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Technical Briefs |
1 Department of Pediatrics,
2
University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104;
3
Medical Research Foundation, Oklahoma City, OK 73109;
aaddress correspondence to this author at: Children’s Hospital of Oklahoma, Room 2426, 940 NE 13th St., Oklahoma City, OK 73104; fax 405-271-3093, e-mail piers-blackett{at}ouhsc.edu
Obesity in women is a major risk factor for type 2 diabetes (1) and predicts increased mortality (2) and cardiovascular disease (3). In addition, a tendency for clustering of hypertension and dyslipidemia in obese adolescents has been observed (4). This association, known as syndrome X, may occur in obese, insulin-resistant children before pubertal onset (5). Because recent studies have shown that heparin-precipitated apolipoprotein (apo)C-III is strongly related to risk of atherosclerosis (6), which may be true even in normolipidemic individuals (7), we sought to assess early manifestations of the syndrome in obese girls during late adolescence with the aim of assessing apoC-III distribution between non-HDL and HDL.
Both obesity and insulin resistance are associated with a characteristic atherogenic plasma lipid profile that includes increased triglycerides and small, dense LDL (8), and decreased HDL-cholesterol (HDL-C) (9)(10). Triglycerides are also more strongly related to obesity than LDL-cholesterol (LDL-C) or apoB (11). We studied apoC-III, which is known to correlate with triglycerides and triglyceride-rich lipoproteins and plays an important role in modulating their lipolytic degradation (12) and in preventing their uptake by the LDL receptor (13). These mechanisms may explain the finding that the lipoprotein distribution of apoC-III is a significant predictor of atherosclerosis progression (6)(14).
Seventeen obese and 12 nonobese girls (ages, 15–20 years) were recruited from the Adolescent Clinic at the Children’s Hospital of Oklahoma. Informed and signed consent was obtained from all participants, and parents also gave consent for participation of girls under the age of 18 years.
After the girls’ height was measured with a stadiometer and their weight was measured with standard balanced scales, their body mass index (BMI) was computed; the girls were then assigned to obese and nonobese groups according to their BMI (15)(16)(17). Obesity was defined as a BMI above the 95th percentile. Girls in the nonobese control group had a BMI below the 50th percentile, according to percentiles standardized for age from the National Health and Nutrition Examination Survey (NHANES) data (15). Single right arm blood pressures were measured with a sphygmomanometer with the girls at rest. The percentage of body fat was determined by bioelectrical impedance (RJL Systems Inc.) (18). Waist and hip circumferences were measured, and waist-to-hip ratios were computed as indicators of abdominal fat distribution (19). Triceps and subscapular skinfolds were measured using Lange calipers, and the mean of three measures were computed. After fasting blood samples were obtained, the participants were given a glucose load of 75 g of glucose as "Glucola". Blood was obtained for glucose and insulin concentrations before and 2 h after the glucose load.
Cholesterol, triglycerides, and HDL-C were measured by previously reported methodologies using Lipid Research Clinics standardization (20). HDL was separated by heparin-Mn2+ precipitation (21). LDL-C was calculated by the Friedewald formula (22). The apoC-III concentrations in whole plasma and heparin-Mn2+ supernatants (HDL) and precipitates (VLDL + LDL) were determined by electroimmunoassay as described previously (23). Fasting insulin was measured by RIA (24) and glucose by a glucose oxidase method using a portable glucose meter (Boehringer Inc.). Hemoglobin A1c was determined by tabletop immunonephelometry (DC2000; Ames Co.).
Statistical analysis was conducted using the SAS package (Statistical Analysis Systems). Total cholesterol, triglycerides, non-HDL cholesterol, HDL-C, apoC-III, the ratio of apoC-III in the heparin-Mn2+ supernatant to that in the precipitate, and the amount of apoC-III in each fraction were compared in the obese and nonobese girls by paired t-tests. The Homeostasis Assessment Score (HOMA) was computed from the fasting insulin and glucose values (25). Pearson correlations were applied to all variables within the obese and nonobese groups.
After separation of the obese and nonobese groups according to their BMI, all measures of obesity (weight, BMI, subscapular and triceps skinfolds, waist-to-hip ratio, and percentage of body fat) correlated and were significantly different between groups (Table 1A
). Both systolic and diastolic blood pressures were higher in the obese than in the nonobese girls (P <0.05). Triglycerides (P <0.01) and heparin-Mn2+-precipitated apoC-III (apoCIII-HP; P <0.01) were significantly higher, whereas HDL-C (P <0.01) and the apoC-III ratio (P <0.01) were lower in the obese (Table 1A
). Although there was no significant difference in the LDL-C concentrations, obese girls had significantly higher non-HDL cholesterol (P <0.05) than did nonobese girls. Fasting insulin (P <0.05), the 2-h insulin (P <0.01), and the HOMA (P <0.05) were higher in the obese, but the fasting glucose, 2-h glucose, and hemoglobin A1c were not different (Table 1A
). Within the group of obese girls, the waist-to-hip ratio and BMI correlated significantly with fasting insulin and HOMA score but did not correlate in the nonobese group (Table 1A
). apoC-III and apoCIII-HP were more highly correlated with cholesterol, triglycerides and LDL-C in the obese group (P <0.001) than in the nonobese group. Non-HDL cholesterol was more highly correlated with apoCIII-HP than with apoC III in the obese (P <0.001 vs P <0.05) and the nonobese groups (P <0.05 vs not significant; Table 1B
).
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Higher triglyceride and lower HDL-C concentrations in obese adolescent girls when compared with the same measures in the nonobese group indicate a more atherogenic lipid profile and may contribute to formation of arterial lesions even in adolescence and young adulthood (2)(26). In our study, the obese girls had higher apoC-III in the heparin-precipitated fraction (apoCIII-HP) and a lower apoC-III ratio. These findings indicate that they had higher amounts of apoC-III bound to apoB-containing lipoproteins in the form of lipoprotein B:C particles because heparin-Mn2+ binds to apoB. Higher non-HDL cholesterol in the obese, a known correlate with apoB (27)(28), supports an increased apoB concentration, composed of apoB-100 and apoB-48, both of which are increased in obese men (29). Increased amounts of apoC-III bound to apoB-containing lipoproteins may result in part from their inefficient lipolytic degradation. Because apoC-III is efficiently transferred to HDL during normal lipolysis (30)(31), the ratio of apoC-III in HDL to that in the heparin-precipitable triglyceride-rich apoB-containing lipoproteins serves as a measure of triglyceride-rich particle catabolism (32); the higher the apoC-III ratio, the higher the lipolytic degradation of triglyceride-rich lipoproteins, and vice versa. This observation in obese individuals can be attributed to insulin resistance, which reduces synthesis of lipoprotein lipase, an insulin-dependent enzyme (33), leading to less plasma triglyceride hydrolysis, hypertriglyceridemia, and decreased transfer of apoC-III from the triglyceride-rich lipoproteins to HDL (34)(35). The increased apoCIII-HP in the insulin-resistant girls may be caused in part by increased synthesis of apoC-III, which is a result of the effect of insulin on apoC-III transcription (36)(37), but total plasma apoC-III did not differ between the groups, in contrast to the finding of increased apoC-III in obese men (29). apoC-III is also known to modulate the action of lipoprotein lipase, thus regulating triglyceride clearance (12) and delaying the receptor-mediated uptake of triglyceride-rich lipoproteins (13)(38).
The significance of a relationship of excess of apoC-III in apoB-containing lipoproteins to atherosclerotic lesion progression has been demonstrated in five clinical trials (6)(14)(39)(40)(41). Thus B:C particle assessment is an important additional component that when added to the lipid profile may provide early evidence of future atherosclerotic risk for the obese insulin-resistant adolescent. In this study, we used a relatively simple method to assess B:C particle concentrations without the need for column separation by measuring apoC-III in heparin-Mn2+-precipitated apoB-containing lipoprotein, a step that separates these lipoproteins before apoC-III measurement by electroimmunoassay (23). Furthermore, the observation that apoCIII-HP was more strongly correlated than apoC-III with non-HDL cholesterol confirms that apoCIII-HP is a measure of particles in VLDL and LDL that have been recognized as atherogenic when measured both as cholesterol (non-HDL cholesterol) (42)(43)(44) and as apoC-III (apoCIII-HP) (6)(14).
In syndrome X, insulin resistance is known to be associated with high triglycerides, low HDL-C, and hypertension (45). In our group of obese adolescent girls, we found evidence of higher fasting insulin concentrations and insulin resistance as computed by the HOMA equation (25). This concurs with previous observations of high insulin concentrations in obese children who had associated insulin resistance (46). Both lipid values and blood pressures were significantly higher in the obese, compounding atherosclerotic risk (47). Thus, components of the triad known as syndrome X tended to occur in this group of young obese girls, concurring with previous documentation of the syndrome in youth (4)(5). However, total cholesterol and calculated LDL-C were not significantly different, as has previously been observed in the dyslipidemia of insulin resistance (48). Although triglyceride concentrations were significantly higher in the obese, the mean value remained close to the reference interval. Thus, the differences in apoC-III distribution can be regarded as subtle early indicators of deranged lipid transport in the obese state.
We conclude that obese girls in late adolescence have significant tendencies to develop dyslipidemia associated with hypertension and insulin resistance when compared with nonobese girls. These findings show that obesity in adolescent girls is associated with the development of insulin resistance and components of syndrome X. We have also characterized their dyslipidemia as having apoC-III distributed predominantly in apoB-containing lipoproteins, measured as apoC-III in the heparin-Mn2+ precipitate, an observation known to predict atherosclerosis progression. Because the mean triglyceride concentrations in the obese remained close to reference values, measures of apoC-III distribution provide early evidence of deranged lipid transport.
Acknowledgments
Children’s Medical Research Inc. provided three summer research scholarships for medical students to conduct the study at the beginning of their second year.
References
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