Fasting hypertriglyceridemia in noninsulin-dependent diabetes mellitus is an important predictor of postprandial lipid and lipoprotein abnormalities

Postprandial lipoprotein metabolism may be important in atherogenesis and has not been studied in detail in noninsulin-dependent diabetes mellitus (NIDDM). We used the vitamin A fat-loading test to label triglyceride-rich lipoprotein particles of intestinal origin after ingestion of a high fat mixed meal containing 60 g fat/m2 and 60,000 U vitamin A/m2 in 12 untreated NIDDM subjects with normotriglyceridemia (NTG; triglycerides, less than 1.7 mmol/L), 7 untreated NIDDM subjects with moderate hypertriglyceridemia (HTG; triglycerides, 1.7-4.7 mmol/L), and 8 age- and weight-matched normotriglyceridemic nondiabetic controls. The postprandial triglyceride increment was greater in NIDDM with HTG (P = 0.0001) and correlated strongly in all groups with the fasting triglyceride concentration (r = 0.83; P = 0.0001). Retinyl palmitate measured in whole plasma, an Sf greater than 1000 chylomicron fraction, and an Sf less than 1000 nonchylomicron fraction was also significantly greater in NIDDM with HTG, but did not differ significantly between NIDDM with NTG and controls. In NIDDM with HTG, chylomicrons appeared to be cleared at a slower rate, as evidenced by the significantly later intersection of the chylomicron and nonchylomicron retinyl palmitate response curves (13.7 h in HTG NIDDM vs. 8.5 h in NTG NIDDM vs. 7.3 h in controls; P less than 0.01). Although fasting FFA levels were similar in all three groups, the HTG diabetic subjects had a late postprandial surge in FFAs that lasted for up to 14 h. The postprandial FFA elevation in all groups correlated with the fasting triglyceride concentration (r = 0.57; P less than 0.002) and postprandial triglyceride increment (r = 0.80; P = 0.0001). The fasting core triglyceride content of the HDL particles in NIDDM with HTG was significantly elevated compared to those in NIDDM with NTG and controls (21.0% vs. 14.0% vs. 14.1% respectively; P less than 0.05), and this increased proportionately in all groups after the meal at the expense of cholesteryl ester, the increase correlating with total plasma postprandial triglyceride increment (r = 0.51; P less than 0.01). We conclude that moderate fasting hypertriglyceridemia in NIDDM is predictive of a constellation of postprandial changes in lipids and lipoproteins that may potentiate the already unfavorable atherogenic fasting lipid profile in these subjects.     

Role of basal triglyceride and high density lipoprotein in determination of postprandial lipid and lipoprotein responses.

The present study reports on the interaction between basal triglyceride and high density lipoprotein (HDL) cholesterol in determining the magnitude of postprandial triglyceridemia. The vitamin A fat-loading test was used to label intestinally derived triglyceride-rich particles after a high fat meal in 18 subjects with low HDL cholesterol and 6 control subjects who had normal fasting triglyceride and HDL cholesterol levels. The patients with low HDL cholesterol were divided into 2 groups on the basis of their basal triglyceride concentrations; 11 had normal triglyceride levels, and 7 had elevated serum triglycerides (HTG). In the HTG-low HDL group, the incremental area under the triglyceride curve was significantly greater (P less than 0.0003) than that in the other 2 groups, between whom no significant differences in triglyceride response were observed. Retinyl palmitate levels measured in whole plasma, an Sf greater than 1000 chylomicron fraction, and an Sf less than 1000 nonchylomicron fraction were also significantly greater in low HDL subjects with HTG, while the concentrations in low HDL subjects with normal triglyceride levels and control subjects were similar. Although basal HDL cholesterol levels in all study subjects were negatively correlated with the area under the incremental triglyceride curve (r = -0.42; P less than 0.05), this correlation was weak, in contrast to the correlation between fasting triglyceride levels and incremental triglyceride area (r = 0.56; P less than 0.005). Furthermore, basal HDL cholesterol levels did not correlate with the area under the chylomicron or nonchylomicron curves, whereas basal triglyceride levels were significantly correlated (P = 0.0001) with both of these variables. The HDL particles of both low HDL groups had a significantly higher proportion of triglyceride compared to the HDL particles in the control subjects. In conclusion, 1) fasting triglyceride levels are a more powerful indicator of the postprandial lipid response than basal HDL cholesterol in subjects with low HDL cholesterol levels; 2) patients with low HDL cholesterol levels do not preferentially accumulate chylomicron remnants after a meal unless they have coexisting hypertriglyceridemia; and 3) abnormalities in the levels of triglyceride-rich particles post-prandially are unlikely to be responsible for the increased incidence of atherosclerosis in low HDL patients who are normotriglyceridemic.     

Inverse relationship between blood levels of high density lipoprotein subfraction 2 and magnitude of postprandial lipemia.

Triglyceridemic response to a standard oral fat meal was determined in 28 healthy subjects and related to the levels of several lipids, lipoproteins, and apolipoproteins in the post-absorptive plasma. A fatty test meal was administered orally, and postprandial plasma triglyceride levels were determined. In the fasting blood samples, concentrations of apolipoproteins (apo) A-I, A-II, and B were determined by radioimmunoassay, and those of high density lipoprotein (HDL) subfractions HDL2 and HDL3, by zonal ultracentrifugation. The magnitude of triglyceridemic response showed a negative correlation with the plasma levels of HDL2 (r = -0.860, P less than 0.001), HDL-associated cholesterol (r = -0.605, P less than 0.001), and apoA-I (r = -0.459, P less than 0.02). No correlation was found between the triglyceridemic response and the levels of total cholesterol, HDL3, and apoA-II. Triglyceridemic response was correlated positively with fasting triglyceride concentrations (r = 0.450, P less than 0.02) and apoB levels (r = 0.396, P less than 0.03). In two subjects followed for 3 yr, when HDL2 levels rose or fell, the triglyceridemic response decreased or increased, respectively (r = -0.944; r = -0.863). Our data indicate that normolipidemic individuals with high HDL2 levels in the plasma are able to clear alimentary fat at a faster rate than normolipidemic subjects with low HDL2 levels. The pronounced difference in severity and duration of postprandial lipemia among subjects with varying HDL2 levels may help to explain the negative correlation between the risk of atherosclerosis and HDL cholesterol levels.     

Postprandial plasma vitamin A metabolism in humans: a reassessment of the use of plasma retinyl esters as markers for intestinally derived chylomicrons and their remnants

We investigated postprandial vitamin A metabolism by measuring retinyl ester, triglyceride, and apolipoprotein (apo)B-48 in the plasma lipoproteins of human subjects before and after fat-feeding. Following a 14-hour fast, eight healthy subjects (two men, six women, 28 to 79 years) were given a fat-rich meal (1 g fat/kg body weight) containing vitamin A (40 retinol equivalents per kilogram body weight). Blood was collected every 3 hours for 12 hours and lipoproteins were isolated by sequential ultracentrifugation. Mean plasma retinyl ester concentration peaked 6 hours after the fat-rich meal, whereas mean plasma triglyceride peaked at 3 hours. Data obtained from hourly samples in 3 subjects showed that changes in the postprandial plasma concentration of retinyl ester occurred 1 to 2 hours after changes in the plasma triglyceride concentration. In triglyceride-rich lipoproteins (TRL) of d less than 1.006 g/mL, retinyl ester similarly peaked at 6 hours, whereas triglyceride as well as apoB-48 peaked at 3 hours. Although retinyl esters were found mainly in TRL in the initial postprandial period (84%, 3 hours; 83%, 6 hours), in fasting and postprandial plasma, particularly 9 or more hours after fat-feeding, a large percentage of plasma retinyl esters were in low-density lipoproteins (LDL) (44%, fasting; 9%, 3 hours; 9%, 6 hours; 19%, 9 hours; 32%, 12 hours). A small percentage of retinyl esters were also found in postprandial high-density lipoproteins (HDL) (2% to 7%). ApoB-48 was not detected in LDL of fasting or postprandial plasma.(ABSTRACT TRUNCATED AT 250 WORDS)     

Independent effects of Apo E phenotype and plasma triglyceride on lipoprotein particle sizes in the fasting and postprandial states.

LDL particle sizes and Apo E phenotypes were determined in 212 subjects of whom 51 had angina. LDL diameter was significantly less in subjects with an epsilon2 allele (24.76+/-0.08 vs 24.94+/-0.02 nm, P=0.02), and this was evident for both E2/E3 (24.77+/-0.09 nm) and E2/E4 (24.69+/-0.08 nm) phenotypes. Although there was a negative relation between LDL diameter and plasma triglyceride, the effect of apo E2 was still evident with adjustment for triglyceride. In multiple regression analysis, the significant determinants of LDL diameter were gender (with females having larger particles than males), body mass index, and the presence (or absence) of E2. HDL particle sizes and compositions were determined on fasting samples and, additionally, 5 and 8 hours after a fat-rich meal for 48 coronary heart disease cases and 49 control subjects. Fasting HDL particle sizes were not related to the presence of E2 but were significantly smaller for subjects possessing an epsilon4 allele (8. 09+/-0.08 vs 8.39+/-0.05 nm, P=0.003) and were negatively related to plasma triglyceride. However, the effect of E4 persisted after adjustment for triglyceride. In a multiple regression analysis, the only significant determinant of fasting HDL diameter was the presence (or absence) of E4 with fasting plasma triglyceride just failing to reach significance (P=0.06). There was a postprandial increase in HDL diameter that was less marked in subjects with coronary heart disease. The postprandial increase in HDL diameter was of sufficient magnitude to result in size reclassification of HDL particles. The influence of E4 was also evident at both postprandial time points. Compositional analysis demonstrated that the increase in HDL diameters postprandially could be attributed to triglyceride enrichment, with an accompanying fall in cholesterol ester content. Phospholipid changes postprandially were biphasic with an initial fall followed by a rise in concentration. The increase in triglyceride content was significantly less in those subjects with angina despite an equivalent rise in plasma triglyceride. The present study demonstrates significant, but different, effects of variation in apo E phenotype on the particle sizes of both HDL and LDL. Such effects were still evident with adjustment for differences in plasma triglyceride and suggests that variation in apo E phenotype exerts effects on lipoprotein particle sizes by mechanisms additional to those dependent on change in plasma triglyceride.     

Evidence for a cholesteryl ester donor activity of LDL particles during alimentary lipemia in normolipidemic subjects.

Postprandial hypertriglyceridemia represents an independent risk factor for coronary artery disease. In the postprandial state, elevated levels of triglyceride-rich lipoproteins (TRL) are minor acceptors of HDL-cholesteryl ester (CE) transferred by CETP in normolipidemic subjects: indeed, LDL particles represent the major CE acceptors. In order to evaluate further the potential atherogenicity of lipoprotein particles characteristic of the postprandial phase in normolipidemic subjects, we determined the quantitative and qualitative features of apoB- and apoAI-containing lipoproteins over an 8-h period following consumption of a mixed meal. During postprandial lipemia, we observed a significant decrease (-12%) in plasma AI concentration (138+/-4 and 156+/-4 mg/dl, at 3 h and baseline, respectively, P<0.005). Concomitantly, a progressive increase (+13%) was detected in HDL2 concentrations (138+/-7 mg/dl at 4 h vs. 122+/-12 mg/dl at baseline, P<0.005), as well as a significant reduction (-9%) in HDL3 levels (137+/-6 mg/dl at 3 h vs. 150+/-4 mg/dl at baseline; P<0.05). Additionally, plasma LDL was reduced by 5% (247+/-12 mg/dl at 3 h vs. 260+/-15 mg/dl at baseline; P<0.05) 3 h following meal intake. Moreover, a significant reduction (-10%) occurred in the CE/TG ratio in LDL at 2 h postprandially (8+/-2 at 2 h vs. 9+/-3 at baseline; P<0.005). These changes reflected an increment (17+/-3 mg/dl at 3 h vs. 15+/-4 mg/dl at baseline; P<0.05) in LDL triglyceride concentrations. Despite the high CE acceptor capacity of LDL particles, no measurable increase in their CE content was detected during the postprandial phase. We demonstrated that CE accepted by LDL particles from HDL are secondarily transferred to chylomicrons by CETP. As chylomicrons displayed a 260-fold lower CE/TG ratio than LDL (0.03:1 and 7.8:1 in chylomicrons and LDL, respectively), CE-rich LDL may act to donate CE to chylomicrons. In conclusion, our data indicate that the presence of elevated levels of chylomicrons induces LDL to act as a secondary donor of CE during the postprandial phase.     

Pronounced postprandial lipemia impairs endothelium-dependent dilation of the brachial artery in men.

OBJECTIVE: Pronounced postprandial lipemia has been established as a risk factor for cardiovascular disease, but reports regarding its effect on endothelial function have been controversial. In the present study the influence of a standardized fatty meal with its ensuing postprandial lipemia of highly varying magnitude on endothelium-dependent dilation (EDD) was investigated. METHODS: In 17 healthy, normolipidemic men EDD of the brachial artery was quantified in two series of three measurements each. In both series initial measurements were performed at 08:00 h after an overnight fast followed by measurements at 12:00 and 16:00 h, in the first series with continued fasting and in the second following the ingestion of a standardized fatty test meal 4 and 8 h postprandially. RESULTS: Measurements of EDD in the fasting state revealed the recently appreciated diurnal variation with higher values in noon and afternoon hours compared with morning values (2.5+/-1.6% at 08:00, 7.5+/-2.7% at 12:00, and 7.0+/-2.1% at 16:00 h, P<0.001 by analysis of variance). Postprandial EDD values measured at 12:00 h were, at the average, lower than fasting EDD values measured at 12:00 h and correlated inversely with the magnitude of postprandial triglyceridemia (r=-0.81, P<0.001). In multivariate analysis, higher postprandial lipemia was associated with impaired postprandial EDD (P<0.001) independent of fasting triglycerides, low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol, insulin, age and body mass index. CONCLUSION: We conclude that pronounced postprandial lipemia is associated with transient impairment of endothelial function. Our findings support the notion that impaired triglyceride metabolic capacity plays an important role in atherogenesis.     

Plasma lipoprotein distribution of apolipoprotein(a) in the fed and fasted states.

In order to quantitate the contribution of triglyceride-rich lipoprotein (TRL) apolipoprotein(a) to total plasma apo(a) concentration in the fed and fasted states, we have studied a group of 20 male subjects (age 49 +/- 3 years) with fasting apo(a) concentrations varying from 39 to 1385 U/l. After a 12-h overnight fast, each subject was given a fat-rich meal (1 g fat/kg body weight) and venous blood samples were obtained at hourly intervals for 10 h. TRL were isolated from bihourly plasma samples by ultracentrifugation (d less than 1.006 g/ml) and apo(a) was measured by radioimmunoassay. Total plasma apo(a) concentration did not change after the meal. However, TRL apo(a) increased significantly (0 h: 3 +/- 1, 4 h: 30 +/- 7 U/l; p less than 0.001) and 'd greater than 1.006' apo(a) decreased (0 h: 267 +/- 56, 4 h: 231 +/- 50 U/l; P less than 0.05). Similar postprandial changes were observed in apoB concentration (TRL apo B at 0 h: 10.3 +/- 1.5, 4 h: 13.6 +/- 1.7 g/l, P less than 0.001, 'd greater than 1.006' apoB at 0 h: 118 +/- 7, 4 h: 110 +/- 7 g/l, P less than 0.001). In the fasted state 2.0 +/- 1.0% and in the fed state (4 h postprandially) 16.0 +/- 4.6% of total plasma apo(a) was found in the TRL fraction. Eleven subjects had less than 10% of total apo(a) in TRL, 5 had 25% or more apo(a) in TRL in the fed state. Postprandial increase in TRL apo(a) was significantly correlated (r = 0.75, P less than 0.001) with increase in plasma triglycerides. TRL apo(a) concentration in the fed state was not correlated with total fasting cholesterol, triglyceride, apo(a) or HDL cholesterol concentration. We conclude that in some individuals, TRL apo(a) makes a significant contribution to total plasma apo(a) concentration in the fed state.     

The effect of apolipoprotein E isoform difference on postprandial lipoprotein in patients matched for triglycerides, LDL-cholesterol, and HDL-cholesterol.

The postprandial response to three test meals provided during a single day was investigated in subjects with either the apo E3/3 phenotype (n = 8), or the apo E4/3 phenotype (n = 4), who had LDL-C greater than 160 mg/dl. Vitamin A (60,000 U/m2) was ingested with the first meal and retinyl palmitate determined four hours later. Triglyceride and total cholesterol concentration were determined on whole plasma and total cholesterol and free cholesterol determined following single spin ultracentrifugation (d less than 1.006 g/ml) and dextran precipitation of the d greater than 1.006 fraction to separate apoprotein-B containing lipoproteins. Fasting values revealed significantly lower HDL-cholesterol ester (p less than 0.03) and HDL3-cholesterol ester (p less than 0.03) and significantly greater HDL-free cholesterol (p less than 0.03) and HDL3-free cholesterol (p less than 0.02) in subjects with the E4/3 phenotype. Four hour postprandial HDL and HDL3 cholesterol ester increased significantly more (p less than 0.05) in E4/3 patients and HDL and HDL3 free cholesterol decreased significantly more (p less than 0.05) in E4/3 subjects. Eight-hour postprandial change values maintained the significant HDL3-cholesterol ester and free cholesterol difference, and, revealed a significantly greater triglyceride rich lipoprotein cholesterol ester reduction (p less than 0.01) in the E4/3 group. Individuals with the apolipoprotein E4/3 phenotype reveal significant differences in postprandial lipemia compared to individuals with the E3/3 phenotype, and, postprandial lipemia following multiple meals reveals differences not apparent from responses to a single meal.     

Basal and postprandial serum-promoted cholesterol efflux in normolipidemic subjects: Importance of fat mass distribution.

Excess of adipose tissue may affect the reverse cholesterol transport mediated by high-density lipoprotein (HDL). Impairments in this system may be one possible factor favoring atherosclerosis development in obesity. To investigate if gender and regional fat mass distribution independently influence reverse cholesterol transport (RCT), we studied in vitro the capacity of serum to promote the cell cholesterol efflux. Measurements were performed both in the fasting state and in the postprandial state, a setting known to stimulate cholesterol transport and altered in obesity. Thirteen obese women with an android phenotype, waist-to-hip ratio (WHR): 0.98 to 0.85 and 51 normal-weight subjects: 25 women and 26 men, with a similar WHR range: 0.96 to 0.67, were recruited. All the participants were normolipoproteinemic in the fasting state and were given an oral fat load. Blood samples were taken before giving the oral fat load and after every 2 hours. The measurements of the ability of serum to promote cholesterol efflux from cells were performed using 3H-cholesterol labeled Fu5AH hepatoma cells in the fasting state 6 and 8 hours after the lipid rich meal. Incremental serum triglyceride (TG), area under the curve (iAUC) and AUC of retinyl palmitate (RP) for the obese women and nonobese subjects were similar. Basal cholesterol efflux was reduced in obese women compared with normal-weight women (26.75% +/- 3.1% v 30.81% +/- 4.2%, P =.004). However, the magnitude of cholesterol efflux promoted by whole serum increased similarly in all the groups. In the subjects with similar WHR, no gender difference was observed in the postprandial TG response and in the first step of RCT. Multivariate regression analyses indicated that plasma HDL-cholesterol (HDL-C) concentration is the best predictor of cholesterol efflux in the fasting state with an independent mild additive effect of WHR. Conversely, postprandial efflux appeared to be mostly related to the WHR with a mild additive effect of HDL-C. Our results indicate that alterations in the first step of RCT can occur in normolipidemic obese subjects and are tightly associated with the abdominal distribution of fat mass. Android obesity in women brings them to the level of men with respect to RCT.     

Effects of acarbose on serum lipoproteins in healthy individuals during prolonged administration of a fiber-free formula diet

The effects of the disaccharidase inhibitor acarbose on serum lipoprotein lipid concentrations were investigated in healthy subjects during prolonged feeding of a fiber-free formula diet. Acarbose was shown to decrease cholesterol and fasting triglyceride concentrations, whereas the postprandial increment of triglycerides was not diminished. The response of fasting triglycerides to acarbose treatment appeared to be related to dietary fat intake, but not to the drug-induced reduction of postprandial glucose and insulin concentrations. Both the triglyceride and the cholesterol lowering efficacy were less pronounced with a higher amount of saturated fat than with a lower intake of fat mainly composed of polyunsaturated fatty acids. The decrease in total cholesterol was shown to be a consequence of a significant reduction in low density lipoprotein (LDL) cholesterol. Since high density lipoprotein (HDL) cholesterol concentrations remained unaltered, the ratio of HDL/LDL cholesterol changed in a beneficial way.     

Black-white differences in postprandial triglyceride response and postheparin lipoprotein lipase and hepatic triglyceride lipase among young men.

Black-white differences in serum triglycerides and high-density lipoprotein (HDL) cholesterol concentrations are known. However, the metabolic basis for these differences is not clear. This study determined the magnitude of postprandial triglyceride concentrations, lipoprotein lipase and hepatic triglyceride lipase activities in postheparin plasma, and serum lipid and lipoprotein cholesterol concentrations in healthy young adult black men (n = 22) and white men (n = 28). Postprandial triglyceride concentrations were measured at 2, 3, 4, 5, 6, and 8 hours after a standardized test meal. Serum lipid and lipoprotein cholesterol concentrations were similar between the races in this study sample. However, incremental (above basal) increases in triglycerides were significantly greater in white men versus black men at 2 hours (P = .01) and tended to be greater at 3 hours (P = .12) and 4 hours (P = .06) after the fat load. In a multivariate analysis that included age, race, apolipoprotein E (apoE) genotype, fasting triglycerides, obesity measures, alcohol intake, and cigarette use, fasting triglycerides (P = .04) and, to a lesser extent, race (P = .07) were associated independently with the 2-hour incremental increase in triglycerides. The incremental triglyceride response correlated inversely with HDL cholesterol in both whites (r = -.38, P = .04) and blacks (r = -.59, P = .004). Lipoprotein lipase activity was higher (P = .049) and hepatic triglyceride lipase activity lower (P = .0001) in black men compared with white men; racial differences persisted after adjusting for the covariates. While lipoprotein lipase activity tended to associate inversely with the postprandial triglyceride concentration in both races, hepatic triglyceride lipase activity tended to correlate positively in whites and inversely in blacks. These results suggest that compared with whites, blacks may have an efficient lipid-clearing mechanism that could explain the black-white differences in lipoproteins found in the population at large.     

Impairment of endothelial function after a high-fat meal in patients with coronary artery disease.

OBJECTIVE: To determine the effect of postprandial lipid changes on endothelial function in patients with coronary artery disease (CAD) after a high-fat meal. METHODS: We studied 50 CAD patients and 25 control participants, who were all normocholesterolemic. Flow-mediated vasodilatation of the brachial artery was evaluated by the high-resolution ultrasound technique before and after a single high-fat meal (800 calories; 50 g fat). RESULTS: Postprandial serum triglyceride level increased significantly at 2-7 h and mean flow-mediated vasodilatation was impaired significantly (from 4.22 +/- 0.44 to 2.75 +/- 0.33%, P < 0.01) for 75 subjects. The increment in 2 h serum triglyceride level correlated positively with the decrement in postprandial flow-mediated vasodilatation (r = 0.459, P < 0.01). Postprandial triglyceride level was significantly higher in CAD patients than in control participants. Flow-mediated vasodilatation was significantly impaired in CAD patients (from 3.04 +/- 0.39 to 1.69 +/- 0.23%, P < 0.01) and control participants (from 6.58 +/- 0.52 to 4.87 +/- 0.19%, P < 0.05) after a high-fat meal. The impairment of flow-mediated dilatation was more severe in CAD patients (44.41%) than in control participants (25.99%, P < 0.01). CONCLUSION: Postprandial endothelium-dependent vasodilatation after a single high-fat meal was severely impaired in normocholesterolemic CAD patients and control participants. The disordered postprandial metabolism of triglyceride-rich lipoproteins may play an atherogenic role by inducing endothelial dysfunction.     

Postprandial remnant-like lipoproteins in hypertriglyceridemia.

It has been proposed that remnants of chylomicrons and very-low-density lipoproteins (VLDL) are atherogenic. We have used an immunochemical method to isolate remnant-like particles (RLP) and measured them in terms of their cholesterol and triglycerides (TG). RLP consist of apoB-48-containing triglyceride-rich lipoproteins and remnant-like VLDL containing apoB-100. The study aim was to look for information from postprandial RLP data that could not be known from other markers of triglyceride-rich lipoproteins and fasting TG and RLP data alone. A total of 41 subjects were studied. Eight subjects had hypertriglyceridemia (HTG) and low high-density lipoprotein (HDL), 14 had combined hyperlipidemia (CH), 5 had the apo E2/2 genotype receiving gemfibrozil, 10 were normolipidemic (NL) controls, and 4 had hypercholesterolemia. As a whole group, there was correlation among 1) fasting TG, RLP cholesterol (RLP-C), and RLP-TG but not VLDL apo B100, VLDL apo B48 and their respective postprandial responses measured as incremental area under the curve (IAUC), 2) fasting TG and postprandial IAUC of RLP-C and RLP-TG, 3) RLP-C IAUC, RLP-TG IAUC, and TG IAUC, retinyl palmitate (RP) IAUC, and VLDL apo B48 IAUC but not VLDL apo B100 IAUC. The HTG/low HDL-C and CH groups had higher IAUC for RLP-C, RLP-TG, TG, and RP than the NL group. Fasting and postprandial RLP were triglyceride enriched in the HTG/low HDL-C group and to a lesser extent in the CH group. The HTG/low HDL-C and CH groups had a delay in their RLP-C but not RLP-TG peaks suggesting a delay in hepatic clearance of RLP and/or a protracted period of lipolysis and/or processing of RLP. The fasting and postprandial RLP-C/RLP-TG and RLP-C/TG ratios were elevated in the apo E2/2 group in spite of gemfibrozil therapy. The increment in postprandial RLP was, however, not exaggerated. Our data indicate that 1) postprandial RLP lipemia is enhanced in HTG subjects when compared with NL subjects, 2) postprandial RLP lipemia is proportional to fasting RLP and TG levels and mirrors, to a large extent, increases in postprandial TG, RP, and VLDL apo B48 but not VLDL apo B100, 3) there are compositional differences in fasting and postprandial RLP in the three forms of HTG studied, RLP being triglyceride enriched in the HTG/low HDL-C group and to a lesser extent in the CH group, and cholesterol-enriched in the apo E2/2 group, and 4) apo E2/2 subjects had high fasting and postprandial RLP-C concentrations in spite of being on treatment with gemfibrozil and having normal fasting and postprandial TG concentrations.     

Insulin-like growth factor-I lowers fasting and postprandial triglyceride levels without affecting chylomicron clearance in healthy men

OBJECTIVES: To study whether IGF-I treatment alters the postprandial lipid and lipoprotein metabolism. DESIGN: Randomized, crossover study. SETTING: University Hospital, Zürich, Switzerland. SUBJECTS: Seven young healthy male subjects (aged 27+/-4 years, body mass index (BMI) 21.8+/-1.7 kg m(-2)). INTERVENTIONS: Each subject was studied two times at 2-week intervals, treated with saline 0.9% (S) and IGF-I (8 microg kg(-1) h(-1)) by a continuous subcutaneous infusion. 60 h after the start of treatment a vitamin A loading test was performed after an overnight 12-h fast. MAIN OUTCOME MEASURES: Glucose, insulin, total and free IGF-I, FFA, triglycerides and retinyl palmitate, total cholesterol, HDL and LDL cholesterol, lipoprotein (a) and apolipoprotein B were measured in serum before and after the fatty meal. RESULTS: Total IGF-I levels rose from 29.0+/-3.3 nmol L(-1) to 113.3+/-9.0 nmol L(-1) (P<0.02) and free IGF-I from 0.24+/-0.05 to 1.08+/-0.28 nmol L(-1) (P<0.02) during IGF-I treatment. IGF-I administration reduced insulin concentrations by 50% (P<0.02), as assessed by the area under the curve. Serum triglyceride levels were significantly lower at baseline and after the fat load during IGF-I treatment (P<0.02), whereas the retinyl palmitate concentrations in chylomicron and nonchylomicron lipoprotein fractions were similar during both treatment periods. CONCLUSIONS: IGF-I treatment reduces the triglyceride levels most probably by decreasing insulin secretion and the production of VLDL particles, and possibly by increasing their turnover. IGF-I treatment has no significant effect on the metabolism of intestine-derived triglyceride-rich lipoproteins after a high fat meal in healthy young men.     

High-monounsaturated fat, olive oil-rich diet has effects similar to a high-carbohydrate diet on fasting and postprandial state and metabolic profiles of patients with type 2 diabetes

Whether metabolic control in type 2 diabetes mellitus (DM) is best achieved with the traditional high-carbohydrate (CHO), low-fat diet or a low-CHO, high-fat diet is still controversial. In a randomized crossover study, we compared the effects of a low-fat (30% of daily energy) diet and a high-fat (40% of daily energy), high-monounsaturated-fat diet for 6 weeks each on fasting and postprandial glucose, insulin, and lipoprotein concentrations in 12 patients with well-controlled type 2 DM (fasting blood glucose, 176 +/- 54 mg/dL; hemoglobin A1c, 6.4% +/- 0.7%) and no overt dyslipidemia (serum total cholesterol, 235 +/- 43 mg/dL; triglycerides, 180 +/- 63 mg/dL). Home-prepared foods were used and olive oil was the main edible fat, accounting for 8% and 25% of daily energy requirements in the low-fat and high-fat diets, respectively. For postprandial studies, the same mixed meal containing 36% fat was used in both dietary periods. Body weight and fasting and 6-hour postprandial blood glucose, insulin, and lipoprotein levels were similar after the two diets. The mean incremental area under the curve of serum triglycerides 0 to 6 hours after the challenge meal, adjusted for baseline levels, did not change significantly after the high-fat diet compared with the low-fat diet (1,484 +/- 546 v 1,714 +/- 709 mg x 6 h/dL, respectively, P = .099). Mean postprandial triglyceride levels at 6 hours were increased about 2 times over fasting levels and were still greater than 300 mg/dL after either diet. A diet high in total and monounsaturated fat at the expense of olive oil is a good alternative diet to the traditional low-fat diet for patients with type 2 DM. However, ongoing postprandial hypertriglyceridemia with either diet points to the need for other therapies to decrease triglyceride-rich lipoproteins (TRL) and the inherent atherogenic risk in type 2 diabetics.     

Postchallenge plasma lipoprotein retinoids: chylomicron remnants in endogenous hypertriglyceridemia

This study was conducted to determine whether chylomicron remnants accumulate in the plasma of patients with "endogenous" hypertriglyceridemia. Retinyl esters were used as markers of chylomicrons and chylomicron remnants since they are carried mainly if not exclusively by lipoproteins of intestinal origin. Seventy-six fasting normotriglyceridemic and hypertriglyceridemic patients were studied 12 to 15 hours after ingesting 25,000 IU of vitamin A. Plasma retinol and retinyl esters were measured by reversed-phase high-performance liquid chromatography. Chylomicronemia was assessed by flotation at unit gravity and by chylomicron flocculation in 3% polyvinylpyrrolidone. Plasma lipids, retinoids, lipoprotein cholesterol, and the electrophoretic mobility of very-low density lipoproteins were determined in a subset of 36 subjects. Progressively elevated plasma retinyl ester concentrations were observed among patients with mild, moderate, and severe hypertriglyceridemia. All subjects with fasting chylomicronemia had retinyl ester retention. The majority of subjects with mild or moderate hypertriglyceridemia (predominantly type IV hyperlipoproteinemia) also had elevated plasma concentrations of retinyl esters. Total plasma retinyl ester and plasma triglyceride concentrations correlated significantly (rs = 0.721, P less than 0.001) in nonchylomicronemic subjects. In addition, total plasma retinol concentrations were mildly elevated among hypertriglyceridemic subjects because retinol, as well as retinyl esters, is transported by triglyceride-rich lipoproteins. If lipoprotein remnants are atherogenic in man, then chylomicron remnant retention may accelerate atherogenesis in hypertriglyceridemic individuals.     

Differences in postprandial concentrations of very-low-density lipoprotein and chylomicron remnants between normotriglyceridemic and hypertriglyceridemic men with and without coronary heart disease

It has been suggested that the postprandial elevation of plasma triglycerides is more closely linked to coronary heart disease (CHD) than the fasting triglyceride level. However, the postprandial situation is complex, as hepatogenous triglyceride-rich lipoprotein (TRL) particles (apolipoprotein [apo]B-100 and very-low-density lipoprotein [VLDL]) are mixed in the blood with apoB-48-containing lipoproteins secreted from the intestine. To analyze the relative proportion of liver-derived and intestinal apoB-containing TRL in subjects with and without CHD, we performed standardized oral fat-loading tests in young survivors of myocardial infarction, a large proportion of whom are hypertriglyceridemic (HTG), as well as sex- and population-matched healthy control subjects. A special effort was made to recruit healthy HTG subjects as controls for the HTG patients. Fasting plasma triglycerides (3.74+/-1.35 v3.01+/-0.83, NS), low-density lipoprotein (LDL) cholesterol, and VLDL lipids, and apoB-100 and apoB-48 content at Svedberg flotation rate (Sf) 60-400, Sf 20-60, and Sf 12-20 did not differ between HTG patients (n = 10) and HTG controls (n = 14). Normotriglyceridemic (NTG) patients (n = 15) had higher fasting plasma triglycerides (1.44+/-0.39 v 0.98+/-0.33 mmol/L, P < .05) and LDL cholesterol (4.07+/-0.71 v 3.43+/-0.64, P < .05) than NTG controls (n = 34). The triglyceride elevation was accounted for by a higher level of small VLDL (apoB-100 in the Sf 20-60 fraction, 52+/-17 v29+/-20 mg/L, P < .05). HTG patients responded with clearly elevated plasma triglycerides in the late postprandial phase, ie, 7, 8, and 9 hours after fat intake. Essentially, this was explained by a retention of large VLDL particles, since HTG patients exhibited no major differences in apoB-48 concentrations in the Sf > 400, Sf 60-400, and Sf 20-60 fractions but showed marked differences in the level of apoB-100 at Sf 60-400 (large VLDL) 9 hours after fat intake when compared with HTG controls (101+/-13 v 57+/-5 mg/L, P < .01). NTG patients were characterized by a more rapid increase of large VLDL in the early postprandial state, ie, 3 hours after fat intake, with a mean increase from baseline to 3 hours of 24.1+/-6.7 mg/L for NTG patients and 11.8+/-2.0 mg/L for controls (P < .05). ApoB-48 levels were also slightly higher, but all TRL parameters returned to baseline within 9 hours after fat intake. In conclusion, elevated triglyceride levels in the postprandial state in CHD patients are explained to a large extent by the accumulation of endogenous TRL. This suggests that the postprandial dyslipidemia encountered in CHD is more dependent on a failure of regulation of endogenous TRL versus the exogenous TRL species.     

Elevated high-density lipoprotein cholesterol in endurance athletes is related to enhanced plasma triglyceride clearance

We compared the clearance rate (K2) of plasma triglycerides (TG) following the intravenous (IV) infusion of a fat emulsion in 13 male endurance athletes (age 33 +/- 5.6 years, mean +/- SD) and 12 sedentary men (33 +/- 5.6 years). The athletes had lower fasting triglycerides (TG) (75 +/- 30.4 mg/dL v 125 +/- 52.5 mg/dL) and higher high-density lipoprotein (HDL) cholesterol concentrations (64 +/- 16.2 mg/dL v 42 +/- 9.4 mg/dL) than the sedentary subjects (P less than .01 for all). The higher HDL concentrations were due to increases in both the HDL2 and HDL3 subfractions. K2 in the athletes was 92% higher than that in the sedentary men (4.8 +/- 2.3%/min v 2.5 +/- 0.7%/min, P less than .01), but there was no difference in postheparin lipoprotein lipase activity (LPLA) between the groups (P greater than .05). K2 was positively correlated with LPLA (r = .51) and inversely related to fasting TG concentrations (r = -.73, P less than .01 for both). Furthermore, K2 was directly related to HDL (r = .75), HDL2 (r = .72), and HDL3 (r = .60) cholesterol concentrations (P less than .01 for all). These data suggest that the low TG levels in endurance athletes result at least in part from increased TG removal and that the elevated HDL concentrations of endurance athletes are related to enhanced fat clearance.     

Atorvastatin improves postprandial lipoprotein metabolism in normolipidemlic subjects

Atorvastatin is a potent HMG-CoA reductase inhibitor that decreases low-density lipoprotein (LDL) cholesterol and fasting triglyceride concentrations. Because of the positive association between elevated postprandial lipoproteins and atherosclerosis, we investigated the effect of atorvastatin on postprandial lipoprotein metabolism. The effect of 4 weeks of atorvastatin therapy (10 mg/day) was evaluated in 10 normolipidemic men (30+/-2 yr; body mass index, 22+/-3 kg/m2; cholesterol, 4.84+/-0.54 mmol/L; triglyceride, 1.47+/-0.50 mmol/L; high-density lipoprotein cholesterol, 1.17+/-0.18 mmol/L; LDL-cholesterol, 3.00+/-0.49 mmol/L). Postprandial lipoprotein metabolism was evaluated with a standardized fat load (1300 kcal, 87% fat, 7% carbohydrates, 6% protein, 80,000 IU vitamin A) given after 12 h fast. Plasma was obtained every 2 h for 14 h. A chylomicron (CM) and a chylomicron-remnant (CR) fraction was isolated by ultracentrifugation, and triglycerides, cholesterol, apolipoprotein B, apoB-48, and retinyl-palmitate were determined in plasma and in each lipoprotein fraction. Atorvastatin therapy significantly (P < 0.001) decreased fasting cholesterol (-28%), triglycerides (-30%), LDL-cholesterol (-41%), and apolipoprotein B (-39%), whereas high-density lipoprotein cholesterol increased (4%, not significant). The area under the curve for plasma triglycerides (-27%) and CR triglycerides (-40%), cholesterol (-49%), and apoB-48 (-43%) decreased significantly (P < 0.05), whereas CR retinyl-palmitate decreased (-34%) with borderline significance (P = 0.08). However, none of the CM parameters changed with atorvastatin therapy. This indicates that, in addition to improving fasting lipoprotein concentrations, atorvastatin improves postprandial lipoprotein metabolism presumably by increasing CR clearance or by decreasing the conversion of CMs to CRs, thus increasing the direct removal of CMs from plasma.