Triglyceride-rich lipoprotein and LDL particle subfractions and their association with incident type 2 diabetes: the PREVEND study

Background Triglyceride-rich lipoproteins particles (TRLP) and low density lipoprotein particles (LDLP) vary in size. Their association with β-cell function is not well described. We determined associations of TRLP and LDLP subfractions with β-cell function, estimated as HOMA-β, and evaluated their associations with incident T2D in the general population. Methods We included 4818 subjects of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study without T2D at baseline. TRLP and LDLP subfraction concentrations and their average sizes were measured using the LP4 algorithm of the Vantera nuclear magnetic resonance platform. HOMA-IR was used as measure of insulin resistance. HOMA-β was used as a proxy of β-cell function. Results In subjects without T2D at baseline, very large TRLP, and LDL size were inversely associated with HOMA-β, whereas large TRLP were positively associated with HOMA-β when taking account of HOMA-IR. During a median follow-up of 7.3 years, 263 participants developed T2D. In multivariable-adjusted Cox regression models, higher concentrations of total, very large, large, and very small TRLP (reflecting remnants lipoproteins) and greater TRL size were associated with an increased T2D risk after adjustment for relevant covariates, including age, sex, BMI, HDL-C, HOMA-β, and HOMA-IR. On the contrary, higher concentrations of large LDLP and greater LDL size were associated with a lower risk of developing T2D. Conclusions Specific TRL and LDL particle characteristics are associated with β-cell function taking account of HOMA-IR. Moreover, TRL and LDL particle characteristics are differently associated with incident T2D, even when taking account of HOMA-β and HOMA-IR.

Triglyceride-Rich Lipoprotein and LDL Particle Subfractions and Their Association With Incident Type 2 Diabetes: The PREVEND Study.

Background: Triglyceride-rich lipoproteins particles (TRLP) and low density lipoprotein particles (LDLP) vary in size. Their association with β-cell function is not well described. We determined associations of TRLP and LDLP subfractions with β-cell function, and evaluated their associations with incident T2D in the general population.Methods: We included 4818 subjects of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study without T2D at baseline. TRLP and LDLP subfraction concentrations and their average sizes were measured using the LP4 algorithm of the Vantera nuclear magnetic resonance platform. HOMA-IR was used as measure of insulin resistance. HOMA-β was used as a proxy of β-cell function.Results: In subjects without T2D at baseline, very large TRLP, large LDLP and LDL size were inversely associated with HOMA-β, whereas large TRLP, medium TRLP and TRL size were positively associated with HOMA-β taking account of HOMA-IR. During a median follow-up of 7.3 years, 263 individuals developed T2D. In multivariable-adjusted Cox regression models, higher concentrations of total, very large, large, and very small TRLP and TRL size were associated with an increased T2D risk after adjustment for relevant covariates, including age, sex, BMI, HDL-C, HOMA-β, and HOMA-IR. On the contrary, higher concentrations of large LDLP and LDL size were associated with a lower risk of developing T2D.Conclusions: Specific TRL and LDL particle characteristics are associated with β-cell function taking account of HOMA-IR. Moreover, TRL and LDL particle characteristics are differently associated with incident T2D, even when taking account of HOMA-β and HOMA-IR.

Higher D-lactate levels are associated with higher prevalence of small dense low-density lipoprotein in obese adolescents

Background: Childhood obesity is associated with insulin resistance (IR), increased levels of small dense low-density lipoprotein (sd-LDL) as well as with augmented hepatic de novo lipogenesis, which implies increased triose phosphate fluxes that may lead to increased methylglyoxal (MG) and its catabolic end product D-lactate. We hypothesized that obese adolescents have increased D-lactate serum levels associated with high incidence of sd-LDL. Methods: This is a cross-sectional study where the anthropometric characteristics, atherogenic dyslipidemia complex, sd-LDL (Lipoprint, Quantimetrix) and D-lactate (kinetic enzymatic analysis) were explored in 30 lean vs. 30 obese adolescents (16 females and 14 males per group) without metabolic syndrome (MetS). Endothelial function by flow-mediated dilation (FMD, by ultrasound) and arterial lesion by carotid intima media thickness (CIMT, by ultrasound) were also measured. Results: The mean age of participants was 16.8 ± 1.4 years. Obese adolescents had a body mass index of 32.7 ± 3.8 vs. 21.8 ± 2.1 in lean participants. The obesity group showed higher D-lactate levels: 6.2 ± 3.0 vs. 4.5 ± 2.5 μmol/L, higher levels of insulin: 15 (9.6–23.5) vs. 7.9 (6.5–10.5) μIU/mL; triglyceride (TG): 1.46 (1.1–1.8) vs. 0.84 (0.6–1.2) mmol/L; non-high-density lipoprotein-cholesterol (NON-HDL-C): 2.8 ± 0.9 vs. 2.3 ± 0.7 mmol/L; total cholesterol (TC)/HDL-C) index: 2.9 ± 0.7 vs. 2.4 ± 0.5; TG/HDL-C index: 2.2 (1.5–2.8) vs. 1.1 (0.8–1.8); %LDL-3: 4.2 ± 4.07 vs. 1.9 ± 2.7; smaller LDL size: 270.6 ± 3 vs. 272.2 ± 1.1 Å. D-lactate correlated positively with LDL-2: r = 0.44 and LDL-3 (sd-LDL): r = 0.49 and negatively with large LDL-1: r = −0.48 and LDL size: r = −0.46; (p<0.05, p<0.01, p<0.001 and p<0.0001, respectively). Obese adolescents showed higher CIMT: 0.51 ± 0.08 vs. 0.46 ± 0.08 mm and lower FMD: 20.3% ± 6.7% vs. 26.0% ± 9.3%. Conclusions: Obese adolescents display subclinical signs of IR and endothelial dysfunction. Higher serum sd-LDL levels correlated positively with D-lactate levels. These findings suggest an association between atherogenic dyslipoproteinemia and whole body MG fluxes already detectable in apparently healthy obese adolescents.

Abstract 197: Characterization of the Effects of Angiopoietin-Like 3 on Plasma Lipids and Lipoproteins in Humans

Angiopoietin-like 3 (ANGPTL3) deficiency due to loss-of-function (LOF) gene mutations causes familial combined hypobetalipoproteinemia type 2 (FHBL2) in homozygotes and compound heterozygotes, with a lipid phenotype much milder in heterozygotes. We aim to determine whether a critical reduction in plasma ANGPTL3 levels is a major determinant of FHBL2 lipid phenotype. We studied 126 subjects from 19 families with ANGPTL3 LOF mutations. Individuals homozygous for mutations in ANGPTL3 manifest the full FHBL2 phenotype of reduced total cholesterol, triglycerides, very low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol (-C) and particle concentration (-p), and LDL size. Heterozygotes only displayed with low total cholesterol, HDL-C, HDL-p and VLDL-p compared with non-carriers. Using multivariate adaptive regression splines, we found that: ( i ) total cholesterol, triglycerides, LDL-C, HDL-C, HDL-p, and LDL size correlated with ANGPTL3 but only for levels below 25% of normal (<60 ng/dl); ( ii ) VLDL-p and LDL-p correlate with ANGPTL3 irrespective of its plasma levels; and ( iii ) homozygotes exhibited reduced levels of mature proprotein convertase subtilisin/kexin type 9 (PCSK9), a known regulator of plasma LDL-C levels. These results indicate that the full FHBL2 phenotype seen in homozygous carriers of LOF mutations in ANGPTL3 is caused by a critical reduction of more than 75% of its plasma levels, thus uncovering the relationship between mutation status, plasma ANGPTL3 concentrations, and the lipid phenotype. Furthermore, our study suggests that the low plasma LDL seen in homozygous carriers of ANGPTL3 LOF mutations is mediated by the modulation of plasma PCSK9.

Abstract 16055: Lipoprotein Subclasses, Size, and Statin-Associated Incident Diabetes: An Analysis From the JUPITER Trial

Statins reduce CVD events, LDL cholesterol (LDL-C) and triglycerides, with an increased risk of diabetes. The underlying predictors of statin-associated diabetes are unclear. We evaluated lipoprotein subclass and size changes in response to rosuvastatin to identify predictors of diabetes on statin therapy Among 11,918 non-diabetic participants in JUPITER (NCT00239681), lipoprotein subclasses and size were quantified by NMR spectroscopy (LipoScience, NC) prior to and 1 year after randomization to placebo or rosuvastatin (total 370 incident diabetes). Cox regression models were adjusted for diabetes risk factors Compared to baseline, rosuvastatin lowered LDL-C and particles by lowering cholesterol-enriched large LDL (58%) and IDL (46%), with less relative lowering of cholesterol-poor small LDL (22%), resulting in smaller LDL size (1.5%). Rosuvastatin lowered (15%-20%) triglycerides, VLDL triglycerides, and VLDL particles by lowering large (15%), medium (7%), and small (27%) particles, and increasing VLDL size (3%) (all p<0.0001). Among statin-allocated individuals, after adjusting for typical risk factors, incident diabetes was inversely associated with baseline levels of LDL-C, HDL-C, large LDL particles, and LDL size, and positively associated with baseline triglycerides, non-HDL-C, ApoB, LDL particles, VLDL particles, VLDL triglycerides and size (Table). Similar associations were seen in on-treatment rosuvastatin and placebo groups In JUPITER, random allocation to rosuvastatin altered the lipoprotein subclass profile in a manner associated with the development of diabetes Adjusted Hazard Ratios (95% CI) and Risk of Incident Diabetes with Rosuvastatin Baseline parameters HR per 1-SD p value LDL-C .86 (0.76-0.98) .02 HDL-C .69 (0.54-0.87) .002 Triglycerides 1.62 (1.41-1.86) <.0001 Non-HDL-C 1.20 (1.04-1.39) .01 ApoB 1.35 (1.18-1.55) <.0001 Total LDL* 1.32 (1.15-1.51) <.0001 Large LDL* .79 (0.71-0.87) <.0001 Small LDL* 1.71 (1.40-2.08) <.0001 IDL* .97 (0.85-1.11) .69 LDL size .66 (0.58-0.75) <.0001 Total VLDL* 1.16 (1.00-1.34) .046 Large VLDL* 1.78 (1.51-2.10) <.0001 Medium VLDL* 1.35 (1.15-1.58) .0002 Small VLDL* .93 (0.82-1.06) .30 VLDL size 1.58 (1.39-1.80) <.0001 VLDL triglycerides 1.51 (1.31-1.73) <.0001 *particles

Plasma Levels of Acylation-Stimulating Protein Are Strongly Predicted by Waist/Hip Ratio and Correlate with Decreased LDL Size in Men

The association of abdominal obesity with cardiovascular risk is often linked to altered secretion of adipose-derived factors and an abnormal lipid profile including formation of atherogenic small dense low density lipoprotein particles (sdLDL). Acylation-stimulating protein (ASP) is an adipose-derived hormone that exhibits potent lipogenic effects. Plasma ASP levels increase in obesity; however, the association of ASP levels with body fat distribution is not yet established, and no study to date has investigated the association of ASP with LDL size. In this study, we examined the association of ASP levels with abdominal obesity measures and the lipid profile including LDL size in 83 men with a wide range of abdominal girths. Regression analysis showed that waist/hip ratio was the main predictor of ASP levels (β = 0.52, P<0.0001), significantly followed by decreased LDL size. BMI and TG levels, although positively correlated with ASP levels, were excluded as significant predictors in regression analysis. No correlation was found with LDL-C or apoB levels. ASP levels were 62.5% higher in abdominally obese compared to nonobese men. Waist/hip ratio presenting as the main predictor of ASP levels, suggests increased ASP production by abdominal fat which, as proposed previously, may result from resistance to ASP function causing delayed TG clearance and subsequent formation of atherogenic sdLDL.

The Triglyceride to HDL Ratio and Its Relationship to Insulin Resistance in Pre- and Postpubertal Children: Observation from the Wausau SCHOOL Project

Insulin resistance (IR) is a risk factor for ischemic heart disease and diabetes and raises the triglyceride/high-density lipoprotein (TG/HDL) ratio in adults, but is not well defined in children. Purpose. To investigate the TG/HDL ratios in children as an IR marker. Methods. Wausau SCHOOL Project assessed 99 prepubertal and 118 postpubertal children. The TG/HDL ratio was correlated with numerous risk factors. Results. TG/HDL ratio was significantly correlated with QUICKI, HOMA-IR, zBMI, waist-to hip ratio, systolic and diastolic BP, LDL size and LDL number. A group of 32 IR children (HOMA-IR > 1 SD from the mean, i.e., >2.45) had significantly higher TG/HDL (3.11 ± 1.77) compared to non-IR children (1.86 ± 0.75). A TG/HDL ratio of ≥2.0 identified 32 of the 40 children deemed IR by HOMA-IR (>2.45) with a sensitivity of 0.80 and a specificity of 0.66. Children with TG/HDL ratio ≥3 were heavier and had higher BP, glucose, HOMA-IR, LDL number, and lower HDL level, QUICKI, and LDL size, regardless of pubertal status. Conclusion. The TG/HDL ratio is strongly associated with IR in children, and with higher BMI, waist hip ratio, BP, and more athrogenic lipid profile.