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【摘要】
Objectives- Whereas postprandial hyperlipidemia is a well-described feature of insulin-resistant states and type 2 diabetes, no previous studies have examined intestinal lipoprotein production rates (PRs) in relation to hyperinsulinemia or insulin resistance in humans.
Methods and Results- Apolipoprotein B-48 (apoB-48)-containing lipoprotein metabolism was examined in the steady-state fed condition with a 15-hour primed constant infusion of [D3]- L -leucine in 14 nondiabetic men with a broad range of body mass index (BMI) and insulin sensitivity. To examine the relationship between indices of insulin resistance and intestinal lipoprotein PR data were analyzed in 2 ways: by correlation and by comparing apoB-48 PRs in those whose fasting plasma insulin concentrations were above or below the median for the 14 subjects studied (60 pmol/L). ApoB-48 PR was significantly higher in hyperinsulinemic, insulin-resistant subjects (1.73±0.39 versus 0.88±0.13 mg/kg per day; P <0.05) and correlated with fasting plasma insulin concentrations ( r =0.558; P =0.038), despite great heterogeneity in apoB-48 kinetic parameters, particularly among the obese subjects. There was no significant difference in clearance of apoB-48 between the 2 groups, nor was there a significant correlation between apoB-48 fractional clearance rate and fasting insulin or homeostasis model assessment-insulin resistance.
Conclusions- These are the first human data to conclusively demonstrate that intestinal apoB-48-containing triglyceride-rich lipoprotein PR is increased in hyperinsulinemic, insulin-resistant humans. Intestinal lipoprotein particle overproduction is a newly described feature of insulin resistance in humans.
In the present study, we investigated whether intestinal lipoprotein particle production rate is related to indices of insulin resistance in humans. ApoB-48-containing lipoprotein metabolism was examined in 14 nondiabetic men with a broad range of BMI and insulin sensitivity. We demonstrate that intestinal apoB-48-containing TRL production rate is increased in hyperinsulinemic, insulin-resistant humans.
【关键词】 lipoprotein intestinal insulin resistance hyperinsulinemia stable isotype kinetic triglyceride
Introduction
Dyslipidemia is a prominent feature of insulin resistance and obesity and may contribute to increased risk of cardiovascular disease. 1 Dyslipidemia associated with these conditions is typically characterized by elevated plasma triglyceride (TG) concentration, low high-density lipoprotein (HDL) cholesterol level, and increased proportion of small, dense, low-density lipoprotein (LDL) particles. 1 It is also now well established that insulin-resistant and type 2 diabetic individuals have elevated levels of TG-rich lipoprotein (TRL) particles and remnants, including intestinally derived apolipoprotein B-48 (apoB-48)-containing TRL, in both the fasted and postprandial states. 2-6 The latter is of particular clinical importance because these remnant lipoprotein particles may impair endothelial function and may enter and be retained in the subendothelial space of the vascular wall, thus potentially accelerating the development of atherosclerotic lesions. 7-9 Indeed, elevated intestinally derived remnant lipoproteins have been associated with increased cardiovascular disease. 10 It is therefore of considerable clinical interest to better understand the mechanism(s) leading to TRL accumulation so that strategies can be formulated to reduce their plasma levels.
Fasting hypertriglyceridemia in insulin resistance has been attributed largely to apoB-100-containing TG-rich very low-density lipoprotein (VLDL) overproduction and secretion by the liver, with a lesser contribution from impaired VLDL removal. 11 In addition, postprandial lipemia has been well described in insulin-resistant humans and in animal models of insulin resistance. Indeed, in humans, insulin resistance is associated with postprandial elevation of apoB-48-containing TRL particles, and fasting hypertriglyceridemia predicts this abnormal postprandial response. 2,12 However, the precise mechanisms underlying this overaccumulation of intestinal lipoproteins in insulin-resistant states are not yet fully understood. To date, studies have focused on the delayed clearance of TRL remnants, attributed to: (1) impaired lipolysis attributable to decreased lipoprotein lipase activity, (2) modified lipoprotein composition, (3) reduced remnant recognition by hepatic receptors, or (4) an expanded pool of VLDL leading to competition for removal between VLDL and chylomicrons. 13-15 Whether exaggerated postprandial lipemia also involves intestinal overproduction of chylomicrons and remnants in addition to a delayed clearance has not been fully investigated, and little information is available regarding the factors that regulate apoB-48-containing lipoprotein production in insulin-resistant humans. We have recently shown that diet-induced insulin resistance in Syrian Golden hamsters is associated with a marked increase in intestinal lipoprotein production rate (PR) in both the fasting and the fed states, 16-18 and insulin sensitization partially reversed apoB-48-containing lipoprotein oversecretion. 17,18 However, to date, the relevance of these findings to humans is not known, and there is no evidence that insulin resistance is associated with increased intestinal apoB-48-containing lipoprotein particle overproduction in humans. Therefore, the aim of the present study was to determine whether intestinal TRL-apoB-48 production or clearance is perturbed in men with features of hyperinsulinemia and insulin resistance.
Materials and Methods
Subjects
Fourteen healthy, normoglycemic men, 31 to 60 years of age, with a broad range of body weights (from 64.3 to 134.3 kg), BMIs (from 20.0 to 41.6 kg/m 2 ), and waist girth (from 77 to 135 cm) participated in the study. Subjects were included if their total plasma cholesterol was 5.5 mmol/L, HDL cholesterol 0.8 mmol/L, LDL cholesterol 4.0 mmol/L, and TGs 4.0 mmol/L. All participants were nonsmokers, and none had a previous history of cardiovascular disease or systemic illness. None had any surgical intervention within 6 months before the studies. No subject was taking medications, and all had a normal 75-g oral glucose tolerance test performed immediately before enrollment in the study. An index of insulin sensitivity was derived from fasting insulin and glucose concentrations using the homeostasis model assessment-insulin resistance (HOMA-IR) method, as described previously. 19
The research ethics board of the University Health Network, University of Toronto, approved the study, and all subjects gave written informed consent before their participation.
Lipoprotein Kinetic Studies
After a 14-hour overnight fast, an intravenous catheter was inserted into a superficial vein in each forearm: 1 for infusion and 1 for sampling. After the withdrawal of a baseline sample, the subject was instructed to ingest 15 identical hourly volumes of a liquid food supplement called Boost (Mead Johnson Nutritionals), each equivalent to one fifteenth of their total daily caloric needs, using the Harris Benedict equation to determine the total energy requirements (based on height, weight, age, and activity factors). 20,21 Boost contains 20% of total calories from protein, 62% carbohydrates, and 18% fat (of the total energy derived from fat, 25% was polyunsaturated fat, 65% monounsaturated fat, and 13% saturated fatty acid). Three hours later (at 10 AM ), all subjects received a primed constant infusion (10 µmol/kg bolus followed by 10 µmol/kg per hour for 12 hours) of deuterium-labeled leucine 22 ( L -[5,5,5- 2 H 3 ]-leucine; 98%; Cambridge Isotope Laboratories) to enrich apoB-48 in intestinally derived lipoprotein particles and to calculate the production and clearance rates of the particles as described previously (see the online supplemental methods, available at http://atvb.ahajournals.org). 23 Blood samples were collected at 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 7 hours, 9 hours, 10 hours, 11 hours, and 12 hours into sterile tubes containing 0.1% EDTA and 10 µL preservative (containing 17 µg/ ml aprotinin and 0.2 mg sodium azide) and placed immediately on ice.
Sample Processing, Laboratory Measurements, Analysis of Lipoprotein Production and Clearance Rates, and Statistical Analysis
Please see the online data supplement, available at http://atvb.ahajournals.org.
Results
Demographic and Biochemical Characteristics of Subjects
As a method of analyzing the data to determine whether apoB-48 PRs are increased in those with features of insulin resistance, subjects were divided into 2 groups based on their fasting plasma insulin concentration. The second method of data analysis was to examine correlations between apoB-48 PR and indices of insulin resistance, as reported below. By design, subjects in the higher-insulin group (above the median of 60 pmol/L) had a mean (±SEM) insulin level of 128.9±8.9 pmol/L compared with the lower-insulin group, which had a mean insulin of 45.4±4.4 pmol/L ( P =0.000001).Data in the tables are presented separately for these 2 arbitrarily segregated groups of subjects. Subjects with higher fasting plasma insulin concentrations had significantly elevated waist circumference and HOMA-IR compared with those with lower insulin levels ( Table 1 ). BMI and body weight were elevated in the hyperinsulinemic group, but the difference was not significant. Fasting blood glucose and free fatty acid (FFA) levels were not significantly different.
TABLE 1. Demographic and Biochemical (Fasting Plasma Metabolites, Hormone, and Lipids) Characteristics of Subjects With Insulin Above and Below the Median
Plasma and TRL Lipid and Apolipoprotein Concentrations
Plasma total cholesterol, HDL cholesterol, and LDL cholesterol were not significantly different between individuals with fasting insulin levels above or below the median ( Table 2 ). Fasting TG levels tended to be higher (1.6-fold higher) (high-insulin group 1.59±0.26 versus low-insulin group 1.09±0.08 mmol/L; P =0.121), although the difference was not statistically significant.
TABLE 2. Plasma Lipids and TRL TG and ApoB Concentrations in the Fasted State and Postprandial TRL ApoB-48 PR and FCR in Subjects With Insulin Above and Below the Median
In the fasting state, TRL TGs (TRL-TGs) tended to be higher (1.6-fold) in the high-insulin group and were positively correlated with plasma insulin concentrations ( r =0.692; P =0.006) and HOMA-IR ( r =0.697; P =0.006; Table 2 ). TRL apoB-48 concentrations tended to be higher in the higher versus the lower-insulin group, but the difference was not statistically significant (0.66±0.15 versus 0.39±0.05 mg/dL; P =0.15; Table 2 ).
Plasma and TRL-TGs and TRL ApoB-48 Concentrations in Response to Feeding
TRL-TGs were higher in the higher-insulin group compared with the lower-insulin group throughout the kinetic study ( Figure 1 A; mean TRL-TGs 1.72±0.10 versus 1.12±0.08 mmol/L; P =0.0005). As expected, TRL-TGs during feeding were positively correlated with fasting plasma TGs ( r =0.609; P =0.021) and were significantly associated with fasting plasma insulin concentration ( r =0.890; P <0.001) and HOMA-IR ( r =0.843; P <0.001). As can be seen in Figure 1 B, no statistically significant difference in steady-state-fed TRL apoB-48 concentrations was found between the 2 groups (mean TRL-apoB-48 0.87±0.16 versus 0.74±0.11 mg/dL; P =0.481; in the higher versus the lower-insulin group, respectively). There was no significant change in VLDL, intermediate-density lipoprotein, LDL, or HDL cholesterol concentrations over the time course of the study (data not shown).
Figure 1. TRL-TG and TRL apoB-48 concentrations over the time course of the kinetic study. TRL-TG (A) and TRL apoB-48 (B) were measured throughout the 15-hour lipoprotein turnover study in subjects with low (<60 pmol/L; 60 pmol/L;; n=6) insulin levels. Time 0 hours was fasting, immediately before starting hourly ingestion of liquid formula as described in methods. Analysis of the kinetics of apoB-48 was performed between 3 and 15 hours (ie, over a 12-hour period). Values are mean±SEM for each group. Asterisks indicate difference between high- and low-insulin groups for each time point: * P <0.005 and ** P <0.001 as analyzed by ANOVA (the overall significance over the time being achieved for TRL-TG: P <0.0001; and for TRL apoB-48: P =0.0288).
Effects of Fasting Plasma Insulin Concentration and HOMA-IR on Intestinal Lipoprotein Production and Clearance Rates
The influence of fasting plasma insulin concentration on apoB-48-containing TRL metabolism during constant fat feeding was next examined by kinetic studies in patients using a 12-hour primed constant infusion of a stable isotope as described in the Methods. The clearance of TRL-apoB-48 tended to be higher in subjects with high-versus lower-insulin, but the difference was not statistically significant (higher-insulin group 4.83±1.27 versus lower-insulin group 3.23±0.84 pool per day; P =0.29; Table 2; Figure 2 B). However, TRL-apoB-48 PR was significantly higher in the group with higher insulin levels and HOMA-IR score ( Table 2; Figure 2 A).
Figure 2. TRL apoB-48 production and FCRs in subjects with high- vs low-insulin levels or high vs low HOMA-IR. ApoB-48 PR (A) and FCR (B) were determined at steady-state in subjects with low (<60 pmol/L) insulin levels and HOMA-IR ( 2.3; n=6).
Correlation of TRL-Apo-B48 PR With Plasma Insulin and HOMA-IR
TRL-apoB-48 PR was positively correlated with fasting insulin concentration ( r =0.558; P =0.038) and tended to be correlated with HOMA-IR index ( r =0.515; P =0.059; Table 2 ). Because subjects within the higher-insulin group were overweight compared with those with lower insulin, we performed univariate ANOVAs to test whether body weight, BMI, and waist may have contributed to the effect of insulin level on TRL-apoB-48 PR. However, none of these parameters were found to influence our results ( P =0.219, P =0.426, and P =0.340, respectively). There was no association between TRL-apoB-48 fractional clearance rate (FCR) and either fasting insulin levels ( r =0.295; P =0.306) or HOMA-IR ( r =0.314 and P =0.273, respectively).
Discussion
In the present study, apoB-48 PRs were found to be positively correlated with fasting insulin concentrations, despite great heterogeneity in apoB-48 kinetic parameters, particularly among the obese subjects. We also demonstrated a higher PR of intestinally derived apoB-48-containing lipoprotein particles in men with hyperinsulinemia and insulin resistance compared with those with lower insulin levels and greater insulin sensitivity. The clearance of apoB-48-containing lipoproteins in those with hyperinsulinemia and insulin resistance tended to be higher than in those with normoinsulinemia, although this difference was not significant, and there was no significant correlation between apoB-48 FCR and fasting insulin or HOMA-IR. Overproduction of intestinally derived apoB-48-containing lipoproteins appears to be a component of the dyslipidemia of hyperinsulinemic/insulin-resistant individuals.
An interesting finding of the present study was the lack of association between the clearance of apoB-48-containing TRL and insulin sensitivity indices. Other studies have suggested defective catabolism of intestinally derived TRL and remnant lipoprotein TG in insulin-resistant and obese individuals. 24-26 However, the design of those studies differed from ours in a number of respects, not least of which was that they examined TRL particle clearance in a non-steady-state condition after ingestion of an oral fat load. In that setting, the large influx of chylomicrons derived from the rapidly ingested fat load compete for clearance by lipoprotein lipase with endogenous VLDL, resulting in greater impairment in chylomicron clearance in those with even mild fasting hypertriglyceridemia, such as occurs with abdominal obesity and insulin resistance. In the present study, we assessed TRL apoB-48 production and clearance at steady-state plasma TRL-apoB-48 and TRL-TG concentrations induced by repeated, small-quantity liquid meals. Different findings between the studies may also be explained by the use of different methodological and modeling approaches. Most other studies have labeled the TG moiety of lipoprotein particles and examined TRL-TG clearance or modeled the area under the curve of plasma apoB-48 or plasma TG concentration after an oral fat load. TGs are contained in both intestinally derived as well as hepatically derived plasma lipoproteins, and there is no way of distinguishing the origin of TGs by this in vivo methodology. In the present study, we used a primed continuous infusion of deuterated leucine to label the apolipoprotein (apoB-48) moiety of the intestinally derived lipoprotein particles, allowing us to examine apoB-48 particle clearance rather than TRL-TG clearance. Others have used different approaches such as the measurement of 13 CO 2 appearance in breath after ingestion of a labeled chylomicron-like emulsion, which requires not only uptake of TRL-TG and remnant TG by the liver but also, and different from our method, subsequent metabolism of hydrolyzed fatty acids. 25,27 Using this method, Watts et al 28 failed to find a significant correlation between chylomicron remnant clearance and HOMA-IR in obese men. Studies performed using diabetic rats showed delayed clearance attributable to particle compositional changes with no change in apoB-48 concentration. 29,30 Our study by no means negates the finding that chylomicron and chylomicron remnant clearance is delayed after ingestion of a high-fat meal in those with even mild degrees of fasting hypertriglyceridemia, such as occurs in individuals with insulin resistance and type 2 diabetes. The fact that we did not demonstrate a defective clearance of apoB-48-containing lipoproteins in the present study may relate to the slow and modest rate of fat delivery to the intestine with frequent small liquid formula ingestion, which perhaps was insufficient to impair the clearance from the circulation of intestinally derived lipoproteins in those with hyperinsulinemia/insulin resistance. To our knowledge, PR of apoB-48-containing TRL has not been assessed directly in insulin-resistance states in humans to date, and our results represent the first human data to demonstrate higher apoB-48-TRL PRs in hyperinsulinemic individuals. We suggest that overproduction of TRL-apoB-48 in hyperinsulinemia may be an important contributor to postprandial hyperlipidemia in these conditions and may be an important cause of the accumulation of remnant lipoproteins even in the fasted state. This does not necessarily imply that it is the lipids secreted from the intestine per se that contribute directly to the hyperlipidemia of insulin-resistant states. An equally plausible explanation is that the increased numbers of circulating intestinally derived lipoprotein particles that result from higher PRs compete with hepatically derived lipoproteins for clearance mechanisms that become saturated postprandially, thereby impairing their removal and resulting in accumulation of lipoprotein particles of both hepatic and intestinal origin. The relative contributions of overproduction and defective clearance of intestinally derived lipoproteins to postprandial lipemia in insulin-resistant states is currently not known.
The volume of the liquid formula administered to maintain a constant fed state during the lipoprotein turnover study was adjusted for height, weight, and activity factors. Previous apoB-48 turnover studies performed in the constant fed state have also calculated and adjusted calorie/fat intake during the study based on the usual daily intake requirement of the subjects 31,32 or using the Harris Benedict equation 20,21 as we did. This allows us to study intestinal lipoprotein turnover during a fed state that is simulated to match the daily caloric intake of each study participant, making it closer to that subject?s "normal" physiology. Consequently, the total calorie and fat content ingested by the more obese hyperinsulinemic subjects was greater than that ingested by those with normoinsulinemia. Although we cannot exclude the possibility that this difference may have contributed to the observed differences in apoB-48 PRs between hyperinsulinemic and normoinsulinemic individuals, the caloric intake values and fat content of ingested liquid supplements were not correlated with fed TRL-TG levels ( r =0.468; P =0.091), TRL apoB-48 PR ( r =0.024; P =0.935), or TRL apoB-48 FCR ( r =0.033; P =0.910). Covariance analysis indicated that the feeding did not significantly influence the effect of insulin levels on any of the study parameters except the anticipated body weight, waist, and body weight.
The present study does not address the cellular mechanisms that underlie the overproduction of lipoproteins by the intestine in hyperinsulinemic, insulin-resistant humans. Nevertheless, previous studies from our group and those of others using animal models of insulin resistance provide important clues regarding potential mechanisms that may also be applicable to humans. For instance, we have reported that oversecretion of apoB-48-containing lipoprotein in fructose-fed insulin-resistant Syrian Golden hamsters in both the fasted and fed states is associated with enhanced intracellular stability of nascent apoB-48 in cultured primary enterocytes derived from these animals. 16,18 Moreover, this is paralleled by increased de novo lipogenesis in enterocytes. Several studies in humans have suggested that lipogenesis in the hepatocyte is increased in insulin resistance and contributes to the overproduction of VLDL TG. 33,34 It is tempting to speculate that increased intestinal de novo lipogenesis may also play a role in intestinally derived lipoprotein production in insulin resistance, perhaps making a more important contribution to the assembly and secretion of small, lipid-poor apoB-48-containing lipoproteins in the fasted state rather than in the fed state. Elevated FFA flux from adipose tissue to the liver in insulin-resistant states is considered to play an important role in diabetic dyslipidemia. 11 Insulin resistance-associated increased FFA flux is known to drive hepatic VLDL assembly and secretion. FFAs stimulate the hepatic synthesis and secretion of VLDL TG in vitro in HepG2 cells and cultured rat hepatocytes 35-37 and in humans. 38 Guo et al have recently shown that ex vivo incubation of hamster enterocytes with oleic acid leads to stimulation of intestinal apoB-48-containing particle production. 39 We have shown that an acute elevation of plasma FFAs in hamsters markedly increased the basal intestinal apoB-48 PR. 40 Although fasting FFA plasma levels were not significantly different in subjects with higher and lower insulin concentrations in the present study, fasting FFA concentrations are not a sensitive measure of total FFA flux from adipose tissue to liver. Further studies are required to evaluate whether elevated plasma FFAs drive intestinal lipoprotein production in humans, as has been demonstrated for hepatic VLDL secretion. 38
We have shown that intestinal lipid synthesis and transfer to lipoprotein particles is increased in insulin-resistant hamsters, at least in part via increased microsomal transfer protein (MTP) mass and activity and enhanced lipoprotein assembly and secretion. 16 MTP has also been shown to be increased in diabetic rats, 29 New Zealand rabbit, 41 and the desert gerbil Psammomys obesus. 42 In addition, humans carrying a common MTP gene polymorphism leading to increased MTP expression were found to have elevated accumulation of small apoB-48-containing lipoproteins in the postprandial state. 43 Along the same line, Lundahl et al have shown that polymorphism in the MTP promoter leading to increased transcriptional activity of the gene was associated with increased apoB-48 in the small TRL fraction after a fat meal. These results indicate that MTP polymorphisms may be linked to the generation of small TRL from the intestine. 44 Although we did not characterize the MTP promoter in our subjects, it is plausible that variation in the intestinal expression of MTP may influence postprandial TRL-apoB48 metabolism. Overproduction of hepatic VLDL in fructose-fed insulin-resistant hamsters has been associated with reduced hepatic insulin signaling as documented by increased protein-tyrosine phosphatise 1B levels, decreased phosphorylation of insulin receptors IRS-1 and IRS-2, as well as Akt and reduced phosphatidyl inositol-3kinase activity, 45,46 and this may determine whether apoB is targeted for secretion or degradation. Impaired insulin signaling in primary cultured enterocytes is associated with enhanced apoB-48 stability, lipoprotein particle assembly, and secretion. 47 Therefore, it appears that the mechanism leading to increased apoB-48-containing TRL in insulin resistance is complex and multifactorial.
It has long been assumed that intestinally derived lipoproteins mainly transport exogenous TG derived from food absorption. However, there is evidence to suggest that the intestine constitutively synthesizes smaller TRL particles 48 and maintains a basal level of apoB-48, even in the fasting state. 2 The current thinking is that chylomicron formation involves the formation of small, phospholipid-rich, TG-poor primordial particles in the membrane of the smooth endoplasmic reticulum, with subsequent core lipid expansion and particle transfer from the smooth endoplasmic reticulum to the golgi for secretion. 49 We have shown previously that hamster enterocytes have the capacity to secrete small, lipid-poor (HDL size) apoB-48-containing particles, and that in hamsters made insulin-resistant with fructose or high-fat feeding, there is a marked increase in TRL apoB-48 secretion not only in the fed but also in the fasted state. 16,18 We would have liked to examine TRL apoB-48 particle production in fasted humans, but in pilot studies, we were unable to accurately quantify apoB-48 PRs in fasted normolipidemic humans because of their extremely low plasma concentrations of apoB-48.
In the present study, individuals with higher insulin levels were overweight compared with the low-insulin group, and we cannot exclude that higher body weights may have contributed to the observed increase in TRL apoB-48 particle production or may have affected its clearance. However, ANOVA did not reveal any significant contribution of body weight, BMI, or waist girth on the effect of insulin on TRL apoB-48 production or FCRs.
In conclusion, the present report provides evidence that increased production of apoB-48 is characteristic of hyperinsulinemic men. Further studies are needed to explore the mechanisms underlying the increased production of intestinal lipoproteins in insulin-resistant states and to better determine the contribution of intestinal lipoproteins to atherosclerosis in this population.
Acknowledgments
This work was supported by funding from the Canadian Institutes for Health Research (MOP-43839). G.F.L. holds a Canada Research Chair in Diabetes and is a career investigator of the Heart and Stroke Foundation of Canada. B.L. holds a Canada Research Chair in Nutrition and Cardiovascular Health. H.D. is the recipient of a postdoctoral fellowship award from the Heart and Stroke Foundation of Canada. We are indebted to Patricia Harley, RN, for her assistance with subject recruitment and conducting the clinical protocol. This paper is dedicated to Kristine Uffelman, who contributed enormously to this work. Kristine passed away tragically in December 2005, before the publication of this study.
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作者单位：Departments of Medicine and Physiology (H.D., K.D.U., R.V., G.F.L.), Division of Endocrinology and Metabolism, University of Toronto, Ontario, Canada; Institut des nutraceutiques et aliments fonctionnels (B.L.), Université Laval, Québec, Canada; and Clinical Research Institute of Montr