Simvastatin but not bezafibrate decreases plasma lipoprotein-associated phospholipase A(2) mass in type 2 diabetes mellitus: Relevance of high sensitive C-reactive protein, lipoprotein profile and low-density lipoprotein (LDL) electronegativity

ObjectivePlasma lipoprotein-associated phospholipase A₂ (Lp-PLA₂) levels predict incident cardiovascular disease, impacting Lp-PLA₂ as an emerging therapeutic target. We determined Lp-PLA₂ responses to statin and fibrate administration in type 2 diabetes mellitus, and assessed relationships of changes in Lp-PLA₂ with subclinical inflammation and lipoprotein characteristics.MethodsA placebo-controlled cross-over study (three 8-week treatment periods with simvastatin (40 mg daily), bezafibrate (400 mg daily) and their combination) was carried out in 14 male type 2 diabetic patients. Plasma Lp-PLA₂ mass was measured by turbidimetric immunoassay.ResultsPlasma Lp-PLA₂ decreased (? 21 ± 4%) in response to simvastatin (p < 0.05 from baseline and placebo), but was unaffected by bezafibrate (1 ± 5%). The drop in Lp-PLA₂ during combined treatment (? 17 ± 3%, p < 0.05) was similar compared to that during simvastatin alone. The Lp-PLA₂ changes during the 3 active lipid lowering treatment periods were related positively to baseline levels of high sensitive C-reactive protein, non-HDL cholesterol, triglycerides, the total cholesterol/HDL cholesterol ratio and less LDL electronegativity (p < 0.02 to p < 0.01), and inversely to baseline Lp-PLA₂ (p < 0.01). LpPLA₂ responses correlated inversely with changes in non-HDL cholesterol, triglycerides and the total cholesterol/HDL cholesterol ratio during treatment (p < 0.05 to p < 0.02).ConclusionsIn type 2 diabetes mellitus, plasma Lp-PLA₂ is likely to be lowered by statin treatment only. Enhanced subclinical inflammation and more severe dyslipidemia may predict diminished LpPLA₂ responses during lipid lowering treatment, which in turn appear to be quantitatively dissociated from decreases in apolipoprotein B lipoproteins. Conventional lipid lowering treatment may be insufficient for optimal LpPLA₂ lowering in diabetes mellitus.     

Ezetimibe alone and in combination lowers the concentration of small, dense low-density lipoproteins in type 2 diabetes mellitus

ObjectiveThe effectiveness of the cholesterol absorption inhibitor ezetimibe on LDL subfractions and ultimately on the atherosclerotic risk profile remains controversial. We thus determined the concentration of atherogenic small, dense LDL (sdLDL) in patients with type 2 diabetes and an elevated cardiovascular risk profile.Research design and methodsMulticenter, randomized, open-label 6-week study investigating the effect of ezetimibe 10 mg (E), simvastatin 20 mg (S) and the combination of ezetimibe-/simvastatin 10/20 mg (C) on the concentration of sdLDL separated from fresh plasma by gradient ultracentrifugation in patients with type 2 diabetes (NCT01384058).ResultsFifty-six patients were screened for sdLDL, 41 were randomized, and 40 patients (12 E, 14 S and 14 C) completed the study. Total and LDL cholesterol fell by 14% (p = 0.004) and 15% (p = 0.006) with E, 22% (p < 0.001) and 32% (p < 0.001) with S, and 32% (p < 0.001) and 44% (p < 0.001) with C, respectively. E reduced the concentration of sdLDL by 20% (p = 0.043) whereas S and C reduced sdLDL by 24% (p = 0.020) and 33% (p = 0.003), respectively, and non-sdLDL by 28% (p = 0.004) and 42% (p < 0.001), respectively. However, the further drop in sdLDL by adding E to S was not significant.ConclusionEzetimibe alone and in combination with simvastatin reduced the concentration of atherogenic sdLDL in patients with type 2 diabetes.     

LDL and HDL subclasses in acute ischemic stroke: Prediction of risk and short-term mortality

ObjectiveSmall, dense low-density lipoprotein (sdLDL) and small-sized high-density lipoprotein (HDL) particles are established risk factors for ischemic heart disease. However, their clinical significance for acute ischemic stroke (AIS) is uncertain. This study evaluates associations of LDL and HDL particle sizes and subclasses with AIS risk and short-term mortality after AIS.MethodsTwo hundred AIS patients hospitalised for first-in-a-lifetime stroke and 162 apparently healthy controls were included in the study. LDL and HDL particles were separated by gradient gel electrophoresis and serum lipid parameters were measured by standard laboratory methods. Baseline characteristics of LDL and HDL particles were evaluated for the prediction of AIS and short-term mortality after AIS.ResultsAIS patients had significantly more LDL III and IVb, but less LDL I and II particles. They also had significantly smaller HDL size, more HDL 3a, 3b and 3c and less HDL 2b subclasses. The relative content of both sdLDL and small-sized HDL particles was significantly increased in patients (P < 0.001 and P < 0.001, respectively). In addition, sdLDL was significantly higher in AIS fatalities (n = 25) compared with survivors (n = 175, P < 0.05). Increased sdLDL was a significant predictor of AIS (OR = 4.31; P < 0.001) and in-hospital mortality after AIS (OR = 5.50; P < 0.05). The observed relationships persisted after adjustment for conventional risk factors.ConclusionsAIS is associated with adverse distributions of LDL and HDL subclasses. In addition, short-term mortality after AIS is associated with increased sdLDL particles. Our results indicate that sdLDL is an independent predictor of both AIS onset and consecutive short-term mortality.     

Effects of moderate-intensity exercise training on plasma biomarkers of inflammation and endothelial dysfunction in older patients with type 2 diabetes

Background and aimsSome plasma biomarkers of inflammation and endothelial dysfunction have been recently recognized as important cardiovascular risk factors. Currently, there is little information about the effects of aerobic exercise training on these biomarkers in older adults with type 2 diabetes. We have therefore assessed the effects of a twice-weekly moderate, aerobic exercise programme, without a concomitant weight loss diet, on plasma inflammatory and endothelial dysfunction biomarkers in older type 2 diabetic patients.Methods and resultsA group of 16 sedentary, overweight, non-smoking, older patients with type 2 diabetes volunteered to participate in a 6-month, supervised, progressive, aerobic training study, two times per week. Plasma levels of hs-C-reactive protein (hs-CRP), soluble tumour necrosis factor (TNF)-α receptors, P-selectin and intercellular adhesion molecule-1 (ICAM-1) were measured before and after physical training. While hs-CRP and soluble TNF-α receptors remained essentially unaffected by physical training, plasma concentrations of P-selectin (P < 0.001) and ICAM-1 (P < 0.01) markedly decreased; physical training also increased HDL cholesterol by 12% (P < 0.05) and decreased uric acid levels by ∼33% (P = 0.021). Body weight, waist circumference, blood pressure, haemoglobin A1c, plasma triglyceride and LDL cholesterol concentrations did not change. Interestingly, the exercise-induced changes in ICAM-1 and P-selectin levels remained significant after adjustment for the percent variations of body weight, waist circumference, haemoglobin A1c, HDL cholesterol and uric acid concentrations.ConclusionsA twice-weekly, 6-month, progressive aerobic-training programme, without a concomitant weight loss diet, is associated with significant decreases in circulating P-selectin and ICAM-1 levels and with a less atherogenic lipid profile in overweight, non-smoking, older type 2 diabetic individuals.     

Carbohydrate restriction favorably alters lipoprotein metabolism in Emirati subjects classified with the metabolic syndrome

Background and aimsCarbohydrate restriction (CR) has been shown to improve dyslipidemias associated with metabolic syndrome (MetS). We evaluated the effects of CR on lipoprotein subfractions and apolipoproteins in Emirati adults classified with the MetS.Methods and results39 subjects (15 men/24 women) were randomly allocated to a CR diet [20–25% energy from carbohydrate (CHO)] for 12 wk (CRD group) or a combination treatment consisting of CRD for 6 wk followed by the American Heart Association diet (50–55% CHO, AHA group) for an additional 6 wk. All subjects reduced body weight, LDL cholesterol and triglycerides (P < 0.01). At baseline all subjects had low concentrations of medium VLDL and total HDL particles associated with the very low plasma triglycerides and HDL cholesterol in this population. After 12 wk, the large VLDL subfraction was decreased over time for subjects in the CRD group (P < 0.01) while these changes were not observed in those subjects who changed to the AHA diet. The number of medium and small LDL particles decreased for all subjects rendering a less atherogenic lipoprotein profile. In agreement with these results, a significant decrease in apolipoprotein (apo) B was observed (P < 0.01). The medium HDL subfraction and apo A-II, which can be considered pro-atherogenic, were also decreased over time in the CRD group only.ConclusionsThese results suggest that weight loss favorably affects lipoprotein metabolism and that the CRD had a better effect on atherogenic VLDL and HDL than the low fat diet recommended by AHA.     

Effects of a phytosterol-enriched dairy product on lipids, sterols and 8-isoprostane in hypercholesterolemic patients: a multicenter Italian study

Background and aimsPlant sterols, added to several food sources, lower serum cholesterol concentrations. Plant sterol-induced cholesterol lowering is paralleled by a mild decrease in plasma levels of the antioxidant β-carotene, the amount of this decrease being considered clinically non-significant. Whether the effect on lipid profile of daily consumption of plant sterol-enriched low-fat fermented milk (FM) is paralleled by a concomitant variation in a reliable marker of the oxidative burden like plasma isoprostane levels is unresolved.Methods and resultsThe effect of plant sterol consumption on plasma lipid and isoprostane levels of hypercholesterolemic patients was evaluated in a multicenter, randomized double blind study. Hypercholesterolemic patients consumed a FM daily for 6 weeks. Subjects were randomized to receive either 1.6 g of plant sterol-enriched FM (n = 60) or control FM product (n = 56). After 6 weeks of plant sterol-enriched FM consumption, LDL cholesterol was reduced from 166.2 ± 2.0 to 147.4 ± 2.8 mg/dL (p = 0.01). A significant reduction was observed for total cholesterol (from 263.5 ± 2.6 to 231.0 ± 3.2 mg/dL, p = 0.01). There was greater LDL cholesterol lowering among hypercholesterolemic patients with higher LDL cholesterol at baseline. We found a reduction of plasma 8-isoprostane in patients taking plant sterol-enriched FM (from 43.07 ± 1.78 to 38.04 ± 1.14 pg/ml, p = 0.018) but not in patients taking the control product (from 42.56 ± 2.12 to 43.19 ± 2.0 pg/ml, p = NS). Campesterol and β-sitosterol levels were not influenced by phytosterol consumption.ConclusionsDaily consumption of low-fat plant sterol dairy product favourably changes lipid profile by reducing LDL-cholesterol, and may also have an anti-oxidative effect through a reduction of plasma isoprostanes.     

Plasma proprotein convertase subtilisin-kexin type 9 does not change during 24h insulin infusion in healthy subjects and type 2 diabetic patients

PurposeProprotein convertase subtilisin–kexin type 9 (PCSK9) promotes low density lipoprotein (LDL) receptor degradation, thereby providing a key pathway for LDL metabolism. PCSK9 mRNA expression may be upregulated by insulin in murine models. Here we examined effects of exogenous hyperinsulinemia on plasma PCSK9 levels in humans without and with type 2 diabetes mellitus.MethodsA 24 h moderately hyperinsulinemic glucose clamp (30 mU/kg/h) was performed in 8 healthy men and 8 male type 2 diabetic patients. Plasma PCSK9 was measured using a sandwich enzyme-linked immunosorbent assay.ResultsPlasma LDL cholesterol and apolipoprotein B were lowered by insulin in healthy subjects and diabetic patients (P < 0.01 for all), whereas triglycerides were also decreased in healthy subjects (P < 0.01). Plasma PCSK9 levels remained unchanged in healthy subjects (median (interquartile range) change, ?23 (?63 to 25) %, P = 0.50) and in diabetic patients (change, 4 (?17 to 44) %, P = 0.20). Individual absolute and relative changes in LDL cholesterol, apolipoprotein B and triglycerides after 24 h of insulin were unrelated to changes in PCSK9 (P > 0.15 for all).ConclusionPlasma PCSK9 levels are not increased by exposure to moderate 24 h hyperinsulinemia in healthy and type 2 diabetic individuals.     

Atherosclerosis regression study in rabbits upon olive pomace polar lipid extract administration

Background and aimsVirgin olive oil polar lipid extract (OOPL) and olive pomace polar lipid extract (PPL) have similar antiatherosclerotic effects in cholesterol-fed rabbits. Our aim was to compare the effect of PPL with that of simvastatin on the progression of atherogenesis.Methods and resultsRabbits were fed an atherogenic diet for 6 weeks in order to develop dyslipidemia and atheromatous lesions. Following documentation of these events in random animals (group A, n = 6), the remaining were fed for 3 weeks with: standard chow alone (group B, n = 6), chow supplemented with PPL (group C, n = 6), and chow supplemented with simvastatin (group D, n = 6). Blood was collected at 0, 6 and 9 weeks, to determine plasma lipid levels, plasma PAF-AH activity, platelet aggregation (PAF-EC₅₀), resistance of plasma to oxidation (RPO) and extent of atheromatous lesions in aortas. The atherogenic diet induced dyslipidemia and increased PAF-AH activity. Dyslipidemia and PAF-activity reduced more effectively in groups C and D. RPO decreased in group B only. PAF-EC₅₀ values decreased in group C only. Atherogenesis progression in group C was prevented to an extent indistinguishable from that in group D. PAF-AH activity was positively correlated, whereas RPO was negatively correlated with the extent of atheromatous lesions.ConclusionPPL, as a dietary supplement, is equipotent to simvastatin in preventing the progression of atherogenesis.     

Orlistat and sibutramine beyond weight loss

Background and aimTo investigate, through a meta-analysis of clinical trials, the effect of two weight-reducing drugs, such as orlistat and sibutramine, on serum lipid profiles in overweight and obese subjects, independently of weight loss.MethodsA systematic search strategy, incorporating the terms orlistat, sibutramine, fat, cholesterol, lipid profile, cardiovascular risk, was developed to identify randomized trials in MEDLINE from inception to the end of May 2005. Trial selection was limited by language of publication (English) and duration (6–12 months).ResultsFifteen and ten randomized, double-blind, placebo-controlled trials on orlistat and sibutramine respectively, were eligible for inclusion. In the 15 trials with orlistat, mean weight loss showed a significant correlation with mean reduction of total cholesterol (r = 0.48; p < 0.05), which maintained statistical significance after adjustment for mean weight loss (B = −2.81 ± 1.28; p < 0.05). Conversely, in the ten trials with sibutramine, treatment was not associated with a significant decrease in cholesterol levels after adjustment for weight loss (B = 3.25 ± 4.13; p not significant).ConclusionOrlistat or sibutramine, when individually compared to placebo, are effective in promoting significant weight loss. In addition, orlistat determines a significant reduction of total cholesterol, independent of weight loss itself. These observations indicate that orlistat is a useful adjunctive tool for improving cardiovascular risk factor profiles in overweight and obese patients.     

Effects of the PPAR-δ agonist MBX-8025 on atherogenic dyslipidemia

ObjectiveDetermine the effects of treatment with a selective PPAR-δ agonist ± statin on plasma lipoprotein subfractions in dyslipidemic individuals.MethodsIon mobility analysis was used to measure plasma concentrations of subfractions of the full spectrum of lipoprotein particles in 166 overweight or obese dyslipidemic individuals treated with the PPAR-δ agonist MBX-8025 (50 and 100 mg/d) ± atorvastatin (20 mg/d) in an 8-week randomized parallel arm double blind placebo controlled trial.ResultsMBX-8025 at both doses resulted in reductions of small plus very small LDL particles and increased levels of large LDL, with a concomitant reduction in large VLDL, and an increase in LDL peak diameter. This translated to reversal of the small dense LDL phenotype (LDL pattern B) in ～90% of the participants. Modest increases in HDL particles were confined to the smaller HDL fractions. Atorvastatin monotherapy resulted in reductions in particles across the VLDL–IDL–LDL spectrum, with a significantly smaller reduction in small and very small LDL vs. MBX-8025 100 mg/d (?24.5 ± 5.3% vs. ?47.8 ± 4.9%), and, in combination with MBX-8025, a reversal of the increase in large LDL.ConclusionPPAR-δ and statin therapies have complementary effects in improving lipoprotein subfractions associated with atherogenic dyslipidemia.     

The G-250A polymorphism in the hepatic lipase gene promoter is associated with changes in hepatic lipase activity and LDL cholesterol: The KANWU Study

Background and aimsHepatic lipase (HL) catalyzes the hydrolysis of triglycerides and phospholipids from lipoproteins, and promotes the hepatic uptake of lipoproteins. A common G-250A polymorphism in the promoter of the hepatic lipase gene (LIPC) has been described. The aim was to study the effects of the G-250A polymorphism on HL activity, serum lipid profile and insulin sensitivity.Methods and resultsAltogether 151 healthy subjects (age 49 ± 8 years, BMI 26.5 ± 3.0 kg/m²) were randomly assigned for 3 months to an isoenergetic diet containing either a high proportion of saturated fatty acids (SFA diet) or monounsaturated fatty acids (MUFA diet). Within groups there was a second random assignment to supplements with fish oil (3.6 g n-3 FA/day) or placebo. At baseline, the A-250A genotype was associated with high serum LDL cholesterol concentration (P = 0.030 among three genotypes). On the MUFA diet carriers of the A-250A genotype presented a greater decrease in LDL cholesterol concentration than subjects with other genotypes (P = 0.007 among three genotypes). The rare -250A allele was related to low HL activity (P < 0.001 among three genotypes). The diet did not affect the levels of HL activity among the genotypes.ConclusionThe A-250A genotype of the LIPC gene was associated with high LDL cholesterol concentration, but the MUFA-enriched diet reduced serum LDL cholesterol concentration especially in subjects with the A-250A genotype.     

The Mediterranean and CHO diets decrease VCAM-1 and E-selectin expression induced by modified low-density lipoprotein in HUVECs

Background and AimThe oxidative modifications of low-density lipoprotein (LDL) are crucial for the atherosclerosis process. The aim of this study was to determine if the minimally modified LDL, obtained after the ingestion of three different diets, produce differential effects on the vascular cell adhesion molecule-1 (VCAM-1) and E-selectin expression in human umbilical endothelial cells (HUVECs).Methods and ResultsTwenty healthy young males were exposed to three dietary periods. Each period lasted four weeks. During the first period, all subjects consumed a saturated fat (SFA) enriched diet (38% fat, 20% SFA). The second and third dietary periods were administered following a randomized crossover design: a low fat high carbohydrates diet (CHO diet) and a Mediterranean diet. LDL particles, isolated during each dietary period, were oxidized by exposure to UV light and incubated for 48 h with HUVEC. Thereafter, 100 U/mL of TNF-α was added and incubation continued for 6 h. Cellular ELISA determined adhesion molecules expression. Lag time, propagation rate and total amounts of formed conjugated dienes were calculated in LDL incubated with 10 μmol/L Cu²⁺. When compared to the SFA diet, LDL isolated from the Mediterranean and CHO diets induced a lower expression of VCAM-1 and E-selectin in HUVECS (P < 0.007). There were no differences between both lipid lowering diets. However, lag time of LDL from the Mediterranean diet was higher than with the CHO diet (P < 0.042). This parameter was inversely correlated with E-selectin expression (r = − 0.497; P < 0.04).ConclusionOur results suggest that both the Mediterranean and CHO diets may decrease the pro-inflammatory environment induced by modified LDL in endothelial cells.     

Usefulness of lipoprotein ratios in assessing carotid atherosclerosis in Japanese type 2 diabetic patients

ObjectiveIt is indicated that total/HDL cholesterol and LDL/HDL cholesterol ratios have more predictive power for cardiovascular disease compared to classic lipid parameters. However, there have been few reports about the usefulness of these indices for the assessment of early stage atherosclerosis in Japanese type 2 diabetic subjects.MethodsWe examined the relation between various lipid parameters and carotid atherosclerosis in 934 type 2 diabetic subjects without apparent atherosclerotic diseases (males, 71.7%; age, 59.6 ± 10.5 years (mean ± SD)). Serum concentrations of total cholesterol (TC), HDL cholesterol (HDL-C), and triglyceride were measured. LDL cholesterol (LDL-C) level was calculated using the Friedewald formula. The presence of carotid plaque and intima-media thickness (IMT) were evaluated by ultrasonography.ResultsA stepwise multivariate regression analysis demonstrated that HDL-C (β = ?0.110, p < 0.001), TC/HDL-C (β = 0.132, p < 0.001) and LDL-C/HDL-C ratios (β = 0.132, p < 0.001) were independent determinants of IMT even after adjustment of other conventional risk factors. However, there was no significant correlation between IMT and TC, triglyceride, LDL-C, and non-HDL-C levels. TC/HDL-C and LDL-C/HDL-C ratios and non-HDL-C levels were significantly higher, but HDL-C levels were significantly lower in patients with carotid plaque than those without it (p < 0.05). There was no significant difference between the groups regarding TC, LDL-C, and triglyceride levels. Furthermore, TC/HDL-C (OR; 1.34, p < 0.001) and LDL-C/HDL-C (OR; 1.54, p < 0.001) ratios showed a positive and linear relationship with the prevalence of carotid plaque, whether covariates were adjusted or not.ConclusionsTC/HDL-C and LDL-C/HDL-C ratios are useful as a tool to assess the risk of early stage atherosclerosis in Japanese type 2 diabetic patients.     

Moderate alcohol consumption and lipoprotein-associated phospholipase A2 activity

Background and aimsTo investigate the effect of moderate alcohol consumption on lipoprotein-associated phospholipase A2 activity, markers of inflammation and oxidative stress and whether these effects are modified by BMI.Methods and resultsEleven lean (BMI: 18.5–25 kg/m²) and 9 overweight (BMI > 27 kg/m²) men participated in a randomized controlled crossover trial. After consuming 3 cans of beer (40 g ethanol) or alcohol-free beer daily during 3 weeks, fasting blood samples were taken. HDL cholesterol increased by 18.2% (p < 0.001) after beer compared to alcohol-free beer, while LDL cholesterol decreased by 7.8% (p = 0.008). Lipoprotein-associated phospholipase A2 activity was not different (p = 0.23) between beer (47.5 ± 0.8) and alcohol-free beer (48.9 ± 0.8). High-sensitive C-reactive protein was unaffected, but urinary isoprostanes tended to increase (p = 0.09) after beer (114.0 ± 6.9) compared to alcohol-free beer (96.9 ± 6.5). An interaction between BMI and treatment (p < 0.05) on liver enzymes was observed, indicating an increase of liver enzymes after moderate alcohol consumption in overweight men only.ConclusionDespite profound effects on HDL and LDL cholesterol, moderate alcohol consumption did not affect lipoprotein-associated phospholipase A2 activity. Liver enzymes increased after alcohol consumption in overweight men only, suggesting a less favorable response to moderate alcohol consumption in overweight people.     

The effect of statin alone or in combination with ezetimibe on postprandial lipoprotein composition in obese metabolic syndrome patients

IntroductionFasting and postprandial hypertriglyceridemia are essential features of metabolic syndrome. Statins decrease fasting lipid levels but fail to reduce fat load induced hypertriglyceridemia. We established whether ezetimibe combined with simvastatin differently influences post fat load lipid levels and lipoprotein composition as compared to simvastatin 80 mg monotherapy in obese male metabolic syndrome patients.MethodsProspective, randomized, double blind, crossover trial. Male obese metabolic syndrome (ATPIII) patients (n = 19) were treated with simvastatin 80 mg and simvastatin/ezetimibe 10 mg/10 mg for 6 weeks. At the start of the study and after each treatment period oral fat loading tests were performed. Lipoprotein fractions (triglyceride-rich lipoproteins (TRL), IDL, LDL, and HDL) were isolated by density gradient ultracentrifugation. Postprandial changes in lipid levels were integrated as areas under the curve (AUCs).ResultsFasting LDL-C, RLP-C and triglycerides were lowered equally by both simvastatin 80 mg and simvastatin/ezetimibe 10 mg/10 mg. Also postprandial plasma triglyceride levels (net AUC-TG) were equally lowered after both treatments (5.16 ± 0.50 mmol h/l after simvastatin/ezetimibe 10 mg/10 mg and 6.09 ± 0.71 mmol h/l after simvastatin 80 mg) compared to fat loading without treatment (6.64 ± 0.86 mmol h/l). In addition, triglyceride-content in lipoprotein fractions after fat load (net AUCs) were also equally reduced after both treatments. Similarly, TRL. IDL and LDL cholesterol and apoB concentrations were equally affected by both treatment regimens, leading to a reduced number of circulating particles, in both conditions. However the composition of these particles remained the same.ConclusionSimvastatin 80 mg and simvastatin/ezetimibe 10 mg/10 mg were equally effective in reducing fasting and post fat load plasma lipid, and lipoprotein concentrations and lipoprotein composition in obese metabolic syndrome patients.     

Oxidized to non-oxidized lipoprotein ratios are associated with arteriosclerosis and the metabolic syndrome in diabetic patients

Background and aimType 2 diabetic patients have a greater prevalence of the metabolic syndrome, oxidative stress and accelerated atherosclerosis, compared to non-diabetics. We examined the association between biomarkers of lipid peroxidation and the presence of atherosclerosis and the metabolic syndrome in diabetic patients.Methods and resultsWe studied oxidized LDL (OxLDL), OxLDL/LDL, OxLDL/HDL, lipoperoxides, autoantibodies against OxLDL (OxLDL-Ab), diene formation of LDL (lag phase), vitamin E, vitamin E/cholesterol and PON1 polymorphisms (−108C > T, 55T > A, and 192A > G) in 166 non-smoking type 2 diabetic patients, 119 fulfilling the criteria for the metabolic syndrome, 73 with atherosclerosis and 93 without atherosclerosis. Patients with macrovascular disease had higher values of OxLDL/LDL (11%; P = 0.016), OxLDL/HDL (18%; P = 0.024) and OxLDL-Ab (12%; P = 0.046). OxLDL/LDL and OxLDL/HDL were correlated with the number of components of the metabolic syndrome (P < 0.001). PON1 polymorphisms were not associated to LDL oxidation markers, only PON1 (−108TT) was weakly associated with higher OxLDL-Ab concentrations (22%; P = 0.040) in patients with atherosclerosis.ConclusionOxLDL/LDL, OxLDL/HDL and OxLDL-Ab are the most useful clinical parameters of lipoprotein oxidation for discriminating the presence of macrovascular disease in diabetic patients. The presence of the metabolic syndrome in these patients is also associated with an increase in the oxidized lipoprotein ratios.     

Inhibition of soluble epoxide hydrolase reduces food intake and increases metabolic rate in obese mice

Background and aimsThis study evaluated the responses to soluble epoxide hydrolase (s-EH) inhibition, an essential enzyme in the metabolism of arachidonic acid, on food intake, body weight and metabolic parameters in mice fed a high fat-high fructose diet (HFD) for 10 weeks.Methods and resultsAfter 5 weeks of HFD, mice were divided into two groups: 1) s-EH inhibitor (AR9281, 200 mg/kg/day by gavage twice daily), and 2) vehicle (0.3 ml per gavage). Food intake, body weight, oxygen consumption (VO₂), carbon dioxide production (VCO₂), respiratory quotient (RQ), and motor activity were measured weekly for more 5 weeks. HFD increased body weight (37 ± 1 vs. 26 ± 1 g), and plasma of glucose (316 ± 8 vs. 188 ± 27 mg/dl), insulin (62.1 ± 8.1 vs. 15.5 ± 5.0 μU/ml), and leptin levels (39.4 ± 3.6 vs. 7.5 ± 0.1 ng/ml) while reducing VO₂, VCO₂ and motor activity. s-EH inhibition for 5 weeks decreased caloric intake by ～32% and increased VO₂ by ～17% (42.8 ± 1.4 vs. 50.2 ± 1.5 ml/kg/min) leading to significant weight loss. Inhibition of s-EHi also caused significant reductions in plasma leptin levels and visceral fat content. Uncoupling protein 1 (UCP1) content in brown adipose tissue was also elevated by ～50% during s-EH inhibition compared to vehicle treatment.ConclusionThese results suggest that s-EH inhibition with AR9281 promotes weight loss by reducing appetite and increasing metabolic rate, and that increased UCP1 content may contribute to the increase in energy expenditure.     

Relationship of plasma apolipoprotein M with proprotein convertase subtilisin-kexin type 9 levels in non-diabetic subjects

PurposeApolipoprotein M (apoM) retards atherosclerosis development in murine models, and may be regulated by pathways involved in LDL metabolism. Proprotein convertase subtilisin–kexin type 9 (PCSK9) plays a key role in LDL receptor processing. We determined the extent to which plasma apoM is related to PCSK9 levels in subjects with varying degrees of obesity.MethodsWe sought correlations between plasma apoM and PCSK9, measured using recently developed ELISAs, in 79 non-diabetic subjects.ResultsApoM and PCSK9 levels were both correlated positively with total cholesterol, non-HDL cholesterol, LDL cholesterol and apoB (P < 0.05 to P < 0.001). ApoM correlated positively with PCSK9 in lean individuals (n = 37, r = 0.337, P = 0.041), but not in overweight subjects (n = 32, r = 0.125, P = 0.50) and in obese subjects (n = 10, r = ?0.055, P = 0.88).ConclusionsThe PCSK9 pathway may contribute to plasma apoM regulation in humans. The influence of PCSK9 on circulating apoM appears to be modified by adiposity.     

Apolipoprotein B-48 as a determinant of endothelial function in obese subjects with type 2 diabetes mellitus: effect of fenofibrate treatment

ObjectiveElevated triglyceride-rich lipoproteins may contribute to endothelial dysfunction in obese diabetic subjects. We investigated the association between plasma concentrations of chylomicron-related particles and endothelial function, and the corresponding responses to fenofibrate treatment.MethodsPlasma apolipoprotein (apo) B-48 and remnant-like particle (RLP)-cholesterol concentrations were measured in 28 obese subjects with T2DM. Flow-mediated endothelium-dependent dilation (FMD) and glyceryl-trinitrate mediated dilatation (GTNMD) in the brachial artery during reactive hyperaemia were examined by high-resolution ultrasound technique.ResultsIn univariate analysis, plasma apoB-48 and RLP-cholesterol concentrations were inversely associated with brachial artery FMD (r = ?0.425 and ?0.423, respectively, P < 0.05), but not with GTNMD. In regression models including BMI and HOMA score, plasma apoB-48 was an independent predictors (P < 0.05) of brachial artery FMD (β coefficient = ?0.384). Replacing HOMA-IR score with plasma triglyceride, adiponectin or CRP concentrations did not alter the findings. The subjects were then randomized to a 12-week treatment period of either 200 mg micronized fenofibrate or matching placebo. Compared with the placebo group, fenofibrate treatment (200 mg daily for 12 weeks) achieved significant increase in FMD (+34%) and reduction in plasma triglyceride (?42%), apoB-48 (?52%) and RLP-cholesterol (?51%) concentrations. The increase in FMD with fenofibrate was significantly associated with the corresponding decrease in plasma apoB-48 (r = ?0.644, P < 0.02) concentrations.ConclusionsOur findings demonstrate an association between changes in lipid metabolism and improvement in endothelial function in patients with diabetic dyslipidaemia treated with fenofibrate that may involve the effect of apoB-48 on endothelium-dependent vasodilator function.     

In vivo impact of prodrug isosorbide-5-nicotinate-2-aspirinate on lipids and prostaglandin D2: Is this a new immediate-release therapeutic option for niacin?

ObjectivesTo evaluate the pharmacokinetics and effects of the first immediate-release (IR) niacin–aspirin prodrug (ST0702) on lipid, prostaglandin and thromboxane levels in non-human primates (NHPs).MethodsWe compared 28 mg/kg crystalline IR niacin, equimolar doses of crystalline IR ST0702 and control on low density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB) and triglycerides (Tg) in NHPs (6 per group) over 48 h (daily oral gavage). In addition, we compared IR niacin and ST0702 effects on prostaglandin (PG)D₂, ex vivo thromboxane B₂ (TXB₂) levels and plasma pharmacokinetics.ResultsST0702 is metabolised in vivo to aspirin, niacin and salicylic acid with T_max values of 30, 45 and 95 min respectively using a non-compartmental model. ST0702 resulted in 38% and 40% reductions in LDL-C and ApoB levels compared to control over the 48 h period (p = 0.027 and p = 0.012 respectively). Corresponding values were 32% and 25% for niacin (both p = NS vs control). ST0702, but not niacin, decreased Tg levels (p = 0.017 for between group difference). Post prandial glycaemia was attenuated vs baseline in the ST0702 group only. Ex vivo serum TXB₂ generation was suppressed at 15 min and complete suppression of TXB₂ was sustained at 24 h (p < 0.01 vs niacin). ST0702 suppressed PGD₂ exposure eightfold (p = 0.012) compared to niacin over the first 24 h.ConclusionsThis two-dose study in NHPs suggests that ST0702 is more effective than IR niacin on lipid profiles, while suppressing TXB₂ and PGD₂ increases and prevents post-prandial glycaemia. ST0702 shows promise as a new IR therapeutic option for niacin.