Dense LDLs Research Articles

The IL-10-1082 (rs1800896) G allele is associated with a decreased risk of developing premature coronary artery disease and some IL-10 polymorphisms were associated with clinical and metabolic parameters. The GEA study

Interleukin 10 (IL-10) is an anti-inflammatory cytokine with a protective role in the formation and the development of the atherosclerotic plaque. The aim of the present study was to establish if IL-10 gene polymorphisms are associated with the development of premature coronary artery disease (pCAD) and cardiovascular risk factors in Mexican individuals. Three IL-10 gene polymorphisms [-592C/A (rs1800872), -819C/T (rs1800871), and -1082 A/G (rs1800896)] and IL-10 plasma levels were analyzed in 2266 individuals (1160 pCAD patients and 1106 healthy controls). Under recessive and co-dominant2 models, the -1082 A/G (rs1800896) G allele was associated with decreased risk of developing pCAD (OR = 0.572, Prec = 0.022 and OR = 0.567, Pcod2 = 0.023). In pCAD patients, the polymorphisms were associated with hyperinsulinemia, small and dense LDLs, hypertension, and diabetes mellitus. In the control group, the polymorphisms were associated with hypertension, hyperuricemia, and small and dense LDLs. pCAD patients have significantly higher IL-10 plasma levels than healthy controls [0.91 (0.55–1.67) pg/mL vs 0.45 (0.24–0.98) pg/mL, respectively, P < 0.0001]. Nevertheless, these levels were not associated with the genotypes analyzed in the present study. The results suggest that the IL-10-1082 A/G (rs1800896) G allele is associated with a decreased risk of developing pCAD. In patients and controls, the polymorphisms analyzed were associated with some cardiovascular risk factors. Although, in pCAD patients the IL-10 plasma levels were higher, they were not associated with the genotypes of the polymorphisms examined.

Changes in lipid and carbohydrate metabolism under mTOR- and calcineurin-based immunosuppressive regimen in adult patients after liver transplantation

BackgroundCardiovascular disease is a leading cause of long-term mortality after liver transplantation (LT). Life long immunosuppression harbors the risk of metabolic alterations. We aimed to analyze the impact of calcineurin (CNI)-only containing regimen (group A) compared to mTOR-containing regimen (group B) on lipid and carbohydrate metabolism. Patients/methods92 adult patients after LT, University of Mainz (group A—78 patients, group B—14 patients; 65 M/27 F; mean age 59+/−10.2years; mean time from LT 5.8+/−5years). Clinical data, comorbidities, and medication were assessed. Fasting lipid profile including small dense LDLs (sdLDL) and oral glucose tolerance tests were performed. ResultsGroup B had significantly higher levels of total cholesterol (TC), LDL-cholesterol (LDL-C), triglycerides (TG) and sdLDL, with persistence of higher TC, TG, sdLDLs (mg/dl) after exclusion of patients under lipid lowering medication. Concentrations above the upper limits of normal were found: for LDL-C in 9% of group A/35.7% of group B (p=0.016); for TG: in 32.1% of group A/92.9% in group B (p=0.0001). A positive correlation between time since LT (years) and sdLDL (mg/dl) was found in group B (p=0.018). In patients without previously known diabetes, NODAT and impaired glucose tolerance developed in 27.9% of group A/44.4% of group B (n.s.). ConclusionPatients under mTOR-containing regimen are at higher risk to develop dyslipidemia with increased atherogenic sdLDLs compared to patients under CNI-only-containing regimen and display more frequently a dysglycemic status, with uncertain relevance for long-term cardiovascular risk. A careful monitoring after LT is needed to identify early metabolic risk and manage this appropriately.

Changes in lipid and carbohydrate metabolism under mTOR- and calcineurin-based immunosuppressive regimen in adult patients after liver transplantation

Background: Cardiovascular disease is a leading cause of long-term mortality after liver transplantation (LT). Life long immunosuppression harbours the risk of metabolic alterations. We aimed to analyze the impact of calcineurin (CNI)-only containing regimen (group A) compared to mTOR-containing regimen (group B) on lipid and carbohydrate metabolism. Patients/methods: 92 adult patients after LT, University of Mainz (group A - 78 patients, group B - 14 patients; 65 M/27F; mean age 59+/-10.2 ys; mean time from LT 5.8+/-5 ys). Clinical data, comorbidities, medication were assessed. Fasting lipid profile including small dense LDLs (sdLDL) and oral glucose tolerance tests were performed. Results: Group B had significantly higher levels of total cholesterol (TC), LDL-cholesterol (LDL-C), triglycerides (TG) and sdLDL, with persistence of higher TC, TG, sdLDLs (mg/dl) after exclusion of patients under lipid lowering medication. Concentrations above the upper limits of normal were found: for LDL-C in 9% of group A/35.7% of group B (p = 0.016); for TG: in 32.1% of group A/92.9% in group B (p = 0.0001). A positive correlation between time since LT (years) and sdLDL (mg/dl) was found in group B (p = 0.018). In patients without previously known diabetes, NODAT and impaired glucose tolerance developed in 27.9% of group A/44.4% of group B (n.s.). Conclusion: Patients under mTOR-containing regimen are at higher risk to develop dyslipidemia with increased atherogenic sdLDLs compared to patients under CNI-only-containing regimen and display more frequently a dysglycemic status, with uncertain relevance for long-term cardiovascular risk. A careful monitoring after LT is needed to identify early metabolic risk and manage this appropriately.

Pathophysiology of diabetic dyslipidaemia: where are we?

Cardiovascular disease is a major cause of morbidity and mortality in patients with type 2 diabetes mellitus, with a two- to fourfold increase in cardiovascular disease risk compared with non-diabetic individuals. Abnormalities in lipid metabolism that are observed in the context of type 2 diabetes are among the major factors contributing to an increased cardiovascular risk. Diabetic dyslipidaemia includes not only quantitative lipoprotein abnormalities, but also qualitative and kinetic abnormalities that, together, result in a shift towards a more atherogenic lipid profile. The primary quantitative lipoprotein abnormalities are increased triacylglycerol (triglyceride) levels and decreased HDL-cholesterol levels. Qualitative lipoprotein abnormalities include an increase in large, very low-density lipoprotein subfraction 1 (VLDL1) and small, dense LDLs, as well as increased triacylglycerol content of LDL and HDL, glycation of apolipoproteins and increased susceptibility of LDL to oxidation. The main kinetic abnormalities are increased VLDL1 production, decreased VLDL catabolism and increased HDL catabolism. In addition, even though LDL-cholesterol levels are typically normal in patients with type 2 diabetes, LDL particles show reduced turnover, which is potentially atherogenic. Although the pathophysiology of diabetic dyslipidaemia is not fully understood, the insulin resistance and relative insulin deficiency observed in patients with type 2 diabetes are likely to contribute to these lipid changes, as insulin plays an important role in regulating lipid metabolism. In addition, some adipocytokines, such as adiponectin or retinol-binding protein 4, may also contribute to the development of dyslipidaemia in patients with type 2 diabetes.

Determinants and clinical significance of plasma oxidized LDLs in older individuals. A 9 years follow-up study

Oxidized LDLs (ox.LDLs) uptake by macrophages inside the arterial wall is a crucial step in atherosclerotic disease, and some studies suggest that high ox.LDLs plasma levels might be associated with cardiovascular disease (CVD). However, whether high ox.LDLs continue to be a CVD risk factors in older persons is unknown. We investigated the clinical correlates of plasma ox.LDLs, and their role in predicting long-term CVD/cardiac mortality in 1025 older community dwelling individuals (mean age: 75.5 ± 7.4 years; females: 55%) from the InCHIANTI study. Kaplan–Meier curves were fitted to explore the relationship between tertiles of ox.LDLs (ox.LDL/LDL-C ratio) and time to CVD/cardiac death. Hazard Ratios (HR) were estimated by Cox regression analysis.At multivariate analysis, ox.LDLs were independently associated with LDL-C, triglycerides, and HDL-C (adjusted r2: 0.42; P = 0.001). The ox.LDL/LDL-C ratio (the extent of LDLs oxidation) was independently correlated with HDL-C, triglycerides, and beta-carotene (adjusted r2: 0.15, P = 0.001). Among 1025 individuals, 392 died after 9 years, 166 from CVD. The HR for CVD/cardiac mortality was not significantly different across tertiles of ox.LDLs or ox.LDL/LDL-C ratio, both in the whole sample and in individuals with prevalent CVD.We conclude that in an elderly population LDL-C, triglycerides, and HDL-C are the most important determinants of ox.LDLs levels, indirectly suggesting an association between small dense LDLs and LDLs oxidation. No association emerged between higher ox.LDLs levels and 9 years CVD/cardiac mortality, suggesting that in advanced age the prognostic information added by ox.LDLs on CVD/cardiac mortality might be negligible.

Insulin sensitivity in type 2 diabetes is closely associated with LDL particle size.

Small dense LDLs have been found to be associated with type 2 diabetes (T2DM). This association has been observed in the context of decreased HDL cholesterol and increased triglycerides. In the present study the relationship between LDL particle size and insulin sensitivity was assessed in 46 patients with T2DM (mean age 60 (11) years, HbA1c 7.6 (0.8) %). 75 g oral glucose tolerance testing was performed and composite insulin sensitivity index was calculated by the method of Matsuda and de Fronzo (ISI(comp)). Additional parameters included BMI, waist circumference, blood pressure, HDL cholesterol, triglycerides and LDL cholesterol. LDL particle size was measured by gradient gel electrophoresis. Log ISI(comp) correlated most strongly with LDL particle size (R = 0.61), less closely with HDL cholesterol (R = 0.48) and plasma triglycerides (R = -0.45) and not at all with LDL cholesterol (R = 0.001), as supported by multiple regression analyses where log ISI(com) was associated with LDL particle size (p = 0.004) and HDL cholesterol (p = 0.027) but not with triglycerides and LDL cholesterol. Log ISI(comp) estimated by a formula using endogenous insulin levels is very closely associated with LDL particle size in patients with T2DM. Our data suggest that smaller LDL particle size reflects the impact of insulin resistance on lipoprotein metabolism more strictly than do the traditional lipid parameters.

Insulin sensitivity in type 2 diabetes is closely associated with LDL particle size.

Small dense LDLs have been found to be associated with type 2 diabetes (T2DM). This association has been observed in the context of decreased HDL cholesterol and increased triglycerides. In the present study the relationship between LDL particle size and insulin sensitivity was assessed in 46 patients with T2DM (mean age 60 (11) years, HbA1c 7.6 (0.8) %). 75 g oral glucose tolerance testing was performed and composite insulin sensitivity index was calculated by the method of Matsuda and de Fronzo (ISI(comp)). Additional parameters included BMI, waist circumference, blood pressure, HDL cholesterol, triglycerides and LDL cholesterol. LDL particle size was measured by gradient gel electrophoresis. Log ISI(comp) correlated most strongly with LDL particle size (R = 0.61), less closely with HDL cholesterol (R = 0.48) and plasma triglycerides (R = -0.45) and not at all with LDL cholesterol (R = 0.001), as supported by multiple regression analyses where log ISI(com) was associated with LDL particle size (p = 0.004) and HDL cholesterol (p = 0.027) but not with triglycerides and LDL cholesterol. Log ISI(comp) estimated by a formula using endogenous insulin levels is very closely associated with LDL particle size in patients with T2DM. Our data suggest that smaller LDL particle size reflects the impact of insulin resistance on lipoprotein metabolism more strictly than do the traditional lipid parameters.

Role of Redox Regulation and Lipid Rafts in Macrophages During Ox-LDL–Mediated Foam Cell Formation

Hyperlipidemias and small dense LDLs in patients with high-triglyceride low-HDL syndromes lead to a prolonged half life of apoB-containing particles. This is associated with reactive oxygen species (ROS) activation and leads to formation of oxidized LDL (Ox-LDL). Generators of ROS in macrophages (MACs) include myeloperoxidase (MPO)-mediated respiratory burst and raft-associated NADPH-oxidase. The intracellular oxidant milieu is involved in cellular signaling pathways, like ion-transport systems, protein phosphorylation, and gene expression. Lipid oxidation through ROS can amplify foam cell formation through Ox-LDL uptake, leading to formation of ceramide (Cer)-rich lipid membrane microdomains, and is associated with expansion of the lysosomal compartment and an upregulation of ABCA1 and other genes of the AP3 secretory pathway. Ox-LDL may also affect cell-surface turnover of Cer-backbone sphingolipids and apoE-mediated uptake by LRP-family members. In contrast, HDL-mediated lipid efflux causes disruption of lipid membrane microdomains and prevents foam cell formation. Oxidation of HDL through MPO leads to a failure of lipid efflux and enhancement of MAC loading. Therefore, lipid rafts and oxidation processes are important in regulation of MAC foam cell formation and atherosclerosis, and the balance between oxidant and antioxidant intracellular systems is critically important for efficient MAC function.

Effects of altering the ratio of dietary n−6 to n−3 fatty acids on insulin sensitivity, lipoprotein size, and postprandial lipemia in men and postmenopausal women aged 45–70 y: the OPTILIP Study

Insulin resistance is associated with elevated plasma triacylglycerol, low HDL concentrations, elevated postprandial lipemia, and a predominance of small, dense LDLs (sdLDLs). It has been hypothesized that the dietary ratio of n-6 to n-3 (n-6:n-3) polyunsaturated fatty acids (PUFAs) may have favorable effects on these risk factors by increasing insulin sensitivity. The objective was to measure changes in insulin sensitivity, lipoprotein size, and postprandial lipemia after a 6-mo alteration in n-6:n-3. In a randomized, parallel design in 258 subjects aged 45-70 y, we compared 4 diets providing 6% of energy as PUFAs with an n-6:n-3 between 5:1 and 3:1 with a control diet that had an n-6:n-3 of 10:1. The diets were enriched in alpha-linolenic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), or both. Insulin sensitivity was assessed with the homeostatic model assessment of insulin resistance and the revised quantitative insulin sensitivity test. Dietary intervention did not influence insulin sensitivity or postprandial lipase activities. Fasting and postprandial triacylglycerol concentrations were lower, and the proportion of sdLDLs decreased (by 12.7%; 95% CI: -22.9%, 2.4%), with an n-6:n-3 of approximately 3:1, which was achieved by the addition of long-chain n-3 PUFAs (EPA and DHA). Decreasing the n-6:n-3 does not influence insulin sensitivity or lipase activities in older subjects. The reduction in plasma triacylglycerol after an increased intake of n-3 long-chain PUFAs results in favorable changes in LDL size.

Enhanced aortic atherosclerosis in transgenic Watanabe heritable hyperlipidemic rabbits expressing lipoprotein lipase

This study was designed to address the effects of increased lipoprotein lipase (LPL) activity on atherosclerosis in the setting of LDL receptor deficiency. We generated transgenic (Tg) Watanabe heritable hyperlipidemic (WHHL) rabbits overexpressing human LPL and compared their plasma lipids and aortic atherosclerosis with non-Tg WHHL rabbits. Increased expression of LPL significantly ameliorated hypertriglyceridemia and hypercholesterolemia in Tg WHHL rabbits [64% reduction in total cholesterol (TC) and 91% reduction in triglycerides (TG) vs. non-Tg]. In spite of this beneficial effect of LPL, Tg WHHL rabbits had two-fold greater aortic atherosclerosis than non-Tg WHHL rabbits. Analysis of plasma lipoprotein profiles revealed that increased LPL activity in Tg WHHL rabbits resulted in the dramatic reduction of large TG-rich lipoproteins (VLDL, d<1.006 g/ml and IDL, d=1.006-1.02) but concomitant increases in LDL fractions, especially those of small and dense LDL particles (d=1.04-1.06, 2.6-fold over non-Tg). Using apoB-containing lipoproteins, we found that small-sized LDL from Tg WHHL rabbits contained more oxidizable substrate and exhibited higher affinity to biglycan than large TG-rich LDL of non-Tg WHHL rabbits. We conclude that in the absence of LDL receptor function, increased LPL activity accelerates the catabolism of large TG-rich VLDL (possibly via the LRP pathway) and subsequently improves hyperlipidemia. However, LPL may also enhance the generation and accumulation of small dense LDLs, which are more atherogenic.

Long-chain conversion of [13C]linoleic acid and α-linolenic acid in response to marked changes in their dietary intake in men

We studied the long-chain conversion of [U-13C]alpha-linolenic acid (ALA) and linoleic acid (LA) and responses of erythrocyte phospholipid composition to variation in the dietary ratios of 18:3n-3 (ALA) and 18:2n-6 (LA) for 12 weeks in 38 moderately hyperlipidemic men. Diets were enriched with either flaxseed oil (FXO; 17 g/day ALA, n=21) or sunflower oil (SO; 17 g/day LA, n=17). The FXO diet induced increases in phospholipid ALA (>3-fold), 20:5n-3 [eicosapentaenoic acid (EPA), >2-fold], and 22:5n-3 [docosapentaenoic acid (DPA), 50%] but no change in 22:6n-3 [docosahexanoic acid (DHA)], LA, or 20:4n-6 [arachidonic acid (AA)]. The increases in EPA and DPA but not DHA were similar to those in subjects given the SO diet enriched with 3 g of EPA plus DHA from fish oil (n=19). The SO diet induced a small increase in LA but no change in AA. Long-chain conversion of [U-13C]ALA and [U-13C]LA, calculated from peak plasma 13C concentrations after simple modeling for tracer dilution in subsets from the FXO (n=6) and SO (n=5) diets, was similar but low for the two tracers (i.e., AA, 0.2%; EPA, 0.3%; and DPA, 0.02%) and varied directly with precursor concentrations and inversely with concentrations of fatty acids of the alternative series. [13C]DHA formation was very low (<0.01%) with no dietary influences.

Low-Density Lipoprotein Triglycerides Associated With Low-Grade Systemic Inflammation, Adhesion Molecules, and Angiographic Coronary Artery Disease

Markers of systemic inflammation and LDL cholesterol (LDL-C) have been considered independent risk factors of coronary artery disease (CAD). We examined whether alterations of LDL metabolism not reflected by LDL-C were associated with low-grade inflammation, vascular injury, and CAD. We studied 739 subjects with stable angiographic CAD and 570 matched control subjects in which CAD had been ruled out by angiography. The association of LDL triglycerides (LDL-TGs) (odds ratio [OR], 1.30; 95% CI, 1.19 to 1.43; P<0.001) with CAD was stronger than that of LDL-C (OR, 1.10; 95% CI, 1.00 to 1.21; P=0.047). The predictive value of LDL-TG for CAD was independent of LDL-C. "Sensitive" C-reactive protein (CRP), serum amyloid A, fibrinogen, interleukin 6, intercellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1) increased in parallel to LDL-TG. CRP, ICAM-1, and VCAM-1 were inversely related to LDL-C. To examine whether LDL-TGs were associated with the distribution of LDL subfractions, we studied 114 individuals with impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes mellitus. In subjects with high LDL-TG, LDLs were depleted of cholesteryl esters (CEs), and VLDLs, IDLs, and dense LDLs were significantly elevated. Alterations of LDL metabolism characterized by high LDL-TG are related to CAD, systemic low-grade inflammation, and vascular damage. High LDL-TGs are indicative of CE-depleted LDL, elevated IDL, and dense LDL. LDL-TG may better reflect the atherogenic potential of LDL than LDL-C.

In vivo metabolism of LDL subfractions in patients with heterozygous FH on statin therapy: rebound analysis of LDL subfractions after LDL apheresis

LDL can be subfractionated into buoyant (1.020-1.029 g/ml(-1)), intermediate (1.030-1.040 g/ml(-1)), and dense (1.041-1.066 g/ml(-1)) LDLs. We studied the rebound of these LDL-subfractions after LDL apheresis in seven patients with heterozygous familial hypercholesterolemia (FH) regularly treated by apheresis (58 +/- 9 years, LDL-cholesterol = 342 +/- 87 mg/dl(-1), triglycerides = 109 +/- 39 mg/dl(-1)) and high-dose statins. Apolipoprotein B (apoB) concentrations were measured in LDL subfractions immediately after and on days 1, 2, 3, 5, and 7 after apheresis. Compartmental models were developed to test three hypotheses: 1) that dense LDLs are derived from the delipidation of buoyant and intermediate LDLs (model A); 2) that dense LDLs are generated directly from LDL-precursors (model B); or 3) that a model combining both pathways (model C) is necessary to describe the metabolism of dense LDLs. In all models, it was assumed that apoB production and fractional catabolic rate (FCR) did not change with apheresis. Apheresis decreased buoyant, intermediate, and dense LDL-apoB by 60 +/- 12%, 67 +/- 5%, and 69 +/- 11%, respectively. Models B and C, but not model A, described the rebound data. The model with the greatest biological plausibility (model C) was used to estimate metabolic parameters. FCR was 1.05 +/- 0.86 d(-1), 0.48 +/- 0.11 d(-1), and 0.69 +/- 0.24 d(-1) for buoyant, intermediate, and dense LDLs, respectively. Dense LDL production was 17.3 +/- 0.2 mg/kg(-1)/d(-1), 58% of which was derived directly from LDL precursors (VLDL, IDL, or direct secretion), while 42% was derived from buoyant and intermediate LDLs. Thus, our data indicate that in statin-treated patients with heterozygous FH dense LDLs originate from two sources. Whether this is also valid in other metabolic situations (with predominant small, dense LDLs) remains to be determined.

Overexpression of lipoprotein lipase in transgenic rabbits leads to increased small dense LDL in plasma and promotes atherosclerosis

Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of triglyceride-rich lipoproteins. Previous studies using transgenic mice and rabbits have demonstrated that high level of LPL activity in adipose and skeletal muscle protects against diet-induced hypercholesterolemia and subsequently prevents aortic atherosclerosis. However, it is unknown, per se, whether increased LPL activity itself is antiatherogenic, or whether the antiatherogenic effect of LPL is dependent upon the LPL lipid-lowering effect. To address this issue, we fed LPL transgenic and littermate rabbits diets containing different amounts of cholesterol (0.3–0.6%) adjusted to maintain their plasma cholesterol concentrations at similarly high levels for 16 weeks. We analyzed their lipoprotein profiles and compared their susceptibility to atherosclerosis. The results showed that the overexpression of LPL in transgenic rabbits reduced remnant lipoproteins (β-VLDL, d<1.006 g/ml) but concomitantly led to a significant increase of the large (d=1.02–1.04 g/ml) and small LDLs (d=1.04–1.06 g/ml) compared to the amounts in control rabbits. Furthermore, we found that with equally high hypercholesterolemia, transgenic rabbits developed 1.8-fold more extensive aortic atherosclerosis than control rabbits. To examine the hypothesis that altered lipoprotein profiles may be responsible for the enhanced atherosclerosis in transgenic rabbits, we studied the atherogenic properties of apoB-containing lipoproteins in vitro. These studies revealed that small-sized LDLs of transgenic rabbits were more susceptible to copper-induced oxidation and had higher affinity to biglycan than large remnant lipoproteins. We conclude, therefore, that LPL exerts a dual function in terms of its atherogenicity, namely antiatherogenicity, through enhancing receptor-mediated remnant lipoprotein catabolism and proatherogenicity via the generation of a large amount of small-sized LDLs. At an equal atherogenic-cholesterol level, small and dense LDLs are more atherogenic than large remnant lipoproteins.

Genome-wide scan for quantitative trait loci influencing LDL size and plasma triglyceride in familial hypertriglyceridemia

Small, dense LDLs and hypertriglyceridemia, two highly correlated and genetically influenced risk factors, are known to predict for risk of coronary heart disease. The objective of this study was to perform a whole-genome scan for linkage to LDL size and triglyceride (TG) levels in 26 kindreds with familial hypertriglyceridemia (FHTG). LDL size was estimated using gradient gel electrophoresis, and genotyping was performed for 355 autosomal markers with an average heterozygosity of 76% and an average spacing of 10.2 centimorgans (cMs). Using variance components linkage analysis, one possible linkage was found for LDL size [logarithm of odds (LOD) = 2.1] on chromosome 6, peak at 140 cM distal to marker F13A1 (closest marker D6S2436). With adjustment for TG and/or HDL cholesterol, the LOD scores were reduced, but remained in exactly the same location. For TG, LOD scores of 2.56 and 2.44 were observed at two locations on chromosome 15, with peaks at 29 and 61 cM distal to marker D15S822 (closest markers D15S643 and D15S211, respectively). These peaks were retained with adjustment for LDL size and/or HDL cholesterol. These findings, if confirmed, suggest that LDL particle size and plasma TG levels could be caused by two different genetic loci in FHTG.

Acute hyperinsulinemia and very-low-density and low-density lipoprotein subfractions in obese subjects

The influence of hyperinsulinemia on concentrations of lipoprotein subfractions in obese, nondiabetic persons has not been clarified. We analyzed VLDL and LDL subfractions before and after a euglycemic, hyperinsulinemic clamp. Lipoprotein subfractions were isolated from plasma samples obtained in the basal state and after a 4-h clamp from obese patients, obese patients with type 2 diabetes, and nonobese control subjects. Hyperinsulinemia tended to reduce concentrations (&xmacr;: 20%) of large, triacylglycerol-rich VLDL(1) in obese patients but had a minor effect on VLDL(2) and VLDL(3). Placing obese patients into insulin-sensitive and insulin-resistant subgroups revealed distinct effects of the degree of insulin sensitivity on VLDL. VLDL(1) concentrations decreased by a mean of 38% (P < 0.05) in insulin-sensitive patients after the clamp, similar to but less marked than the decrease observed in control subjects (&xmacr;: 62%; P < 0.01). VLDL(1) concentrations did not change significantly after the clamp in insulin-resistant patients (and patients with type 2 diabetes), whereas VLDL(3) concentrations decreased in both groups, in contrast with the changes seen in the insulin-sensitive patients and control subjects. Acute hyperinsulinemia modified the LDL subfraction profile toward a greater prevalence of small, dense LDLs in insulin-resistant patients and patients with type 2 diabetes. Insulin resistance appears to be the primary determinant of the modifications to VLDL subfraction concentrations. Our results suggest a continuum of impaired insulin action on VLDL, ranging from that in healthy persons to that in patients with type 2 diabetes, in which obese patients occupy a transition state. Insulin resistance may also play a role in detrimental modifications to the LDL profile by allowing the development of hypertriglyceridemia.

Genetic relationship between measures of HDL phenotypes and insulin concentrations.

We used data from the San Antonio Family Heart Study to determine the HDL correlates of the insulin resistance syndrome (IRS), as reflected by insulin concentrations in nondiabetic subjects. We measured insulin concentrations both in the fasting state and 2 hours after a glucose challenge (2-hour insulin) and we assessed seven aspects of HDL phenotype, including size and concentration of both lipid and protein components. Measurements were obtained from 1202 nondiabetic members of 42 families. Initial quantitative genetic analyses revealed that a substantial portion of phenotypic variation in the nine variables was due to genes (heritabilities, h2, ranged from 0.32 to 0.47). We then conducted a series of bivariate genetic analyses, which indicated that there were significant additive genetic correlations (ie, pleiotropy) between the two measures of insulin and five of seven HDL measures tested, including concentrations of HDL cholesterol (fasting insulin only) and triglyceride, and HDL size distributions of apoAI, apoAII, and cholesterol; concentrations of apoAI and apoAII were not genetically related to either insulin measure. Increased insulin levels were associated with relatively smaller HDL phenotypes, and considering a similar association with small, dense LDLs, this finding suggests a common effect of insulin resistance on particle size distributions for these lipoproteins. Thus, these results suggest the existence of genes that pleiotropically influence variation in both HDLs and insulin levels and therefore contribute to the clustering of proatherogenic traits in the IRS.