TG levels were associated with lipid-rich coronary plaques in females, but not in males. TG levels may be more important indicators of residual risk after statin treatment in females than in males.

Effects of Pediococcus acidilactici R037 on Serum Triglyceride Levels in Mice and Rats after Oral Administration.

The biological effects of heat-killed Pediococcus acidilactici R037 (R037) were evaluated when orally administered in mice and rats. Oral R037 administration at a daily dose of 10 and 100 mg/kg for 3 wk dose-dependently reduced fasting and non-fasting serum triglyceride concentrations in KK-Ay/TaJcl mice, a model of type II diabetes, obesity, hypercholesterolemia, and hypertriglyceridemia. Serum levels of free fatty acids in the 100 mg/kg group tended to decrease (not statistically significant), and total cholesterol levels remained unchanged. Treatment with R037 resulted in a significant decrease in blood glucose (at 100 mg/kg) and liver weight (at 10 and 100 mg/kg), and a small body weight gain (at 100 mg/kg) as compared to those in control mice. In addition, oral R037 administration at 100, 200, and 400 mg/kg/d for 1 wk dose-dependently suppressed the increase in serum triglyceride levels in Wistar rats after oral fat loading. Moreover, intraduodenal injection of 120 mg of R037 in Wistar rats suppressed gastric vagal nerve activity (GVNA) indicating suppression of intestinal digestion and absorption of food, and suppression of appetite. The R037 injection potentiated epididymal white adipose tissue sympathetic nerve activity (WAT-SNA) and tended to potentiate pancreatic sympathetic nerve activity (PSNA), suggesting that R037 activated lipolysis. Taken together, these findings indicate that R037 lowers serum triglycerides, possibly through suppressing intestinal absorption and potentiating lipolytic pathways. R037 may be useful for primary prevention of coronary artery diseases in subjects with mild or borderline dyslipidemia in combination with lifestyle changes.

The Effect of Gluten Free Diet on Components of Metabolic Syndrome: A Randomized Clinical Trial

Background:This study aimed to assess the effects of Gluten free diet (GFD) on components of metabolic syndrome (MES).Materials and Methods:In this randomized clinical trial, 50 subjects diagnosed with MES were randomly divided into two groups (n=25). The first group received a GFD and the second group continued their regular diet. Biochemical markers of MES and blood pressure were measured before and after 8-week intervention.Results:Forty five subjects completed the study. A post-hoc comparison of the groups showed no effects of the GFD and control diet on LDL cholesterol, total cholesterol, fasting insulin, HOMA-IR, systolic and diastolic blood pressure levels. The GFD reduced fasting blood glucose, waist circumference (WC) and serum triglyceride concentration significantly compared with the control diet (p<0.05).Conclusion:Short-term GFD reduced WC and improved glycemic control and Triglyceride level in subjects with the metabolic syndrome.

Fructose ingestion impairs expression of genes involved in skeletal muscle\u2019s adaptive response to aerobic exercise

BackgroundThe inverse relationship between exercise capacity and its variation over time and both cardiovascular and all-cause mortality suggests the existence of an etiological nexus between cardiometabolic diseases and the molecular regulators of exercise capacity. Coordinated adaptive responses elicited by physical training enhance exercise performance and metabolic efficiency and possibly mediate the health benefits of physical exercise. In contrast, impaired expression of genes involved in mitochondrial biogenesis or protein turnover in skeletal muscle—key biological processes involved in adaptation to physical training—leads to insulin resistance and obesity. Ingestion of fructose has been shown to suppress the exercise-induced GLUT4 response in rat skeletal muscle. To evaluate in greater detail how fructose ingestion might blunt the benefits of physical training, we investigated the effects of fructose ingestion on exercise induction of genes that participate in regulation of mitochondrial biogenesis and protein turnover in rat’s skeletal muscle.MethodsEight-week-old Wistar rats were randomly assigned to sedentary (C), exercise (treadmill running)-only (E), fructose-only (F), and fructose + exercise (FE) groups and treated accordingly for 8 weeks. Blood and quadriceps femoris were collected for biochemistry, serum insulin, and gene expression analysis. Expression of genes involved in regulation of mitochondrial biogenesis and autophagy, GLUT4, and ubiquitin E3 ligases MuRF-1, and MAFbx/Atrogin-1 were assayed with quantitative real-time polymerase chain reaction.ResultsAerobic training improved exercise capacity in both E and FE groups. A main effect of fructose ingestion on body weight and fasting serum triglyceride concentration was detected. Fructose ingestion impaired the expression of PGC-1α, FNDC5, NR4A3, GLUT4, Atg9, Lamp2, Ctsl, Murf-1, and MAFBx/Atrogin-1 in skeletal muscle of both sedentary and exercised animals while expression of Errα and Pparδ was impaired only in exercised rats.ConclusionsOur results show that fructose ingestion impairs the expression of genes involved in biological processes relevant to exercise-induced remodeling of skeletal muscle. This might provide novel insight on how a dietary factor contributes to the genesis of disorders of glucose metabolism.

Clinical Consequences of Hypertriglyceridemia-Associated Proteinuria in Miniature Schnauzers.

BackgroundPrimary hypertriglyceridemia is a common condition in older Miniature Schnauzers that recently has been associated with proteinuria and underlying glomerular pathology, particularly glomerular lipid thromboemboli. Consequences of glomerular disease can include hypertension, thromboembolic disease, and cardiac disease. The incidence of these sequelae in Miniature Schnauzers with hypertriglyceridemia‐associated proteinuria (HTGP) is unknown.ObjectiveTo investigate prevalence of hypertension, decreased antithrombin III activity, and cardiac disease in Miniature Schnauzers with and without HTGP.AnimalsThirty‐two Miniature Schnauzers ≥7 years old.MethodsProspective case‐control study. Data collected from dogs included a CBC, biochemistry panel, urinalysis, urine protein‐to‐creatinine ratio, urine cortisol‐to‐creatinine ratio, serum total thyroxine concentration, fasting serum triglyceride concentration, indirect blood pressure, antithrombin III activity, and serum cardiac troponin I concentration. Results from dogs with HTGP (serum triglyceride concentration ≥ 100 mg/dL and urine protein‐to‐creatinine ratio >0.5) were statistically compared to normotriglyceridemic, nonproteinuric dogs.ResultsEighteen of the 32 dogs (56%) had primary hypertriglyceridemia. Of those dogs, 8 of 18 had proteinuria. None of the HTGP dogs were azotemic or hypoalbuminemic. Serum albumin concentration, alkaline phosphatase activity, and cholesterol concentration were significantly increased in dogs with HGTP compared to those without HGTP. No increased risk of hypertension, decreased antithrombin III activity, or cardiac disease was noted. Limited data from 8 dogs with HTGP showed no development of hypoalbuminemia or azotemia over a median follow‐up period of 18 months.Conclusions and Clinical ImportanceGeriatric Miniature Schnauzers with HGTP may have a good prognosis overall, and are not typically azotemic or hypoalbuminemic.

Proteinuria and lipoprotein lipase activity in Miniature Schnauzer dogs with and without hypertriglyceridemia

Spontaneous hyperlipidemia in rats causes glomerular disease. Idiopathic hypertriglyceridemia (HTG) is prevalent in Miniature Schnauzers, but its relationship with proteinuria is unknown. Decreased activity of major lipid metabolism enzymes, lipoprotein lipase (LPL) and hepatic lipase (HL), may play a role in the cyclic relationship between hyperlipidemia and proteinuria. These enzymes have also not been previously investigated in Miniature Schnauzers. The aims of this study were to determine the relationship between HTG and proteinuria in Miniature Schnauzers and to measure LPL and HL activities in a subset of dogs. Fifty-seven Miniature Schnauzers were recruited (34 with and 23 without HTG). Fasting serum triglyceride concentrations and urine protein-to-creatinine ratios (UPC) were measured in all dogs, and LPL and HL activities were determined in 17 dogs (8 with and 9 without HTG). There was a strong positive correlation between triglyceride concentration and UPC (r = 0.77–0.83, P < 0.001). Proteinuria (UPC ≥ 0.5) was present in 60% of dogs with HTG and absent from all dogs without HTG (P < 0.001). Proteinuric dogs were not azotemic or hypoalbuminemic. Dogs with HTG had a 65% reduction in LPL activity relative to dogs without HTG (P < 0.001); HL activity did not differ. Proteinuria occurs with HTG in Miniature Schnauzers and could be due to lipid-induced glomerular injury. Reduced LPL activity may contribute to the severity of HTG, but further assay validation is required.

Long-term metabolic alterations in a febrile seizure model

Objective: Febrile seizures (FS) are the most common neurological disease in infancy and early childhood, it can lead to metabolic changes and have long-term health implications. Aim of this study was to investigate the long-term effects of FS on metabolism. Methods: We measured certain metabolic parameters in hyperthermia-prone (HP) rats, which were developed using a selective breeding process and showed a lower seizure threshold than wild-type (WT) rats. Body weight, body length, abdominal circumference and the levels of fasting blood glucose, serum triglyceride, and total cholesterol concentrations were analyzed. The mRNA expression of genes involved in glucose and lipid metabolism was determined by qPCR and the histone methylation level in the liver was determined by western blot. Results: We found that the body weight of the HP rats was significantly lower than that of the WT rats. Similarly, the fasting blood glucose and serum triglyceride levels were lower in the HP group compared with the WT group. These changes were accompanied by increased mRNA expression of genes such as phosphoenolpyruvate carboxykinase (PEPCK) and carnitine palmitoyl transferase-1 (CPT-1), but not peroxisome proliferator-activated receptor α (PPARα). We also found tri-methylation of histone 3 at Lys9 and Lys27 was decreased in the HP group. Conclusions: These data may suggest an underlying mechanism by which FS have a long-term effect on energy metabolism via histone methylation.

Reply

Potential conflict of interest: Nothing to report. This work was supported by a contract from the National Institute of Diabetes and Digestive and Kidney Diseases (HHSN276201200161U). We thank Zhao et al. for their interest in our article.1 They make two points. The first is that patients with hepatic decompensation or cirrhosis are at increased risk of diabetes. This relationship is well known and bears no relevance to our findings and conclusions in the general healthy U.S. population. The second point is that factors that we did not consider might have affected the outcomes of our analyses. They offer no hypotheses in this regard, but do point to a published report that found an association of hepatitis C virus (HCV) infection and diabetes that was revealed in multivariate analysis only when controlling for blood cholesterol and triglyceride concentrations.2 No biological reason was suggested for this finding. Nevertheless, we have now considered serum triglyceride and cholesterol concentrations in the main analysis of our article that demonstrated strong relationships of elevated alanine aminotransferase (ALT) and gamma‐glutamyl transferase (GGT) activities with diabetes that were independent of HCV infection (Fig. 2 of the article). Table 1 shows the multivariate odds ratios (ORs) for ALT and anti‐HCV with diabetes when controlling for fasting serum triglyceride and cholesterol concentrations as well as the other cofactors originally considered (age, sex, race/ethnicity, education, body mass index, elevated C‐reactive protein, smoking, alcohol use, and blood transfusion before 1992). As in the published article, an association of elevated ALT was found with diabetes regardless of anti‐HCV status. For study participants with normal ALT activity, there was no association of anti‐HCV and diabetes. Results were similar for ALT with prediabetes, GGT with diabetes and prediabetes, and when HCV RNA status was considered. Table 1 - Multivariate‐Adjusted ORs for Diabetes by HCV and ALT Status Normal ALT Elevated ALT OR 95% CI P Value OR 95% CI P Value HCV negative 1.0 — — 1.84 1.41‐2.40 <0.001 Anti‐HCV positive 0.70 0.30‐1.63 0.41 2.62 1.15‐5.97 <0.001 Abbreviation: CI, confidence interval.

Implications of Central Obesity-Related Variants in LYPLAL1, NRXN3, MSRA, and TFAP2B on Quantitative Metabolic Traits in Adult Danes

BackgroundTwo meta-analyses of genome-wide association studies (GWAS) have suggested that four variants: rs2605100 in lysophospholipase-like 1 (LYPLAL1), rs10146997 in neuroxin 3 (NRXN3), rs545854 in methionine sulfoxide reductase A (MSRA), and rs987237 in transcription factor activating enhancer-binding protein 2 beta (TFAP2B) associate with measures of central obesity.To elucidate potential underlying phenotypes we aimed to investigate whether these variants associated with: 1) quantitative metabolic traits, 2) anthropometric measures (waist circumference (WC), waist-hip ratio, and BMI), or 3) type 2 diabetes, and central and general overweight and obesity.Methodology/Principal FindingsThe four variants were genotyped in Danish individuals using KASPar®. Quantitative metabolic traits were examined in a population-based sample (n = 6,038) and WC and BMI were furthermore analyzed in a combined study sample (n = 13,507). Case-control studies of diabetes and adiposity included 15,326 individuals. The major G-allele of LYPLAL1 rs2605100 associated with increased fasting serum triglyceride concentrations (per allele effect (β) = 3%(1;5(95%CI)), p additive = 2.7×10−3), an association driven by the male gender (p interaction = 0.02). The same allele associated with increased fasting serum insulin concentrations (β = 3%(1;5), p additive = 2.5×10−3) and increased insulin resistance (HOMA-IR) (β = 4%(1;6), p additive = 1.5×10−3). The minor G-allele of rs10146997 in NRXN3 associated with increased WC among women (β = 0.55cm (0.20;0.89), p additive = 1.7×10−3, p interaction = 1.0×10−3), but showed no associations with obesity related metabolic traits. The MSRA rs545854 and TFAP2B rs987237 showed nominal associations with central obesity; however, no underlying metabolic phenotypes became obvious, when investigating quantitative metabolic traits. None of the variants influenced the prevalence of type 2 diabetes.Conclusion/SignificanceWe demonstrate that several of the central obesity-associated variants in LYPLAL1, NRXN3, MSRA, and TFAP2B associate with metabolic and anthropometric traits in Danish adults. However, analyses were made without adjusting for multiple testing, and further studies are needed to confirm the putative role of LYPLAL1, NRXN3, MSRA, and TFAP2B in the pathophysiology of obesity.

Nonoxidative Free Fatty Acid Disposal Is Greater in Young Women than Men

Large increases in systemic free fatty acid (FFA) availability in the absence of a corresponding increase in fatty acid oxidation can create a host of metabolic abnormalities. These adverse responses are thought to be the result of fatty acids being shunted into hepatic very low-density lipoprotein-triglyceride production and/or intracellular lipid storage and signaling pathways because tissues are forced to increase nonoxidative FFA disposal. The objective of the study was to examine whether variations in postabsorptive nonoxidative FFA disposal within the usual range predict insulin resistance and hypertriglyceridemia. We measured: systemic FFA turnover using a continuous iv infusion of [9-10, (3)H]palmitate; substrate oxidation with indirect calorimetry combined with urinary nitrogen excretion; whole-body and peripheral insulin sensitivity with the labeled iv glucose tolerance test minimal model. the study was conducted at the Mayo Clinic General Clinical Research Center. Participants included healthy, postabsorptive, nonobese adults (21 women and 21 men). There were no interventions. Nonoxidative FFA disposal (micromoles per minute), defined as the FFA disappearance rate minus fatty acid oxidation. Women had 64% greater nonoxidative FFA disposal rate than men but a better lipid profile and similar insulin sensitivity. There was no significant correlation between nonoxidative FFA disposal and whole-body sensitivity, peripheral insulin sensitivity, or fasting serum triglyceride concentrations in men or women. Healthy nonobese women have greater rates of nonoxidative FFA disposal than men, but this does not appear to relate to adverse health consequences. Understanding the sex-specific interaction between adipose tissue lipolysis and peripheral FFA removal will help to discover new approaches to treat FFA-induced abnormalities.

Fasting glucose and triglycerides as biomarkers of mTOR inhibition, evidence of a categorical response.

3091 Background: Hyperglycemia and hypertriglyceridemia are mechanism-based toxicities of mammalian target of rapamycin (mTOR) inhibitors, but have not been intensively studied as potential pharmacodynamic biomarkers. Methods: Changes in fasting serum glucose and triglyceride concentrations were determined in 127 patients (pts) before, and 4 weeks after treatment with the mTOR inhibitor sirolimus/rapamycin (S). Pts were enrolled in three different trials of S administered to achieve AUC of 1,000-6,000 ng-hr/ml. Results: Of these pts (67 male; 60 female; median age 62 y [range of 27-82], 72 had fasting measures for both glucose and triglycerides. Twelve pts had Type II diabetes. Mean/median change: in glucose = 17/8 mg/dL (SD=32, 95% CI 10-25, p< 0.0001), in triglycerides = 51/31 mg/dL (SD= 76, 95% CI 33-69, p< 0.0001) (p values for paired T-test). Changes were not associated with sex, S dose, baseline triglycerides, or use of lipid lowering agents. Change in glucose was significantly associated with a history of diabetes (larger increases in pts with a history, p<0.001) and baseline glucose levels (smaller increases in pts with higher baseline levels, p= 0.002). The Table features a striking observation. Of 72 pts, only 7 had no increase in glucose or triglyceride concentrations, and 9 had S- related increases in both glucose(>20 mg/dL) and triglycerides(>50 mg/dL). Meanwhile, 17 pts increased triglycerides of >50 mg/dL and 14 increased glucose of > 20 mg/dL without a change in the other marker. There was no evidence for association between changes in glucose and triglycerides (p = 0.72 by McNemar's test). Conclusions: Fasting blood glucose and triglyceride changes might be independent effects of mTOR inhibition. This would explain the absence of correlation between glucose and triglyceride changes and, excepting history of diabetes and changes in glucose, lack of association with clinically relevant covariates. These data suggest a new approach for developing these inexpensive validated laboratory measurements for qualification as clinically useful pharmacodynamic markers of mTOR inhibition. Δ glucose≤ 20 mg/dL Δglucose>20 mg/dL Δtriglycerides ≤ 50 mg/dL 32 14 Δtriglycerides > 50 mg/dL 17 9 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories, Amgen, Astellas Pharma, Biomarin, Daiichi Sankyo, Gilead, Millennium, Novartis, Pfizer, Takeda, Wyeth Actelion, Bayer, Bristol-Myers Squibb, EMD Serono, Genentech, Gilead, Lilly, Novartis, Pfizer, Roche patent pending for use of sorafenib in pulmonary hypertension

Dietary Carotenoid Intake Is Associated with Lower Prevalence of Metabolic Syndrome in Middle-Aged and Elderly Men

Carotenoids have antioxidant properties. Little is known about the relation of dietary carotenoid intake on metabolic syndrome risk. We examined whether dietary carotenoid intake was associated with metabolic syndrome and metabolic syndrome risk factors. We conducted a population-based, cross-sectional study in 374 men aged 40–80 y. Intakes of β-carotene, α-carotene, β-cryptoxanthin, lycopene, lutein, and zeaxanthin were estimated using a validated FFQ. Presence of metabolic syndrome was determined using fasting serum glucose, triglyceride, and HDL-cholesterol concentrations, waist circumference, and systolic and diastolic blood pressure. Metabolic syndrome was present in 22% of the men. After adjustment for confounders, total carotenoid and lycopene intakes were inversely associated with presence of metabolic syndrome [relative risk (RR) quartile 4 vs. quartile 1 (95% CI) 0.42 (0.20–0.87), P-trend 0.02; and 0.55 (0.28–1.11), P-trend 0.01, respectively]. For β-carotene, a decreased risk was observed for each quartile of intake compared with the first [RR quartile 4 vs. quartile 1 (95% CI) 0.58 (0.33–1.02)]. Higher total carotenoid, β-carotene, α-carotene, and lycopene intakes were associated with lower waist circumferences and visceral and subcutaneous fat mass. Higher lycopene intake was related to lower serum triglyceride concentrations. In conclusion, higher total carotenoid intakes, mainly those of β-carotene and lycopene, were associated with a lower prevalence of metabolic syndrome and with lower measures of adiposity and serum triglyceride concentrations in middle-aged and elderly men.

Independent and Combined Effects of Aerobic Exercise and Pharmacological Strategies on Serum Triglyceride Concentrations: A Qualitative Review

Elevated fasting and postprandial serum triglyceride concentrations are associated with cardiovascular disease morbidity and mortality. Aerobic exercise reduces serum triglyceride concentrations in the presence or absence of weight loss. Although pharmacological interventions are often used in combination with aerobic exercise to achieve target triglyceride concentrations, information on the combined effects of aerobic exercise and lipid-modifying agents on serum triglycerides is limited. This review examines the independent and combined effects of both interventions on serum fasting and postprandial triglyceride concentrations from the available literature. Reductions in serum triglycerides after aerobic exercise are associated with an increase in skeletal muscle lipoprotein lipase activity and a decrease in hepatic triglyceride and very-low-density lipoprotein (VLDL) synthesis and secretion. Lipid-modifying agents such as niacin, omega-3 fatty acids, and statins also decrease fasting and postprandial triglycerides by increasing lipoprotein lipase (LPL) activity and/or decreasing VLDL synthesis. When combined, lipid-modifying agents may reduce fasting and postprandial triglyceride secretion to an extent in which aerobic exercise cannot provide any additional benefit. These observations indicate that aerobic exercise and pharmacological strategies reduce serum triglycerides by similar mechanisms, which may attenuate the triglyceride-lowering capacity of the concordant treatment.

Drug therapy for hypertriglyceridemia: Fibrates and omega-3 fatty acids

The reduction of low-density lipoprotein cholesterol in patients at risk for acute cardiovascular events is the cornerstone of lipid management in both the primary and secondary prevention settings. Serum triglyceride levels exceeding 150 mg/dL are abnormal and confer increased risk for developing coronary artery disease in both men and women. Serum triglycerides are derived from both dietary and endogenous biosynthetic pathways. Triglyceride metabolism has a complex regulatory circuitry and intimately impacts the production and disposal of multiple lipoprotein species. Hypertriglyceridemia is highly prevalent and is associated with multiple forms of dyslipidemia but tends to be undertreated. Therapeutic intervention with fibric acid derivatives and omega-3 fish oils is associated with significant reductions in both fasting and postprandial serum triglyceride concentrations. A variety of prospective, placebo-controlled clinical trials have also shown that these agents significantly impact risk for multiple cardiovascular end points.

Serum triglyceride concentration in dogs with epilepsy treated with phenobarbital or with phenobarbital and bromide

To compare serum triglyceride concentrations obtained after food had been withheld (i.e., fasting concentrations) in dogs with epilepsy that had been treated long term (> or = 3 months) with phenobarbital or with phenobarbital and potassium bromide with concentrations in healthy control dogs. Cross-sectional study. 57 epileptic dogs that had been treated with phenobarbital (n=28) or with phenobarbital and bromide (29) and 57 healthy, untreated control dogs matched on the basis of age, breed, sex, neuter status, and body condition score. Blood samples were collected after food had been withheld for at least 12 hours, and serum biochemical and lipid concentrations were determined. Oral fat tolerance tests were performed in 15 control dogs and 9 dogs with epilepsy treated with phenobarbital alone. 19 of the 57 (33%) epileptic dogs had fasting serum triglyceride concentrations greater than the upper reference limit. Nine (16%) dogs had a history of pancreatitis, and 5 of the 9 had high fasting serum triglyceride concentrations at the time of the study. A significant relationship was found between body condition score and fasting serum triglyceride concentration in all dogs, but serum triglyceride concentration was not significantly associated with phenobarbital dosage or serum phenobarbital concentration. Results suggested that dogs treated long term with phenobarbital or with phenobarbital and bromide may develop hypertriglyceridemia. Fasting serum triglyceride concentration should be periodically monitored in dogs treated with phenobarbital because hypertriglyceridemia is a risk factor for pancreatitis.