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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-1603
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 1 264-269
Copyright © 2007 by The Endocrine Society

Association of Acylated and Nonacylated Ghrelin with Insulin Sensitivity in Overweight and Obese Postmenopausal Women

David H. St-Pierre, Antony D. Karelis, Lise Coderre, Florin Malita, Jonathan Fontaine, Diane Mignault, Martin Brochu, Jean-Philippe Bastard, Katherine Cianflone, Eric Doucet, Pascal Imbeault and Rémi Rabasa-Lhoret

Département de Nutrition (D.H.S.-P., F.M., J.F., D.M., R.R.-L.) and Médecine (L.C.), Université de Montréal, Montréal, Québec, Canada H3C 3J7; Département de Kinanthropologie (A.D.K.), Université du Québec à Montréal, Montréal, Québec, Canada H3C 3P8; Faculté d’Éducation Physique et Sportive (M.B.), Université de Sherbrooke, Sherbrooke, Québec, Canada J1K 2R1; Institut National de la Santé et de la Recherche Médicale U680 (J.-P.B.), Faculté de Médecine Saint-Antoine et Service de Biochimie et Hormonologie, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Université Pierre et Marie Curie, 75020 Paris, France; Centre de Recherche Hôpital Laval (K.C.), Université Laval, Québec, Canada G1K 7P4; and School of Human Kinetics (E.D., P.I.), Faculty of Health Sciences, University of Ottawa, Ottawa, Ontario, Canada K1N 6N5

Address all correspondence and requests for reprints to: Rémi Rabasa-Lhoret, M.D., Ph.D., Faculté de Médecine, Département de Nutrition, Université de Montréal, 2405 Chemin Cote Ste-Catherine, Pavillon Liliane de Stewart, Montréal, Québec, Canada H3T 1A8. E-mail: remi.rabasa-lhoret{at}umontreal.ca.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Objective: Ghrelin [acylated (AG) and nonacylated (NAG)] has been shown to play a pivotal role in the regulation of food intake and insulin sensitivity. It is presently unclear whether variation in insulin sensitivity is related to AG and NAG levels in obese individuals. To address this issue, we determined whether insulin-sensitive overweight or obese (ISO) and insulin-resistant overweight or obese (IRO) individuals display different total ghrelin (TotG), AG, and NAG profiles during a euglycemic/hyperinsulinemic clamp (EHC).

Design: Eighty-nine nondiabetic overweight and obese postmenopausal women underwent EHC to evaluate insulin sensitivity. Body composition and blood lipid profiles were assessed. Subjects within the highest tertile of insulin sensitivity were described as ISO (n = 31), whereas those within the lowest tertile of insulin sensitivity were considered as IRO (n = 29). Plasma TotG, AG, and NAG profiles were assessed by RIA at 0, 60, 160, 170, and 180 min during the EHC.

Results: TotG and NAG levels were significantly decreased for ISO and IRO individuals during the EHC, whereas only ISO subjects displayed a significant reduction of AG concentrations (P < 0.05). AG area under the curve value and the ratio of AG/NAG (fasting and area under the curve) were significantly decreased in ISO individuals. Furthermore, maximal reduction of TotG and AG concentrations was greater in ISO compared with IRO individuals (P < 0.05). Insulin sensitivity was significantly correlated with maximal reduction of TotG (r = 0.36; P < 0.01) and AG (r = 0.36; P < 0.05) concentrations.

Conclusion: The dysregulation of ghrelin secretion profiles during EHC is associated with insulin resistance. AG may contribute to the variation of insulin sensitivity in overweight or obese postmenopausal women.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GHRELIN, A PEPTIDE mainly derived from the stomach, plays important roles in the regulation of food intake as well as energy metabolism and storage (1). Emerging evidence suggests that nonacylated and acylated ghrelin forms (2) may induce different physiological and metabolic effects. Moreover, acylated ghrelin is the endogenous ligand of the GH secretagogue receptor 1a, whereas recent reports indicate that nonacylated ghrelin may interact with another uncharacterized receptor (3, 4, 5, 6). Interestingly, numerous studies have suggested that total ghrelin (nonacylated + acylated ghrelin) is closely linked to insulin resistance (7). In humans, acute [postprandial and euglycemic/hyperinsulinemic clamp (EHC)] and chronic (insulin resistance) hyperinsulinemic states are associated with decreased circulating total ghrelin levels (8, 9, 10). However, the regulation of acylated vs. nonacylated ghrelin in these conditions still remains poorly understood. In addition, as reported by McLaughlin et al. (11), insulin-sensitive individuals display higher fasting total ghrelin concentrations than insulin- resistant obese subjects. Furthermore, when compared with insulin-resistant obese subjects, insulin-sensitive normal-weight individuals display greater postprandial inhibition of total ghrelin levels (9). In a recent review, van der Lely et al. (12) have proposed that acylated ghrelin could possibly convey detrimental effects on insulin sensitivity. Meanwhile, Paik et al. (13) have shown that reductions of acylated ghrelin levels during an oral glucose tolerance test were correlated to insulin sensitivity in children suffering from Prader-Willi syndrome but not in normal obese children. The rationale to examine the relevance of nonacylated vs. acylated ghrelin comes from the observation indicating that under pharmacological concentrations, acylated ghrelin induces insulin resistance, whereas a combination of nonacylated and acylated ghrelin improves insulin sensitivity (14, 15). These previous results suggest that acylated ghrelin may act as a diabetogenic factor and therefore potentially modulate a deterioration of insulin sensitivity. Although the inhibition of total ghrelin has been shown under hyperinsulinemic conditions, specific modulations of nonacylated vs. acylated ghrelin remain to be examined.

A unique subpopulation of insulin-sensitive obese subjects has been previously described (16, 17). Evidence suggests that highly sensitive individuals may account for as much as 20–30% of the obese population (18, 19, 20, 21). Therefore, this population of insulin-sensitive overweight and obese subjects may be a useful model to understand the relationship between ghrelin and insulin sensitivity. The present study was therefore designed to evaluate fasting and insulin-stimulated total, nonacylated and acylated ghrelin circulating profiles in insulin-sensitive overweight and obese (ISO) and insulin-resistant overweight and obese (IRO) postmenopausal women. Thus, we hypothesized that ISO individuals would display a favorable ghrelin profile characterized by a decreased ratio of acylated over nonacylated ghrelin and by an increased capacity to inhibit both ghrelin forms during hyperinsulinemia (EHC).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The cohort consisted of 89 nondiabetic overweight or obese postmenopausal women between 46 and 73 yr old. Women were included in the study if they met the following criteria: 1) body mass index greater than 27 kg/m2; 2) FSH levels at least 30 U/liter; 3) sedentary lifestyle (<2 h/wk of structured exercise); 4) nonsmokers; 5) low to moderate alcohol consumption (<2 drinks per day); 6) absence of any known inflammatory disease; and 7) no use of hormone replacement therapy within the last 3 months. On physical examination or biological testing, all participants had no history or evidence of: 1) cardiovascular disease, peripheral vascular disease, or stroke; 2) diabetes (2-h serum glucose ≤ 11.0 mmol/liter after a 75-g oral glucose tolerance test); 3) orthopedic limitations; 4) uncontrolled thyroid or pituitary diseases; 5) infection (medical questionnaire examination and complete blood count); and 6) medication that could affect cardiovascular function and/or metabolism. The study was approved by the Université de Montréal Ethics Committee. After reading and signing the consent form, each participant was submitted to a series of tests.

EHC

The test began at 0730 h after a 12-h overnight fast following the procedure described by DeFronzo et al. (22). A catheter was introduced in the antecubital vein for the infusion of 20% dextrose and insulin (Actrapid, Novo-Nordisk, Toronto, Canada). The other arm was cannulated for sampling of arterial blood. Three basal samples of serum glucose and insulin were collected over 40 min. Then, insulin was infused at the rate of 75 mU/m2·min for 180 min. Serum glucose was measured every 10 min with a glucose analyzer (Beckman Instruments, Fullerton, CA) and maintained at fasting level with a variable infusion rate of 20% dextrose. Insulin sensitivity, estimated as glucose clearance, was calculated as the mean rate of glucose infusion measured during the last 30 min of the clamp steady state and is expressed as milligrams per minute x kilograms of fat free mass (FFM). Fasting serum glucose was determined using the mean of three basal values of serum glucose with a Beckman glucose analyzer (Beckman Instruments). Subjects with insulin sensitivity values in the upper tertile were classified as ISO, whereas subjects with insulin sensitivity values in the lower tertile were classified as IRO.

Blood samples

After an overnight fast (12 h), blood samples were collected at times 0, 60, 160, 170, and 180 min during the EHC. Blood samples were centrifuged at 3900 x g for 10 min at 4 C and kept at –80 C until further analyses were achieved. After centrifugation, acylated ghrelin blood samples were processed with 50 µl/ml 1 N HCl and 10 µl/ml phenylmethylsulfonyl to prevent degradation and loss of the octanoyl group on Ser3 of ghrelin. Plasma immunoreactive total (23) and acylated ghrelin (24) levels were measured in duplicate with a commercial RIA using 125I-labeled bioactive human acylated ghrelin as tracers and rabbit polyclonal antibody raised against full-length total ghrelin and against the Ser3-octanoylated portion of acylated ghrelin, respectively (Linco Research, St. Charles, MO). According to the supplier’s specifications, percentage inter- and intraassay coefficients of variation were less than 18% and 10% for total and acylated ghrelin, respectively. Nonacylated ghrelin values were calculated as total minus acylated ghrelin for each time of the EHC. Fasting serum samples were collected for total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, triglyceride, and insulin measurements. Serum blood glucose and the lipid profile were analyzed on the day of collection, whereas insulin samples were kept at –80 C until they were analyzed. Analyses were done on the COBAS INTEGRA 400 (Roche Diagnostic, Montréal, Canada) analyzer for total cholesterol, HDL-cholesterol, and triglycerides. Total cholesterol, HDL-cholesterol, and triglycerides were used in the Friedewald formula (25) to calculate LDL-cholesterol concentration. Serum insulin levels were determined in duplicate by RIA (Medicorp, Montréal, Canada).

Body composition

Body weight was measured using an electronic scale (Balance Industrielles, Montréal, Canada), and standing height was measured using a wall stadiometer (Perspective Enterprises Inc., Portage, MI). The body mass index [BMI: body weight (kilograms)/ height (meters)2] was then calculated. Lean body mass and fat mass were measured by dual energy x-ray absorptiometry (version 6.10.019; General Electric Lunar Corporation, Madison, WI).

Computed tomography (CT)

A GE High Speed Advantage CT scanner (General Electric Medical Systems, Milwaukee, WI) was used to measure visceral fat content. The subjects were examined in the supine position with both arms stretched above their heads. The position of the scan was established at the L4–L5 vertebral disc using a scout image of the body. The visceral adipose tissue area was quantified by delineating the intraabdominal cavity at the most internal aspect of the abdominal and oblique muscle walls surrounding the cavity and the posterior aspect of the vertebral body.

Statistical analysis

The data are expressed as the mean ± SD. We verified the normality of the distribution of variables with a Kolmogorov-Smirnov test and found no significant deviation from normality. Differences between various parameters of ISO and IRO individuals were evaluated by an independent t test. Pearson’s correlations were achieved to evaluate the relationships between hormones and insulin sensitivity. A repeated measures ANOVA was used to detect hormonal changes with time within the EHC (0 vs. 60, 160, 170, and 180 min) and between groups (ISO vs. IRO). If a time and/or group interaction (ISO vs. IRO) was observed, a Bonferroni test was used to detect differences between basal vs. other times of the EHC. Maximal amplitude of insulin-induced inhibition of total, nonacylated, and acylated ghrelin was evaluated for each subject using the lowest value minus the basal (0 min) value during the EHC. Area under the curve (AUC) values were assessed to provide an overall index of hormonal profiles within the EHC and were calculated by the trapezoidal method. The ratio of acylated/nonacylated ghrelin was calculated for fasting and AUC values. Statistical analyses were performed with SPSS for Windows, version 11.5 (SPSS Inc., Chicago, IL). Significance was accepted at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
ISO and IRO were classified based on tertiles for insulin sensitivity using the EHC technique. Women within the highest insulin sensitivity tertile (insulin sensitivity ≥ 12.07 ml·min–1·kg–1 FFM; n = 31) were classified as ISO, whereas women within the lowest tertile of insulin sensitivity (insulin sensitivity ≤ 10.28 ml·min–1·kg–1 FFM; n = 29) were considered as IRO (Table 1Go).


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  		TABLE 1. General characteristics of ISO and IRO postmenopausal women

 
General characteristics of ISO and IRO subjects are presented in Table 1Go. Both groups were comparable for age, height, body weight, BMI, and total fat mass. On the other hand, visceral adiposity (P < 0.05), lean body mass (P < 0.005), and insulin levels (fasting and steady state of the EHC) (P < 0.05) were significantly lower in ISO women. By design, ISO subjects displayed significantly higher insulin sensitivity values than IRO individuals (P < 0.001). They also had significantly lower plasma triglyceride (P < 0.001) and higher plasma HDL-cholesterol levels (P < 0.001) as described in Table 1Go. No differences between groups were noted for total cholesterol, LDL-cholesterol, as well as fasting serum glucose.

Mean fasting values of total ghrelin (ISO, 1246 ± 369 pg/ml; IRO, 1063 ± 399 pg/ml), nonacylated ghrelin (ISO, 1156 ± 359 pg/ml; IRO, 971 ± 395 pg/ml), and acylated ghrelin (ISO, 98 ± 47 pg/ml; IRO, 114 ± 57 pg/ml) concentrations are displayed in Fig. 1Go. At baseline, the ratio of acylated/nonacylated ghrelin was lower in ISO subjects when compared with IRO individuals (0.08 ± 0.03 vs. 0.13 ± 0.11, respectively; P < 0.01). Similarly, total ghrelin levels were marginally increased (P < 0.08) in ISO individuals.


Figure 1
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  		FIG. 1. Total ghrelin (A), nonacylated ghrelin (B), and acylated ghrelin (C) levels at baseline and throughout the EHC in ISO and IRO subjects. Values are means ± SD. *, Significantly different from baseline values (P < 0.01). {dagger}, Significantly different between ISO and IRO subjects (P < 0.05). It should be noted that a significant group effect was detected for total and acylated ghrelin levels (P < 0.05).

 
As described in Fig. 1Go, the comparison of ISO and IRO for both total ghrelin and acylated ghrelin profiles revealed a significant group effect during the EHC. In addition, there was a significant decrease of both total and nonacylated ghrelin concentrations in ISO and IRO individuals during the EHC. Moreover, these reductions were sustained throughout the clamp because time 0 min was significantly different from times 60, 160, 170, and 180 min for total and nonacylated ghrelin conjointly for ISO and IRO individuals. On the other hand, acylated ghrelin levels were significantly decreased from their baseline concentrations only in ISO subjects during the EHC. As presented in both Figs. 1Go and 2Go, IRO subjects displayed significantly higher acylated ghrelin levels at time 160, 170, and 180 min when compared with ISO individuals.


Figure 2
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  		FIG. 2. Baseline, end of clamp value (180 min), and maximal reduction of total, acylated, and nonacylated ghrelin levels in ISO and IRO subjects. Values are mean ± SD.{dagger}, Significantly different between ISO and IRO subjects (P < 0.05).

 
Total, nonacylated, and acylated ghrelin AUC values during the EHC are described in Fig. 1Go. No significant difference was observed for total and nonacylated ghrelin AUC in both groups. In contrast, ISO, but not IRO, individuals displayed significantly decreased acylated ghrelin AUC values (P < 0.05). In addition, the ratio derived from the AUC value of acylated/nonacylated ghrelin was also significantly decreased in ISO individuals compared with IRO subjects (0.07 ± 0.02 vs. 0.14 ± 0.11, respectively; P < 0.05). Maximal reduction of total, nonacylated, and acylated ghrelin occurred at different time points (from 60 to 180 min) throughout the EHC, although no significant time pattern differentiated the response of ISO and IRO individuals. As depicted in Fig. 2Go, during the EHC, ISO individuals displayed a greater maximal reduction capacity than IRO subjects for total (369 ± 184 pg/ml vs. 226 ± 203 pg/ml, respectively; P < 0.05) and acylated (44 ± 33 pg/ml vs. 23 ± 30 pg/ml, respectively; P < 0.05) ghrelin. However, no differences were detected for maximal reduction of nonacylated ghrelin.

As presented in Table 2Go, insulin sensitivity was significantly correlated with maximal reductions of total (r = 0.36; P < 0.01) and acylated (r = 0.36; P < 0.05) ghrelin concentrations during the EHC.


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  		TABLE 2. Pearson’s correlation between insulin sensitivity with AUC and maximal reduction of total, acylated, and nonacylated ghrelin in the total population of overweight or obese postmenopausal women

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Ghrelin is a stomach-derived peptide involved in the regulation of GH secretion (2), food intake (26), and energy metabolism (27, 28). Acylated ghrelin is the endogenous ligand of GH secretagogue receptor 1a, whereas strong evidence suggests that nonacylated ghrelin could activate another unidentified receptor (3, 4, 5, 6). Numerous studies have shown a negative association between total ghrelin levels and insulin resistance (8, 29). In addition, previous reports have suggested that insulin is a potent inhibitor of ghrelin. However, in regards to insulin resistance, the physiological relevance of nonacylated vs. acylated ghrelin is still unclear. Therefore, the EHC is an interesting model to examine acylated and nonacylated ghrelin profiles in ISO and IRO postmenopausal women.

To our knowledge, we are first to investigate the physiological relevance of both acylated ghrelin and the ratio of acylated/nonacylated ghrelin in a context of insulin resistance vs. insulin sensitivity in obese postmenopausal women. The results of the present study suggest that acylated ghrelin levels respond differently in ISO subjects at fasting and during the EHC. That is, ISO individuals display a significantly lower fasting ratio of acylated/nonacylated ghrelin compared with IRO subjects.

We also observed that fasting total ghrelin concentrations tended to be higher in ISO individuals. These results are supported by previous reports suggesting that insulin-resistant obese display lower fasting total ghrelin levels (9, 11). For ISO and IRO subjects, total and nonacylated ghrelin levels were found to decrease throughout the EHC. Moreover, we observed that the reduction of total and acylated ghrelin concentrations was more important in ISO women than IRO individuals. Our results are in agreement with those of le Roux et al. (9) who reported that insulin-resistant obese individuals display a significantly lower postprandial capacity to suppress total ghrelin levels. Similarly, total ghrelin levels are inhibited by insulin in normal, obese, and type 2 diabetic human subjects (10, 30, 31, 32, 33). In contrast to total ghrelin levels, acylated ghrelin concentrations were only significantly reduced in ISO individuals, whereas, these levels increased slightly in IRO subjects under hyperinsulinemia. Thus, during the EHC, ISO individuals displayed an increased and sustained capacity to reduce total, nonacylated, and acylated ghrelin levels. Our data confirm the work of previous authors postulating that insulin is a potent modulator of acylated ghrelin suppression in healthy insulin-sensitive young women (34). Our results are also in agreement with the recent observation by Paik et al. (13) who reported that postprandial acylated ghrelin levels are correlated with insulin sensitivity and decreased to a greater extent in obese children suffering from Prader-Willi syndrome. We extend these previous findings by showing that acylated ghrelin concentrations are decreased to a higher extent in ISO subjects without the confounding effect of total fat mass and/or body weight. Therefore, elevated insulin-induced reduction of acylated ghrelin levels may be considered as a marker of the increased insulin sensitivity in ISO individuals.

In our cohort, maximal reduction of total and acylated ghrelin was observed between 60 and 180 min of the EHC. On the other hand, statistical analyses could not establish one specific time point at which maximal reduction occurred. Therefore, maximal reduction of total, nonacylated and acylated ghrelin values were assigned to each postmenopausal women involved in our study. To our knowledge, we are first to suggest the pertinence of using the maximal reduction value to evaluate the impact of hyperinsulinemia (endogenous or exogenous) on total, nonacylated and acylated ghrelin levels in the circulation. Our results show that ISO individuals display a greater reduction capacity than IRO subjects during the EHC. In addition, insulin sensitivity was significantly correlated with the EHC-induced maximal reduction of total and acylated ghrelin in ISO and IRO individuals. Overall, this report indicates the existence of an association between insulin-induced ghrelin maximal reduction and insulin sensitivity.

Compared with IRO individuals, ISO subjects display decreased values of acylated/nonacylated ghrelin ratio and AUC. These results suggest that the acylated/nonacylated ghrelin ratio is modulated in a different manner in ISO and IRO women. Consequently, it may be hypothesized that the sustained elevation of acylated ghrelin circulating levels combined with lower nonacylated ghrelin concentrations, might contribute, in part, to the development of insulin resistance in overweight or obese postmenopausal women. This is in line with previous work by other authors who proposed that insulin sensitivity is negatively influenced by acylated ghrelin and positively modulated by nonacylated ghrelin administration (14, 15). However, we do not exclude that insulin sensitivity may contribute to the variation of acylated ghrelin levels. Further mechanistic studies should investigate causes and effects underlying the decreased capacity of ghrelin reduction in IRO subjects. Nevertheless, we suggest that ISO individuals display a favorable acylated ghrelin profile during the EHC. Ultimately, a ghrelin profile characterized by higher acylated/nonacylated ghrelin and decreased capacity of maximal reduction may be another indicator of insulin resistance in obese individuals.

Based on our results, we propose that further investigations should take into account the acute and chronic states of total, nonacylated, and acylated ghrelin fluctuations. That is, measuring the concentration of one single, fasting, total ghrelin sample is unlikely to provide meaningful information regarding the physiology of ghrelin regulation in humans.

The present study has several limitations. Firstly, the ISO and IRO cohort included only overweight or obese nondiabetic sedentary postmenopausal women. Therefore, our findings are limited to this gender and obesity level. Secondly, it may be possible that other metabolic modification induced by the EHC (e.g. fatty acid level) could contribute to some extent to our observations. Thirdly, discrepancies presently exist regarding the validity of different methods used to evaluate acylated ghrelin levels. As previously described by other authors, acylated ghrelin levels were evaluated with commercial RIA kits (24, 35). Despite these limitations, our results are supported by the use of gold standard techniques for the evaluation of insulin sensitivity in a relatively large well-characterized cohort.

In conclusion, results of the present study underscore the differential patterns of total, nonacylated, and acylated ghrelin in fasting and hyperinsulinemic states in ISO and IRO subjects. Our study suggests that both increased acylated ghrelin physiological concentrations and elevated acylated/nonacylated ghrelin ratios are associated with insulin resistance in obese or overweight postmenopausal women. Further investigations will be needed to elucidate whether chronic dysregulation of normal acylated ghrelin concentrations influences the development of insulin resistance in obese individuals.


   Acknowledgments
 
We thank Mrs. Lyne Messier for the coordination of this study. We also acknowledge Dr. Huy Ong and the members of his laboratory for their technical and scientific input, and we thank Dr. Miguel Chagnon for his helpful counseling for statistical analyses.


   Footnotes
 
D.H.S.-P. is funded by a Canadian Institutes of Health Research (CIHR) doctoral fellowship. R.R.-L., K.C., and M.B. hold Fond de Recherche en Santé du Québec (FRSQ) research scholar grants. K.C. holds a Canada Research Chair in Adipose Tissue. E.D. is a recipient of a CIHR/Merck-Frosst New Investigator Award and CFI/OIT New Opportunities Award. This study was supported by grants from the Canadian Institute of Health Research New Emerging Teams in Obesity (Université de Montréal and University of Ottawa; MONET project) and from the Canadian Institute of Health Research Operating Grant (200301OHN-116097-SNA-CECA-17184).

Disclosure Statement: The authors have nothing to disclose.

First Published Online October 24, 2006

Abbreviations: AUC, Area under the curve; BMI, body mass index; EHC, euglycemic/hyperinsulinemic clamp; FFM, fat free mass; HDL, high-density lipoprotein; IRO, insulin-resistant overweight or obese; ISO, insulin-sensitive overweight or obese; LDL, low-density lipoprotein.

Received July 25, 2006.

Accepted October 16, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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