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Abstract Context The Early vs Late Intervention Trial with Estradiol (ELITE) showed that hormone therapy (HT) reduced atherosclerosis progression among early but not late postmenopausal women (PMW). Objective Determined by time-since-menopause (1) HT effects on lipids and lipoprotein particle subfractions (LPs), (2) associations of estradiol (E2) level with lipids and LPs, (3) associations of lipids and LPs with atherosclerosis progression. Design Randomized controlled trial stratified by time-since-menopause. Setting Academic institution. Participants Healthy postmenopausal women. Intervention Oral E2 with/without sequential vaginal progesterone. Main Outcome Measures Standard lipids and 21 LPs quantitated by ion mobility every 6 months. Results Among 562 PMW (240 early, 322 late), HT significantly increased total triglycerides (TG), high-density lipoprotein (HDL) cholesterol, small low-density lipoproteins (LDL), large HDL, and TG/C ratio in LDL and HDL and decreased LDL-cholesterol, total very low density lipoproteins (VLDL), small VLDL, intermediate-density lipoproteins, large LDL, and LDL peak diameter. HT showed no lipid or LP differences between time-since-menopause. Associations of E2 level with lipids and LPs explained the HT effects. Despite the nonsignificant P interaction by time-since-menopause, we observed that very small LDL and total HDL LPs were associated with atherosclerosis progression in late PMW. Conclusion HT effects on standard lipids and LPs are consistent with the literature. HT has similar effect on lipids and LPs in early and late PMW. Novel findings include discordant effects of HT on TG and VLDL particles, which can be explained by increased catabolism of atherogenic remnants of TG-rich lipoproteins. Our findings extend the well-known HT effects on standard lipids and LPs that may contribute to the beneficial effects on atherosclerosis progression in PMW.

Dyslipidemia and inflammation exacerbate postprandial metabolic stress in people with diabetes. Acute dietary supplementation with polyphenols shows promise in improving postprandial metabolic stress in type 2 diabetes (T2D). Cocoa is a rich source of dietary polyphenols with demonstrated cardioprotective effects in adults without diabetes. To date, the acute effects of cocoa on postprandial lipids and inflammation have received little attention in the presence of T2D. This report expands on our earlier observation that polyphenol-rich cocoa, given as a beverage with a fast-food-style, high-fat breakfast, increased postprandial high-density lipoprotein-cholesterol (HDL-C) in adults with T2D. We now test whether polyphenol-rich cocoa modulated postprandial apolipoproteins (Apo-A1, B), non-esterified fatty acids, nuclear magnetic resonance (NMR)-derived lipoprotein subclass profiles, and select biomarkers of inflammation following the same dietary challenge. We found that cocoa decreased NMR-derived concentrations of total very low-density lipoprotein and chylomicron particles and increased the concentration of total HDL particles over the 6-hour postprandial phase. Serum interleukin-18 was decreased by cocoa vs. placebo. Thus, polyphenol-rich cocoa may alleviate postprandial dyslipidemia and inflammation following a high-fat dietary challenge in adults with T2D. The study was registered at clinicaltrials.gov as NCT01886989.

Objective: To measure effects of fish oil supplements on lipoprotein subclasses by nuclear magnetic resonance (NMR) in subjects with type II diabetes and relate them to insulin sensitivity. Design: Two-armed, parallel, placebo-controlled, randomized. Subjects: Normotriglyceridemic subjects with type II diabetes without insulin treatment were given either fish oil (n=12, median intake 5.9 g/day total n-3 fatty acids (FA) (1.8 g 20:5n-3, 3.0 g 22:6n-3)) or corn oil (n=14, 8.5 g/day 18:2n-6 FA). Methods: Size and concentration of lipoproteins subclasses were measured by NMR, insulin sensitivity by hyperinsulinemic, isoglycemic clamps. Results: After 9 weeks, there were differences between those treated with fish and corn oil with respect to very low-density lipoprotein (VLDL) size (median -15 vs +0.6%, P=0.001), particle concentrations of large VLDL (-99 vs -4.1%, P=0.041) and small high-density lipoprotein (HDL) (-12 vs +10%, P=0.051). Compared with corn oil fish oil tended to increase HDL size and small low-density lipoprotein (LDL) concentration (P=0.063 and 0.068, respectively, for differences between groups). There was no effect on oxidized LDL. Insulin sensitivity (glucose utilization) decreased in the fish oil group compared with the corn oil group (P=0.049). The decrease in insulin sensitivity did not correlate with the effects on lipoprotein subclasses. Conclusions: A high intake of n-3 FA exerts effects on several lipoprotein subclasses without obvious influence from changes in insulin sensitivity. Sponsorship: Norwegian Foundation for Health and Rehabilitation, Peter Möller AS, Novo Nordisk, Abbot Norge AS, The Norwegian Diabetes Association.

To examine whether nuclear magnetic resonance lipoprotein spectroscopy improves the prediction of coronary artery disease in patients with Type 1 diabetes, independently of conventional lipid and other risk factors. A prospective nested case-control design of subjects with childhood onset Type 1 diabetes from the Pittsburgh Epidemiology of Diabetes Complications Study was used. 59 controls were age-, sex- and duration-matched to 59 incident cases of coronary artery disease (fatal or non-fatal myocardial infarction, angina, coronary stenosis >50%) occurring during 10 years of follow-up. Lipid mass and particle concentrations of VLDL, LDL, and HDL subclasses, grouped into three size categories (large, medium, and small), were assessed prior to event with nuclear magnetic resonance spectroscopy. Univariate analyses showed that both lipid mass and particle concentrations of all three VLDL subclasses, small LDL, medium LDL, and medium HDL were increased in CAD cases compared to controls, while large HDL was decreased. Mean LDL and HDL particle sizes were lower in cases. In multivariate models using conventional lipid and non-lipid risk factors, triglycerides and overt nephropathy were the strongest predictors of CAD. Nuclear magnetic resonance measures further improved the prediction, i.e. large HDL particle concentration (OR=0.43, p=0.030), medium HDL mass (OR=3.79, p=0.026) and total VLDL particle concentration (OR=2.33, p=0.033). While these results underscore the importance of triglycerides and overt nephropathy in CAD risk in Type 1 diabetic patients, they also suggest that nuclear magnetic resonance lipoprotein spectroscopy could further refine its prediction and show novel findings concerning HDL subclasses.

The VADT was a randomized clinical trial designed to assess the effect of intensive vs. standard glucose management on cardiovascular events in Type 2 diabetes. At the end of the study, intensive management failed to improve outcomes. We performed plasma lipoprotein subclass analyses to yield new information on the effects of study randomization on cardiovascular risk. This is a cross-sectional study of a subset of the VADT (740 men: 368 intensive; 372 standard), conducted at least six months (mean±SD: 2.1±0.8years) post-randomization. Conventional lipids, apolipoprotein-defined (ADLS) lipoprotein subclasses, ApoCIII, ApoE, and Nuclear Magnetic Resonance (NMR) lipoprotein subclasses were determined. In intensive vs. standard groups, conventional lipids and ADLS did not differ significantly. However, with intensive treatment, NMR-determined large and medium VLDL subclasses and VLDL diameter were lower, LDL diameter was higher, medium HDL was higher, and small HDL was lower (all p<0.05). Also, ApoCIII levels were lower (p<0.01). In a subset of diabetic men from the VADT, intensive glucose management did not affect conventional lipids or ADLS, but had some beneficial effects on particle characteristics as defined by NMR and on ApoCIII.

Effect of Fish Oil Versus Corn Oil Supplementation on LDL and HDL Subclasses in Type 2 Diabetic Patients Martin Petersen , MSC 1 , Helle Pedersen , MSC 1 , Atheline Major-Pedersen , MD 2 , Tonny Jensen , DMSC 2 and Peter Marckmann , DMSC 1 1 Research Department of Human Nutrition, The Royal Veterinary and Agricultural University, Frederiksberg, Denmark 2 Steno Diabetes Center, Gentofte, Denmark Abstract OBJECTIVE —The increased risk of coronary heart disease associated with type 2 diabetes may be partially explained by dyslipidemia characterized by high plasma triacylglycerol (TAG), low HDL cholesterol, and a predominance of atherogenic small dense LDLs. Fish oil reduces plasma TAG and has previously been shown to improve the distribution of LDL subclasses in healthy subjects and might, therefore, be a good nonpharmacological treatment for type 2 diabetic patients. In the present study, we investigate the effect of fish oil supplementation on the fasting lipid profile, including LDL and HDL subclasses. RESEARCH DESIGN AND METHODS —A total of 42 type 2 diabetic patients were randomized to supplementation (capsules) with 4 g daily of either fish oil ( n = 20) or corn oil ( n = 22) for 8 weeks preceded by a 4-week run-in period of corn oil supplementation. Blood was drawn before and after the 8-week intervention period. Plasma lipoproteins, including LDL and HDL subclasses, were separated by ultracentrifugation. RESULTS —Fish oil lowered TAG (group difference: P = 0.025) and raised HDL-2b cholesterol ( P = 0.012) and HDL-2a cholesterol ( P = 0.007) concentrations as compared with corn oil. We observed no significant effects of fish oil on LDL cholesterol, HDL cholesterol, or the concentration of small dense LDL particles. CONCLUSIONS —Fish oil supplementation may partially correct the dyslipidemia of type 2 diabetic patients. However, the putative very important aspect of diabetic dyslipidemia—the predominance of small dense LDL particles—was unaffected by fish oil. apo, apolipoprotein CETP, cholesterol ester transfer protein DHA, docosahexaenoic acid EPA, eicosapentaenoic acid IDL, intermediate-density lipoprotein TAG, triacylglycerol Footnotes Address correspondence and reprint requests to Martin Petersen, MSc Human Nutrition, Research Department of Human Nutrition, The Royal Veterinary and Agricultural University, Rolighedsvej 30, 2, DK-1958 Frb C, Denmark. E-mail: mpe{at}kvl.dk . Received for publication 27 February 2002 and accepted in revised form 8 July 2002. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. DIABETES CARE

Trans monounsaturated fatty acids (TFA) are hypercholesterolemic compared to oleic acid to a degree approaching or equivalent to saturated FA. However, it is unknown to what extent these effects may be due to cholesterol lowering by oleic acid rather than elevation by saturated FA and TFA. In order to better understand the impact of replacing TFA in foods, it is first necessary to know the relative lipid‐modifying effects of the major FA that change as TFA are lowered or removed. For 5 wk, 50 normocholesterolemic men were fed controlled diets providing approximately 15% of energy from protein, 39% from fat, and 46% from carbohydrate in a randomized, 6×6, crossover design. Eight percent of energy was replaced across diets with the following: carbohydrate (CHO) (1∶1 simple to complex); oleic acid (OL); TFA; stearic acid (STE); TFA/STE (4% of energy from each); carbon 12∶0 16∶0 saturated FA (LMP). LDL cholesterol concentrations (mmol/l) were as follows (different superscripts indicate significance at P≤0.01): OL 2.95a; CHO 3.05a,b; STE 3.10b,c; LMP 3.21c,d; TFA+STE 3.32d,e; and TFA 3.36e. HDL cholesterol concentrations (mmol/L) were as allows: STE 1.16a; IFA 1.16a,b; TFA/STE 1.17a,b; CHO 1.19b; OL 1.24c; and LMP 1.30d. Triacylglycerides were highest after STE (1.13) and lowest after OL (0.88) (P<0.001). Thus, compared to the carbohydrate control diet, TFA raised LDL cholesterol at least equivalent to LMP but had no effect on HDI cholesterol; STE had no effect on LDL cholesterol but lowered HDL cholesterol; LMP raised both LDL cholesterol and HDL cholesterol; and oleic acid raised HDL cholesterol but had no effect on LDL cholesterol.

To investigate the plasma lipoprotein subclasses in patients with primary open-angle glaucoma (POAG), a total of 20 Chinese POAG patients on intraocular pressure (IOP)-lowering treatment and 20 age-matched control subjects were recruited. Based on the levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), the study subjects were divided into elevated- and normal-level subgroups. The plasma lipoprotein, lipoprotein subclasses, and oxidized LDL (oxLDL) levels were quantitatively measured. The discrimination potential of the lipoproteins was evaluated using the area under the receiver operating characteristic curve (AUC), and their correlation with clinical parameters was also evaluated. Compared to the control subjects with elevated TC and/or LDL-C levels, the levels of TC, LDL-C, non-high-density lipoprotein cholesterol (non-HDL), LDL subclass LDL3 and small dense LDL (sdLDL), and oxLDL were significantly higher in POAG patients with elevated TC and/or LDL-C levels. No differences in any lipoproteins or the subclasses were found between the POAG patients and control subjects with normal TC and LDL-C levels. Moderate-to-good performance of TC, LDL-C, non-HDL, LDL3, sdLDL, and oxLDL was found in discriminating between the POAG patients and control subjects with elevated TC and/or LDL-C levels (AUC: 0.710–0.950). Significant negative correlations between LDL3 and sdLDL with retinal nerve fiber layer (RNFL) thickness in the superior quadrant and between LDL3 and average RNFL thickness were observed in POAG patients with elevated TC and/or LDL-C levels. This study revealed a significant elevation of plasma lipoproteins, especially the LDL subclasses, in POAG patients with elevated TC and/or LDL-C levels, providing insights on monitoring specific lipoproteins in POAG patients with elevated TC and/or LDL-C.

Patients with metabolic syndrome (MetS) usually have low high density lipoprotein cholesterol (HDL-C) levels. We determined the HDL distribution profile as well as the HDL-related lipoprotein associated phospholipase A₂ (HDL-LpPLA₂) and paraoxonase-1 (PON1) activities in subjects with MetS (n = 189) but otherwise healthy. Age and sex-matched individuals (n = 166) without MetS served as controls. The lower HDL-C concentration in MetS patients was due to a reduction in both large and small HDL subclasses (P < 0.001 and P < 0.05, respectively). As the number of MetS components increased, the HDL phenotype comprised of a greater percentage of small HDL-3 and less large HDL-2 subclasses, resulting in a decreased HDL-2/HDL-3 ratio (P < 0.001 for all trends). Multivariate analysis revealed that HDL-2 levels and the HDL-2/HDL-3 ratio significantly and independently correlated with HDL-C (positively) and TG (negatively) levels. HDL-3 concentration significantly and independently positively correlated with HDL-C and TG levels. HDL-LpPLA₂ activity was decreased in MetS patients (P < 0.01), a phenomenon that may contribute to the defective antiatherogenic activity of HDL in MetS. PON1 activity did not differ between groups. We conclude that MetS, in addition to the decrease in HDL-C concentration, is associated with alterations in the HDL phenotype, which is comprised of a greater percentage of small HDL subclasses. Furthermore, HDL-LpPLA₂ activity is decreased in MetS patients.

Metabolomics is a powerful molecular phenotyping technology which can be used in population studies to identify metabolites underlying disease conditions. To identify plasma biomarkers potentially predicting chronic diseases we applied 1 H nuclear magnetic resonance (NMR) metabolomics using a 600 MHz spectrometer fitted with an In Vitro Diagnostics Research (IVDr) platform to test associations between 18 known metabolites and 111 lipoprotein constituents that could be quantified and passed our quality control procedure and 944 phenotypes determined in 302 healthy participants of the Japanese Nagahama Study. We identified 907 statistically significant associations ( p  < 4.11 × 10 –7 ) between 34 phenotypes and at least one metabolite or lipoprotein. Eight metabolites and 109 lipoprotein (sub)classes showed evidence of associations with phenotypes predominantly related to lipid and cholesterol metabolism, liver function, fatness and hematology. We confirmed previously reported associations between plasma trimethylamine-N-oxide (TMAO) and cholesterol, and between the branched-chain amino acids leucine and valine and body mass index (BMI). BMI and fatness were positively associated with components of plasma LDL-4 and VLDL-1 and the ratios of apolipoproteins A1 to B100 and LDL to HDL cholesterol, whereas they were inversely associated with HDL-1 constituents. HDL-1 and LDL-4 subclasses systematically follow the patterns of association of HDL and LDL, respectively, and we propose that these can be examined to improve cardiometabolic risk evaluation. Results from our study exemplify the power of quantitative NMR-based metabolome profiling applied to even relatively small cohorts of healthy individuals extensively characterized for multiple phenotypes underlying unrelated clinical conditions to identify potentially disease-predicting metabolite biomarkers.