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HPLC with spectrophotometric or mass spectrometric detection for quantifying very-long chain fatty acids in human plasma and its association with cardiac risk factors.
Shrestha, R, Chen, Z, Gao, Z, Chen, Y, Okada, E, Ukawa, S, Nakagawa, T, Nakamura, K, Tamakoshi, A, Chiba, H, et al
Annals of clinical biochemistry. 2021;(5):400-410
Abstract
BACKGROUND We developed and compared two liquid chromatography methods, one with UV/Visible spectrophotometric detection (HPLC) and the other with mass spectrometric detection (LC-MS), for quantifying very-long chain fatty acids (VLCFA) in human plasma. Association of VLCFA with various cardiovascular risk factors were evaluated. METHOD Fasting blood samples were collected from 541 human volunteers (242 men and 299 women; mean age ±SD, 58.9 ± 12.4 years), including 429 and 112 individuals with and without hypertriglyceridemia, respectively. Esterified VLCFA were saponified and derivatized with 2-nitrophenylhydrazine. Separation of VLCFA species was achieved with C4 Mightysil column (HPLC) and Ascentis Express Phenyl-Hexyl column (LC-MS) followed by spectrophotometric and selected-reaction monitoring mode of mass spectrometric detection, respectively. RESULTS The HPLC assay of VLCFA was precise with intra-assay imprecision of 2.5% to 6.9% and inter-assay imprecision of 3.2% to 9.5%. Moreover, there was an excellent correlation (r > 0.96) between HPLC and LC-MS methods. The 95 percentile reference intervals (RI; upper limit) of VLCFA were determined to be 41.3 µmol/L in healthy volunteers. Plasma VLCFA were significantly correlated with triglycerides (Spearman's ρ = 0.306, P < 0.001) and total cholesterol (Spearman's ρ = 0.251, P < 0.001). All species of VLCFA were significantly elevated in hypertriglyceridaemic individuals compared with control. CONCLUSION We established LC-based assays of VLCFA with either spectrophotometry or mass spectrometry as a detection system. Hypertriglyceridaemia is significantly associated with elevated concentration of each species of VLCFA.
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Trace Element and Mineral Levels in Serum, Hair, and Urine of Obese Women in Relation to Body Composition, Blood Pressure, Lipid Profile, and Insulin Resistance.
Tinkov, AA, Bogdański, P, Skrypnik, D, Skrypnik, K, Skalny, AV, Aaseth, J, Skalnaya, MG, Suliburska, J
Biomolecules. 2021;(5)
Abstract
The objective of this study was to evaluate serum, hair, and urinary trace element and mineral content in normal-weight and obese women in relation to metabolic risk factors. A total of 80 women aged 30-70 y.o. were enrolled in the obese group (n = 40) and normal-weight group (n = 40). Serum, hair, and urinary trace element and mineral levels were assessed using inductively coupled plasma spectrometry. Body fat percentage was evaluated using bioimpedance. Obese subjects were characterized by significantly higher body fat percentage, blood pressure, serum triglyceride concentration, and insulin resistance. Serum Ca, Fe, Mg, Se, V, Zn levels, hair Fe, Mg, V content, and urinary Se and V concentrations were found to be lower in obese subjects as compared to lean controls. In turn, serum Cu and urinary Fe levels in obese women were characterized by a significant increase. In multiple regression models serum Cu, Se, and Zn levels were significantly associated with BMI even after adjustment for blood biochemistry, body composition, and blood pressure. Serum trace element and mineral levels also significantly contributed to group discrimination. These findings allow to propose that obesity-associated disturbances in trace element and mineral status may at least partially contribute to metabolic risk in obese subjects.
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The Pharmacokinetics of Triheptanoin and Its Metabolites in Healthy Subjects and Patients With Long-Chain Fatty Acid Oxidation Disorders.
Lee, SK, Gupta, M, Shi, J, McKeever, K
Clinical pharmacology in drug development. 2021;(11):1325-1334
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Abstract
Long-chain fatty acid oxidation disorders (LC-FAODs) are a group of life-threatening autosomal recessive disorders caused by defects in nuclear genes encoding mitochondrial enzymes involved in the conversion of dietary long-chain fatty acids into energy. Triheptanoin is an odd-carbon, medium-chain triglyceride consisting of 3 fatty acids with 7 carbons each on a glycerol backbone developed to treat adult and pediatric patients with LC-FAODs. The pharmacokinetics of triheptanoin and circulating metabolites were explored in healthy subjects and patients with LC-FAODs using noncompartmental analyses. Systemic exposure to triheptanoin following an oral administration was negligible, as triheptanoin is extensively hydrolyzed to glycerol and heptanoate in the gastrointestinal tract. Multiple peaks for triheptanoin metabolites were observed in the plasma following oral administration of triheptanoin, generally coinciding with the time that meals were served. Heptanoate, the pharmacologically active metabolite of triheptanoin supplementing energy sources in patients with LC-FAODs, showed the greatest exposure among the metabolites of triheptanoin in human plasma following oral administration of triheptanoin. The exposure of heptanoate was approximately 10-fold greater than that of beta-hydroxypentoate, a downstream metabolite of heptanoate. Exposure to triheptanoin metabolites appeared to increase following multiple doses as compared with the single dose, and with the increase in triheptanoin dose levels.
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Association of Serum Alkaline Phosphatase with the TG/HDL Ratio and TyG Index in Korean Adults.
Son, DH, Ha, HS, Lee, YJ
Biomolecules. 2021;(6)
Abstract
Alkaline phosphatase (ALP) has long been considered a marker of hepatobiliary and bone disorders, but recent studies have shown that increased ALP activity is correlated with various cardio-metabolic diseases. Thus, we investigated the association of serum ALP level with surrogate markers of insulin resistance such as triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C ratio) and triglyceride and glucose (TyG) index in the general population. The study included 12,868 men and women aged 19 years and older. Participants were categorized into four groups based on serum ALP level (U/L) as follows: Q1: 55-190 U/L, Q2: 191-224 U/L, Q3: 225-265 U/L, and Q4: 266-923 U/L for men, Q1: 48-161 U/L, Q2: 162-198 U/L, Q3: 199-245 U/L, Q4: 246-790 U/L for women. The insulin resistance cut-off levels were defined corresponding to the 75th percentile of the TyG index and TG/HDL-C ratio in the current samples. Odds ratios (ORs) with 95% confidence intervals (CIs) of insulin resistance according to quartile of serum ALP level were calculated using weighted multivariate logistic regression analysis. Compared with Q1, the adjusted OR (95% CI) for insulin resistance of the Q4 serum ALP group was 1.517 (1.234-1.866) in men and 1.881 (1.399-2.528) in women using the TG/HDL-C ratio and 1.374 (1.093-1.728) in men and 2.047 (1.468-2.855) in women using the TyG index after adjusting for confounding variables. Serum ALP levels are independently and positively associated with surrogate markers of insulin resistance in Korean adults.
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Triglyceride concentrations and non-high-density lipoprotein cholesterol goal attainment in the ODYSSEY phase 3 trials with alirocumab.
Vallejo-Vaz, AJ, Leiter, LA, Del Prato, S, Taskinen, MR, Müller-Wieland, D, Bujas-Bobanovic, M, Letierce, A, Mandel, J, Samuel, R, Ray, KK
European journal of preventive cardiology. 2020;(15):1663-1674
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AIMS: Guidelines recommend targeting non-high-density lipoprotein cholesterol to reduce cardiovascular risk. We assessed the impact of baseline triglycerides on non-high-density lipoprotein cholesterol goal attainment in 10 phase 3 trials with alirocumab versus control (n = 4983). METHODS Trials were grouped into four pools based on alirocumab dose (75-150 mg every 2 weeks), control (placebo/ezetimibe) and statin use. Baseline triglyceride quintiles were built within each pool. Non-high-density lipoprotein cholesterol goal attainment (very high risk: <100 mg/dl; moderate/high risk: <130 mg/dl), low-density lipoprotein cholesterol goal attainment (very high risk: <70 mg/dl; moderate/high risk: <100 mg/dl) and changes from baseline in lipid parameters were assessed at Week 24 among baseline triglyceride quintiles. RESULTS Higher baseline triglycerides were associated with a worse cardiovascular risk profile. Low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol increased with higher triglycerides, but the magnitude in non-high-density lipoprotein cholesterol was three- to four-fold higher compared with the increase in low-density lipoprotein cholesterol. Non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol percentage reductions from baseline with alirocumab were similar regardless of baseline triglycerides. A greater proportion of alirocumab-treated patients attained non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol goals compared with placebo or ezetimibe. Unlike low-density lipoprotein cholesterol goal attainment, non-high-density lipoprotein cholesterol goal attainment significantly declined with increasing baseline triglycerides (p < 0.05 for trend tests). A single standard deviation increase in baseline log(triglycerides) was significantly associated with lower odds ratios of attaining non-high-density lipoprotein cholesterol goals in the different pools and treatment (alirocumab/placebo/ezetimibe) groups, unlike low-density lipoprotein cholesterol goal attainment. CONCLUSION Individuals with increased triglycerides have higher non-high-density lipoprotein cholesterol levels and lower rates of non-high-density lipoprotein cholesterol goal attainment (unlike low-density lipoprotein cholesterol goal attainment). Alirocumab improves non-high-density lipoprotein cholesterol goal attainment in this population. These results highlight the impact of triglycerides on non-high-density lipoprotein cholesterol and the need for novel therapies targeting triglyceride-related pathways.
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Improvement of endothelial dysfunction is mediated through reduction of remnant lipoprotein after statin therapy in patients with coronary artery disease.
Nakamura, T, Uematsu, M, Yoshizaki, T, Kobayashi, T, Watanabe, Y, Kugiyama, K
Journal of cardiology. 2020;(3):270-274
Abstract
BACKGROUND Remnant lipoproteinemia with high levels of low-density lipoprotein cholesterol (LDL-C) is a high risk for endothelial dysfunction. Statins are the first-line lipid-lowering drugs for this combined hyperlipidemia. However, it remains undetermined whether reduction of remnant lipoprotein mediates the relationship between improvement in endothelial dysfunction and reduction of LDL-C level after statin treatment. METHODS A total of 122 coronary artery disease (CAD) patients with impaired flow-mediated dilation (FMD; <5.5%), high levels of LDL-C (≥100 mg/dL), and remnant-like lipoprotein particle cholesterol (RLP-C) (≥5 mg/dL) were examined in this study. The lipid profiles and FMD were measured before and after 6-9 months of statin treatment. The association between changes in LDL-C levels and its relationship with changes in FMD was investigated. Furthermore, mediation analysis was performed to assess the changes in RLP-C level as a mediator of the relationship between the reduction in LDL-C level and improvement of FMD. RESULTS Treatment with statins improved FMD in 69 (56.5%) patients. Patients with improved FMD showed lower percent changes of LDL-C, triglyceride (TG), RLP-C, RLP-C/TG, and C-reactive protein (CRP) levels, and higher percent change of HDL-C level, compared to patients who did not show improved FMD. The percent changes in FMD levels had a significant inverse correlation with the percent changes in LDL-C, (r = -0.18, p = 0.03), RLP-C (r = -0.39, p < 0.001), RLP-C/TG (r = -0.34, p < 0.001), and CRP (r = -0.27, p < 0.01). Mediation analysis showed that the relationship between reduction in LDL-C and improvement of FMD was mediated by reduction of RLP-C (34.5%), RLP-C/TG (24.4%), and CRP (24.9%) levels. CONCLUSION Improvement of remnant lipoproteinemia may be an important mediator for the relationship between improvement of endothelial dysfunction and LDL-lowering after statin treatment in patients with CAD.
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Influence of adiposity, insulin resistance, and intrahepatic triglyceride content on insulin kinetics.
Smith, GI, Polidori, DC, Yoshino, M, Kearney, ML, Patterson, BW, Mittendorfer, B, Klein, S
The Journal of clinical investigation. 2020;(6):3305-3314
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BACKGROUNDInsulin is a key regulator of metabolic function. The effects of excess adiposity, insulin resistance, and hepatic steatosis on the complex integration of insulin secretion and hepatic and extrahepatic tissue extraction are not clear.METHODSA hyperinsulinemic-euglycemic clamp and a 3-hour oral glucose tolerance test were performed to evaluate insulin sensitivity and insulin kinetics after glucose ingestion in 3 groups: (a) lean subjects with normal intrahepatic triglyceride (IHTG) and glucose tolerance (lean-NL; n = 14), (b) obese subjects with normal IHTG and glucose tolerance (obese-NL; n = 24), and (c) obese subjects with nonalcoholic fatty liver disease (NAFLD) and prediabetes (obese-NAFLD; n = 22).RESULTSInsulin sensitivity progressively decreased and insulin secretion progressively increased from the lean-NL to the obese-NL to the obese-NAFLD groups. Fractional hepatic insulin extraction progressively decreased from the lean-NL to the obese-NL to the obese-NAFLD groups, whereas total hepatic insulin extraction (molar amount removed) was greater in the obese-NL and obese-NAFLD subjects than in the lean-NL subjects. Insulin appearance in the systemic circulation and extrahepatic insulin extraction progressively increased from the lean-NL to the obese-NL to the obese-NAFLD groups. Total hepatic insulin extraction plateaued at high rates of insulin delivery, whereas the relationship between systemic insulin appearance and total extrahepatic extraction was linear.CONCLUSIONHyperinsulinemia after glucose ingestion in obese-NL and obese-NAFLD is due to an increase in insulin secretion, without a decrease in total hepatic or extrahepatic insulin extraction. However, the liver's maximum capacity to remove insulin is limited because of a saturable extraction process. The increase in insulin delivery to the liver and extrahepatic tissues in obese-NAFLD is unable to compensate for the increase in insulin resistance, resulting in impaired glucose homeostasis.TRIAL REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGNIH grants DK56341 (Nutrition Obesity Research Center), DK052574 (Digestive Disease Research Center), RR024992 (Clinical and Translational Science Award), and T32 DK007120 (a T32 Ruth L. Kirschstein National Research Service Award); the American Diabetes Foundation (1-18-ICTS-119); Janssen Research & Development; and the Pershing Square Foundation.
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Cardiorespiratory Fitness is Associated with Glycated Hemoglobin and Triglyceride Levels in Severely Obese Men: A Retrospective Clinical Data Analysis.
Wilms, B, Keppler, R, Ernst, B, Schmid, SM, Thurnheer, M, Schultes, B
Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association. 2020;(1):15-19
Abstract
BACKGROUND Even subjects with severe obesity show a wide range of metabolic health states, with some showing marked alterations in glucose and lipid metabolism whereas others do not. In severely obese women, we could recently show that the degree of cardiorespiratory fitness is, independently of body mass and age, associated with several markers of glucose and lipid metabolism. AIMS In our retrospective study on a clinical data set, we questioned whether such an association also exists in severely obese men. METHODS Cardiorespiratory fitness, i. e. workload (Wpeak) and oxygen uptake (V̇O2,peak) at peak exercise, was assessed by a bicycle spiroergometry in 133 severely obese men (all BMI>35 kg m-2). The following metabolic blood markers were also measured: Fasting serum glucose, insulin, triglycerides (TG), total, low-, high-density cholesterol (Chol, LDL, HDL), uric acid, and whole blood glycated hemoglobin (HbA1c). The Chol/HDL ratio and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) were also calculated. RESULTS Multiple stepwise linear regression models including age, body mass, and smoking status as independent variables revealed that Wpeak and V̇O2,peak, explained 4.5 to 10.7% of variance in HbA1c and TG (all beta<- 0.22; all p<0.02). Including fat free mass instead of body mass in respective models revealed that both Wpeak and V̇O2,peak were predictors of HbA1c and TG (all beta<- 0.265; all p<0.013), respectively, while Wpeak also accounted for variance in glucose and Chol (both beta<- 0.259; both p<0.023). CONCLUSIONS Similar to previous observations in women, our data indicate that cardiorespiratory fitness assessed by bicycle ergospirometry test is associated with glucose and lipid metabolism in severely obese men. The strength of the found associations suggest a mild to moderate influence of cardiorespiratory fitness on metabolic health in severe obesity.
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Risk Factor Control and Cardiovascular Event Risk in People With Type 2 Diabetes in Primary and Secondary Prevention Settings.
Wright, AK, Suarez-Ortegon, MF, Read, SH, Kontopantelis, E, Buchan, I, Emsley, R, Sattar, N, Ashcroft, DM, Wild, SH, Rutter, MK
Circulation. 2020;(20):1925-1936
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BACKGROUND To examine the association between the degree of risk factor control and cardiovascular disease (CVD) risk in type 2 diabetes and to assess if the presence of cardio-renal disease modifies these relationships. METHODS A retrospective cohort study using data from English practices from CPRD GOLD (Clinical Practice Research Datalink) and the SCI-Diabetes dataset (Scottish Care Information-Diabetes), with linkage to hospital and mortality data. We identified 101 749 with type 2 diabetes (T2D) in CPRD matched with 378 938 controls without diabetes and 330 892 with type 2 diabetes in SCI-Diabetes between 2006 and 2015. The main exposure was number of optimized risk factors: nonsmoker, total cholesterol ≤4 mmol/L, triglycerides ≤1.7 mmol/L, glycated haemoglobin (HbA1c) ≤53 mmol/mol (≤7.0%), systolic blood pressure <140mm Hg, or <130 mm Hg if high risk. Cox models were used to assess cardiovascular risk associated with levels of risk factor control. RESULTS In CPRD, the mean baseline age in T2D was 63 years and 28% had cardio-renal disease (SCI-Diabetes: 62 years; 35% cardio-renal disease). Over 3 years follow-up (SCI-Diabetes: 6 years), CVD events occurred among 27 900 (27%) CPRD-T2D, 101 362 (31%) SCI-Diabetes-T2D, and 75 520 (19%) CPRD-controls. In CPRD, compared with controls, T2D participants with optimal risk factor control (all risk factors controlled) had a higher risk of CVD events (adjusted hazard ratio, 1.21; 95% confidence interval, 1.12-1.29). In T2D participants from CPRD and SCI-Diabetes, pooled hazard ratios for CVD associated with 5 risk factors being elevated versus optimal risk factor control were 1.09 (95% confidence interval, 1.01-1.17) in people with cardio-renal disease but 1.96 (95% confidence interval, 1.82-2.12) in people without cardio-renal disease. People without cardio-renal disease were younger and more likely to have likely to have suboptimal risk factor control but had fewer prescriptions for risk factor modifying medications than those with cardio-renal disease. CONCLUSIONS Optimally managed people with T2D have a 21% higher CVD risk when compared with controls. People with T2D without cardio-renal disease would be predicted to benefit greatly from CVD risk factor intervention.
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High serum triglyceride levels in the early first trimester of pregnancy are associated with gestational diabetes mellitus: A prospective cohort study.
Zhu, H, He, D, Liang, N, Lai, A, Zeng, J, Yu, H
Journal of diabetes investigation. 2020;(6):1635-1642
Abstract
AIMS/INTRODUCTION Pregnant women with gestational diabetes mellitus (GDM) have been reported to have higher serum triglyceride (TG) levels during the entire gestational period. However, whether TGs contribute to the incidence of GDM remains unclear. This study aimed to evaluate whether higher serum TG level during early first trimester is associated with GDM. MATERIALS AND METHODS A prospective single-center cohort study was carried out among pregnant women (n = 2,949) who received regular antenatal care in Fu Xing Hospital, Capital Medical University, Beijing, China. GDM was diagnosed between 24 and 28 gestational weeks. Serum TG levels were measured during gestational weeks 6-8 (TG0) and 16-18 (TG1). TG elevation was the difference between TG1 and TG0. RESULTS In total, 581 pregnant women developed GDM. A 13.1, 18.5 and 28.8% incidence of GDM was observed in women with low, referent and high TG0 levels, respectively. Among women with prepregnancy body mass index <24 kg/m2 and prepregnancy body mass index ≥24 kg/m2 , those with high TG0 levels had 2.4- and 2.3-fold increased odds of developing GDM, respectively, compared with pregnant women with low TG0 levels. A positive dose-response relationship was observed between continuous TG0 and TG elevation, and the odds of GDM; a positive association was observed between TG elevation and the odds of developing GDM in pregnant women with intermediate to high TG0 levels. CONCLUSION High TG level during the early first trimester, and TG elevation from the first to early second trimester are associated with GDM development, which persists even after adjusting for confounders.