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Journal of the American College of Nutrition, Vol. 19, No. 2, 228-236 (2000)
Published by the American College of Nutrition

Original Research

Plasma Leptin Association with Body Composition and Energy Expenditure in Sickle Cell Disease

Maciej S. Buchowski, PhD,, Lorenza A. Simmons, BS, Kong Y. Chen, PhD, Paul J. Flakoll, PhD, FACN, Beverly G. Mellen, PhD and Ernest A. Turner, MD

Center for Nutrition (M.S.B., L.A.S.) at Meharry Medical College, 1005 D.B. Todd Blvd., 21st Avenue South, Nashville, Tennessee
Comprehensive Sickle Cell Center (E.A.T.) at Meharry Medical College, 1005 D.B. Todd Blvd., 21st Avenue South, Nashville, Tennessee
Department of Medicine (K.Y.C., M.S.B.) at Vanderbilt University Medical Center, 21st Avenue South, Nashville, Tennessee
Department of Surgery (P.J.F.) at Vanderbilt University Medical Center, 21st Avenue South, Nashville, Tennessee
Department of Preventive Medicine (B.G.M.) at Vanderbilt University Medical Center, 21st Avenue South, Nashville, Tennessee

Address reprint requests to: Maciej S. Buchowski, PhD, Associate Professor, Center for Nutrition, Meharry Medical College, 1005 D.B. Todd Blvd., Nashville, TN 37208


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objective: To examine the association between fasting plasma leptin concentrations and the hypercatabolic state observed in sickle cell disease (SCD).

Methods: Plasma leptin concentration and resting energy expenditure (REE) were measured in 37 SCD patients (10 men, 12 boys 14 to 18 years-old, seven women, and eight girls 14 to 18 year-old) and in 37 age, gender and fat mass (FM) matched controls. Body composition was measured hydrostatically, REE by whole room-indirect calorimeter, and plasma leptin using an RIA kit.

Results: Plasma leptin concentration and leptin normalized for body fat (ng/dL*kg FM-1) were significantly lower in SCD patients than in non-SCD controls (4.00±3.23 vs. 9.94±14.69, p=0.021 and 0.406±0.260 vs. 0.643±0.561, p=0.024, respectively). A positive linear association between log plasma leptin and FM was observed in both males and females, adjusting for age and SCD status. The strength of this association was greater in females compared with males (slope=0.699 and 0.382 log ng/mL per 10 kg FM, respectively; p=0.013). SCD patients on average demonstrated a higher REE, adjusting for FFM (p<0.0001). Log plasma leptin and FM were not statistically significant predictors of REE after adjustment for FFM and SCD.

Conclusions: Once corrected for body composition, mean plasma leptin concentration was significantly lower among female SCD patients than among non-SCD matched controls. Although REE was higher in SCD patients, there is no simple association between leptin and REE in SCD.

Key words: leptin, sickle cell disease, resting metabolic rate, body composition


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Sickle cell disease (SCD) is a collective term for a group of genetic disorders characterized by the predominance of hemoglobin S (HbS) [1]. Hemoglobin S results from a point mutation on the ß-chain gene that results in the substitution of valine for glutamic acid at the sixth amino acid position [1]. The cardinal pathophysiological feature of SCD is a chronic hemolytic anemia and intracellular gelation or polymerization resulting in shorter cell survival when compared to the normal red blood cell [2]. Resulting tissue injury is usually produced by hypoxia secondary to the obstruction of blood vessels by an accumulation of sickled erythrocytes [3]. Previously we [4–5] and others [6–9] have reported that resting energy expenditure (REE) is higher in SCD. This increase in REE might be related to elevated metabolic demands of an expended bone mass caused by a chronic hemolytic process and/or the increased cardiac output secondary to the chronic anemia [7]. Disturbances in energy metabolism in SCD children and adolescents are usually manifested as delayed physical growth and delayed onset of puberty, and in SCD adults as an increased rate of infections [10–13]. Unfortunately, there is limited knowledge on the underlying physiological pathways of SCD that cause increases in REE.

Leptin is the protein product of the ob gene and is thought to act as a metabolic signal in the hypothalamus to influence energy intake, energy expenditure (EE) and hormonal function [14–15]. Plasma leptin concentration rises with increased adiposity [16–19], primarily because of increased adipose tissue leptin production rather than decreased clearance. This allows leptin to serve as a marker for body fat stores [20]. Although leptin has characteristics of a regulatory hormone, its physiological action is not completely understood in humans. It has been suggested that a low concentration of leptin might lead to increased food intake and increased weight gain [21], reduced EE, infertility and delayed onset of puberty [22]. Leptin also has been proposed to be a physiological regulator of the neuroendocrine system’s response to fasting [23–24]. Several studies have demonstrated a correlation between plasma leptin concentrations and both total energy expenditure (TEE) and physical activity level [25–26]. For example, serum leptin concentration in obese subjects showed an inverse association with REE, and rate of carbohydrate oxidation [27]. In other studies, serum leptin concentration did not play a significant role in the regulation of EE in adults [28–29] or in prepubertal children after normalizing by fat mass [30].

Most human studies examining leptin have been undertaken in healthy and obese subjects. It has been shown that leptin is involved in the early acute-phase response after surgical trauma [31], and it has been proposed that leptin is involved in the regulation of the neuroendocrine system during starvation [23]. Thus, leptin may play a regulatory role in states with disturbances in energy metabolism such as SCD. However, to the best of our knowledge no study has investigated the possible role of leptin in the pathophysiology of SCD. Thus, the purpose of this study was to examine the potential for involvement of leptin in the regulation of the hypercatabolic state observed in SCD.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
A group of 37 African-Americans with SCD were identified and screened for participation in the study at the Sickle Cell Clinic of the Comprehensive Sickle Cell Center at Meharry Medical College in Nashville, TN. The group included ten 18 to 40 year-old men, twelve 14 to 18 year-old boys, seven 18 to 35 year-old women and eight 14 to 18 year-old girls. Additionally, 37 African-American males and females who did not carry the sickle cell (HbS) gene or any other hemoglobinopathy were matched for age, weight and FM to serve as control subjects for the study. Adolescent boys and girls were matched according to their developmental (Tanner) stage [32]. The research volunteers were participants in studies of energy and protein metabolism in sickle cell disease. Each participant’s Hb genotype was determined using standard electrophoretic methods [33] to confirm the presence of either (a) homozygous sickle cell disease (HbSS) in which both genes coding for the ß chains of Hb produce HbS, (b) sickle cell hemoglobin C disease (HbSC) in which one gene codes for HbS and the other for HbC, (c) sickle cell ß-thalassemia disease (HbS ß-thal) in which one gene codes for HbS and the other for reduced or no production of normal Hb (HbA) or (d) normal (HbAA) in which both genes code for HbA [34]. Subjects received written information and verbal explanation about the nature and purpose of the study, and those who were eligible for participation signed informed consents according to the Declaration of Helsinki. The form was approved by both Meharry Medical College and Vanderbilt University School of Medicine for procedures to be performed at the Vanderbilt University General Clinical Research Center (GCRC).

Prior to participation in the study, subjects gave a medical history and underwent a complete physical examination. Participants were free of any apparent metabolic, hepatic and renal dysfunction as confirmed by blood tests. They were not taking drugs known to affect energy metabolism and were non-smokers. Female subjects were not pregnant as determined by a serum pregnancy test, were pre-menopausal and were studied between days 3 and 12 after the onset of menses (follicular phase) to eliminate influence of menstrual function on EE [35–36]. SCD subjects were studied in the steady state, i.e. they were not experiencing a sickle cell crisis during the study, nor had they experienced a painful crisis for 14 days before the study. Subjects were asked to record the quantity of all food and beverages consumed by weight or in household measures, including brand names and methods of preparation. Subjects and parents of the teenage subjects were trained in keeping food diary and the records were reviewed with the subject and analyzed by the GCRC dietitian using the Food Processor II (Salem, OR) software. This analysis was a base for a qualitative and quantitative formulating of diet for the room calorimeter stay. This individualized diet was prepared in the GCRC metabolic kitchen and contained foods chosen by the subject and was similar to the diet consumed ad libitum. The diet was formulated to contain 1 g of protein and approximately 160 kJ (35 kcal) per kg of body weight per day.

Study Protocol
All subjects reported to the GCRC at Vanderbilt University Medical Center after a 10-hour overnight fast. After initial admission, they were transferred to the whole-room indirect calorimeter where they were asked to engage in a 24-hour protocol involving standard daily activities and a 2-hour non-intensive exercise protocol. The room calorimeter is an airtight environmental room measuring 2.6x3.4x2.4 m3 and contains 19,500 L in net volume. Room temperature was precisely controlled (22.5±0.2°C). Oxygen consumption (O2), carbon-dioxide production (CO2), air flow rate, temperature (inside and ambient), barometric pressure, and humidity of air were sampled 60 times per second and integrated at the end of each minute to calculate EE [37]. The room calorimeter is equipped with a bed, desk, chair, toilet, sink, telephone, television, VCR and stereo system. A step exercise platform and a computer monitored stationary bike are also available inside the room. The exercise protocol included physical activities such as walking and stepping close in intensities to manual work and leisure activities that participants would perform in the free-living. All subjects exercised at the same pace and speed, however they were instructed to shorten any exercise segment if the duration of the tasks were too difficult to perform. Subjects were free to view television, read, write, walk and perform personal care activities or to exercise using the stationary bicycle, step platform and aerobic tapes as much as they would in their normal daily routine. Meals were provided at 0830 hours (breakfast), 1230 hours (lunch), 1500 hours (snack), 1730 hours (dinner) and 2100 hours (snack). Subjects were instructed to consume all the food during the designated meal times, and leftovers were weighed by the kitchen staff and subtracted from the intake. Subjects were not allowed to eat or drink after 2100 hours and were asked to go to bed between 2100 hours and 2200 hours. On the following morning, REE was measured when a subject was still inside the room calorimeter and a fasting blood sample was drawn at 0700 hours after he or she left the room calorimeter.

Leptin Levels
After an overnight fast (>=10 hours) in the room calorimeter, blood was collected by venepuncture from an antecubital vein at 0700 hours in evacuated EDTA blood-collection tubes. The tubes were placed on ice and directly centrifuged for five minutes in a refrigerated (4°C) centrifuge at a speed of 3000xg. Plasma samples were immediately stored at -80°C until analysis. Plasma leptin levels were measured with a commercially available radioimmunoassay (RIA) kit from Linco Research (St. Louis, MO). The within assay coefficients of variation (CV) were 1.2% for the low and 3.0% for the high control and between-assay CVs were 6.5% for the low and 5.0% for the high control.

Energy Expenditure
Total energy expenditure (TEE).
TEE was obtained by measuring the total amount of oxygen used (O2) and carbon dioxide expelled (CO2) during each subject’s 24-hour stay in the room calorimeter [37]. The O2 and CO2 were calculated by measuring the changes in O2 and CO2 concentration in the air sampled from inside the room calorimeter and multiplying the flow rate of the purged air. This allowed variables such as EE to be calculated on a minute by minute basis. Detailed methodology of the room calorimeter has been previously reported [37–38].

Resting energy expenditure (REE).
REE (kJ/min), measured in the room calorimeter, was defined as the average EE during a 30 minute period while the subject lay quietly in bed in the morning following an overnight sleep and 10 hours of fasting. The EE during periods when body motion was detected by the force platform were excluded from REE calculation [38]. Regression models of REE based on predictors FFM and FM were used rather then division of REE by FFM, since division by FFM does not account for nonzero intercepts typically observed in these regressions [39].

Body Composition
Body weight was measured to the nearest 0.05 kg with a digital scale. Fat mass (FM) and fat free mass (FFM) were determined by hydrodensitometry (underwater weighing). The subjects were weighed underwater and their residual lung volume was measured using the nitrogen dilution technique while submerged in water to chest level [40]. Body fat percentage (% BF) was calculated from body density using Schutte’s equation [41], while FM and FFM were calculated from subject’s body mass.

Statistical Analysis
Sample means are presented±1 SD. Comparison of continuous variables between subjects were evaluated using the two sample t test or Wilcoxon rank sum test. Multiple linear regression analysis was performed on plasma leptin concentration and REE using a backward elimination approach. Covariates that were considered for inclusion in the modeling were SCD status (0=non-SCD control, 1=SCD patient), gender (0=male, 1=female), FM, age, and plausible interactions among these. Age was treated as a continuous variable. In the analysis of REE, plasma leptin and FFM were also considered as covariates. Lower order terms were retained in the model when higher order interactions were statistically significant. Covariate centering and multiplication by a constant were used for ease of regression coefficient interpretation. Age was centered at 18 years, FM was centered at 15 kg, plasma leptin level was centered at 3.0 ng/mL, and both age and FM were divided by 10. Thus, the intercept term in a model that includes both age and FM for example is the fitted dependent variable response for 18 year olds with FM equal to 15 kg (and other covariates equal to zero, e.g., male and not with SCD). Furthermore, the coefficients for the age and FM covariates in such models represent fitted differences in the dependent variable per 10-year and 10-kg differences in age and FM, respectively. Residual analysis was performed for evaluation of model adequacy and outliers. Data transformations suggested by these analyses and by previously reported transformations, including natural logarithm (log) and square root, were considered for plasma leptin concentration, FFM, FM, age, and REE values. A p-value <0.05 was used for inclusion of terms in the regression and to indicate statistical significance.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Subjects Characteristics
Table 1 presents descriptive data for the study participants. There were no significant differences between SCD patients and controls in age, BMI, weight, FFM, and % body fat (%BF) in each subgroup (men and women, boys and girls). As expected, there were group differences between men and women, boys and girls, and adults and adolescents. Hemoglobin (Hb) concentration was significantly (p<0.001) lower in SCD patients than in controls (average 8.9±1.8 g/L vs. 13.7±1.1 g/L, respectively) in males and females. For the purpose of this study we used SCD as a collective term for the hemoglobin genotypes in which HBS is produced (HbSS, HbSß thalassemia and HbSC). Hemoglobin level was significantly higher (p=0.031) in HbSC (10.91±1.65 g/dL, n=6) than in HbSS (8.43±1.64 g/dL, n=23) and HbSß-thal (8.81±1.52 g/dL, n=8).


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  		Table 1. Body Composition and Plasma Leptin Measurements in SCD and Control Subjects

 
Energy and Macronutrient Intake
Average measured intake was 1.09±0.37 g protein and 151.5±47.6 kJ (36.2 kcal) per kg of body weight per day. Average macronutrient energy distribution was 12.5±3.4%, 30.3±7.8%, and 59.0±9.9% from protein, fat and carbohydrates, respectively.

Plasma Leptin Concentration and SCD
Results of the multiple regression analysis of plasma leptin concentration are summarized in Table 2. A positive linear association between log plasma leptin and FM was observed in both males and females, adjusting for age and SCD status. The strength of this association was greater in females compared with males (slope=0.699 and 0.382 log ng/mL per 10 kg FM, respectively; p=0.013). Also, based on results of this analysis, predicted log plasma leptin, adjusted for FM and age, is lower in SCD females compared with non-SCD control females (difference=0.901 log ng/mL; p<0.0001). This difference was not observed in males. The overall fitted regression equation is log [leptin]=1.019 + 0.038*SCD + 1.55*gender -0.901*SCD*gender + 0.382*(FM-15)/10 + 0.317*(FM-15)/10* gender -0.174*(age-18)/10. These results are illustrated in Fig. 1.


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  		Table 2. Multiple Regression Model Results for Log Plasma Leptin

 


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  		Fig. 1. Regressions of log plasma leptin (nanograms per milliliter) vs. FM (kilograms)

a.No significant differences were noted between regression lines generated for males (SCD versus non-SCD controls). Thus, these groups are presented together. Although log plasma leptin was found to be 0.174 units lower on average with each 10-year increase in age (adjusting for SCD, gender and FM; see Table 2), for ease of presentation, age was excluded from the model in this graph and in graph 1b. No interactions involving age were significant. The regression equation for 18-year-old males is log [leptin]=1.019+0.038*SCD+0.382*(FM-15)/10.

b.Log plasma leptin concentrations were significantly greater in non-SCD control females versus males (adjusting for FM and age; p<0.0001) and significantly lower in females with SCD versus non-SCD controls (adjusting for FM and age; p<0.0001). The regression equation for 18-year-old females is log [leptin]=2.569-0.863*SCD+0.699*(FM-15)/10.

 
Plasma Concentration of Leptin and Energy Expenditure (EE)
In the modeling of REE, there was evidence for a three-way interaction between gender, SCD status and log leptin (p=0.058). To simplify analyses, separate multiple linear regressions were performed for the two genders. Results are presented in Table 3. In both males and females, FFM was an important predictor of REE as expected (p<0.0001). Also in both males and females, SCD patients on average demonstrated a higher REE, adjusting for FFM. In females, FM and log leptin were not statistically significant predictors after adjustment for FFM and SCD. In males, there was a linear relationship between log leptin and REE, adjusting for FFM, which depended on SCD status. In control subjects, there was a positive relationship between log leptin and REE after adjusting for FFM, whereas no such relation was observed between log leptin and REE in SCD patients. In males, FM was not statistically significant after adjustment for FFM, SCD, and log leptin. These results are illustrated in Fig. 2.


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  		Table 3. Multiple Regression Model Results for Resting Energy Expenditure (REE) (kJ/min)

 


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  		Fig. 2. Residual-residual plots. Each plot shows the relationship between REE and log leptin after both have been adjusted for the effects of FFM using linear regression. The adjusted variables are labeled "Residual REE" and "Residual log leptin," respectively.

a.In males, a positive linear relationship was observed between log leptin and REE in control subjects, after adjusting for FFM (see Table 3 for corresponding analysis; regression coefficient=1.01). This relationship was not observed in SCD patients.

b.In females, no consistent relationship between log leptin and REE was observed after adjusting for FFM, though REE was higher on average in SCD females those in control females (see Table 3 for corresponding analysis; regression coefficient=0.901).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study reports circulating leptin in SCD patients, relating leptin levels to REE in SCD. Plasma leptin concentration per FM, as well as regression slopes for serum leptin vs. FM, was significantly lower among female SCD patients than among non-SCD-matched controls. Furthermore, SCD female patients with higher REE had lower serum leptin concentration per FM.

In healthy, normal-weight humans, the concentration of circulating leptin are highly correlated with adiposity [18,42] and are determined primarily by gender [16,28,43,44]. Higher plasma leptin levels occur in females than in males [18–19]. However, it has been indicated that subcutaneous femoral fat or factors closely related to femoral fat (e.g., sex hormones) may be casual factors for the gender differences in leptin [45]. Our observation of the plasma leptin corrected for gender and FM being significantly lower in SCD patients indicates that in SCD circulating plasma leptin levels might be influenced by other metabolic factors. Insulin, for example, has been shown to increase leptin mRNA expression and leptin secretion in human preadipocytes [28,46]. Although we did not measure plasma insulin concentration in the present study, we have shown previously that there was no difference in insulin levels between SCD patients and non-SCD controls [47]. It has also been suggested that adipose glucose metabolism may be involved in the regulation of leptin secretion [44]. This suggestion was based on the fact that changes in adipose tissue glucose metabolism may be involved in the effect of fasting and refeeding on circulating leptin concentration in vivo [22,44]. We did not investigate glucose metabolism in the present study, but we have demonstrated previously that the rates of whole-body glucose utilization, endogenous glucose production, non-oxidative glucose utilization (glycogen storage and lactate production) and lipolysis during nutrient availability did not differ significantly between SCD patients and non-SCD controls [4].

As we mentioned earlier, leptin is secreted from adipose cells as a hormonal signal of adipose tissue stores. While leptin influences both energy intake and EE in mice [14,48], its physiological role in humans has not been fully elucidated. In general, plasma leptin correlates with body fat, obesity is associated with insensitivity to leptin, and weight loss causes a decrease in plasma leptin concentration [49]. On the other hand, the regulation of REE is likely due to the function of energy intake, energy balance and hormonal and autonomal neural activity. The mechanism by which leptin may be involved in the regulation of EE is still enigmatic, but some studies have demonstrated association of leptin to REE adjusted for body composition [27,50–53]. In the present study, we did not find any direct association between leptin concentration and REE in SCD patients. Others have shown that circulating leptin is involved in the early (<24-hours) acute phase response after moderately severe surgical trauma [31]. Such a state is hypercatabolic with hypoalbuminemia, hyperglycemia and hypoglutaminemia. Similarly, previous reports demonstrated that SCD is a hypermetabolic state with disturbances of energy metabolism and protein homeostasis [4–9,47]. Therefore, present study suggests that SCD is not associated with leptin levels by a comparable mechanism.

After secretion from adipocytes, leptin appears to interact with specific receptors in the hypothalamus [54–56] and acts to decrease levels of neuropeptide Y (NPY) in the arcuate nucleus and the hypothalamic paraventricular nucleus [57]. NPY is implicated in the regulation of energy homeostasis by stimulating food intake and lowering EE [58–59]. Therefore, lower levels of leptin may prevent the possible further increase of REE in SCD via the ß3-adrenergic receptor in adipose tissue. If this hypothesis were correct, leptin levels would be lower in individuals with higher REE in SCD. In present study we indeed found that SCD females with higher RMR had lower leptin levels.

It has been also postulated that leptin acts centrally by stimulating sympathetic outflow, and sympathetic outflow in turn decreases leptin secretion, thus indicating existence of a feedback, regulatory loop between adipose tissue and brain [60]. This is also consistent with the hypothesis that leptin has a primary physiological role as an emergency signal for depletion of energy stores signaling the brain that energy intake and the amounts of energy stored as fat are insufficient [29]. Therefore, we hypothesize that in SCD reduced rates of leptin synthesis per unit of body fat reduce the action of leptin in the central nervous system inducing changes in energy intake and expenditure that favors increase in fat mass.

The reason for the observed gender difference in the relationship between plasma leptin concentration and EE is unclear, but may be associated with the gender differences in REE or may be related to the higher adiposity in women. Recently, Rosenbaum and Leibel [61] suggested that the usual or threshold concentration of leptin in the central nervous system below which compensatory changes in energy intake and output occur are highly individual and influenced by genetic and developmental factors. Whether higher rates of EE in SCD females with lower leptin levels are related to alterations in leptin signaling has yet to be determined. However, it has been reported that prolonged changes in energy intake override the regulation of leptin concentrations by the fat mass in healthy women [62]. These findings are difficult to interpret at this time and suggest that more elaborate experimental models will need to be developed. Moreover, our findings offer little information about specific physiological mechanisms. Nevertheless, these data suggest that SCD may provide an interesting model for examining the role of leptin in the regulation of energy intake and expenditure.

Our findings must be interpreted within the context of our experimental design. Although daytime leptin levels are fairly constant, a 30% nocturnal rise in serum leptin can occur in humans [63]. In the present study, we have assessed the metabolic significance of morning fasting leptin concentrations. Thus, our conclusions pertain to awake ambient leptin levels and the metabolic importance of a possible nocturnal rise in SCD should be further investigated. Other factors including insulin-like growth factor-I (IGF-I) and glucocorticoids could also affect the relationship between SCD and REE [64–68]. Furthermore, our sample of SCD patients had different hemoglobin characteristics. However, REE was significantly higher in all SCD hemoglobin phenotypes than in non-SCD controls. Complex model testing among SCD patients may also require more than 37 subjects. Although we carefully matched our patients for total fat mass, we did not take under consideration differences in regional fat distribution. Finally, this and previous studies have shown that leptin levels are age related [69–70]. Although including age in analyses in this study may have shed some light on possible associations between leptin, EE and age, future studies should involve more SCD participants from various age groups.

In conclusion, the results of this study suggest that, once corrected for FM, mean leptin concentration was significantly lower among female SCD patients than among non-SCD matched controls. Although REE was higher in SCD patients, there is no simple association between leptin and REE in SCD.


   ACKNOWLEDGMENTS
 
This work was supported by grants from the National Institutes of Health HL-03530 (to M.S.B.), HL-56867 (to P.J.F.), General Clinical Research Center Grant RR-00095 (to Vanderbilt University) and RR-1179204 (to Meharry Medical College), Clinical Nutrition Research Unit Grant DK-26657 (to Vanderbilt University), and Meharry COE grant (to M.S.B. and L.A.S.). We thank staff of the General Clinical Research Center (GCRC) at Vanderbilt University for help with this project. We also thank Wanda Snead for her technical help and Karen Townsend for her technical help and assistance in preparing this manuscript. Finally, we acknowledge our subjects for their enthusiasm and participation in this study.

Received October 1, 1999. Accepted January 1, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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