Lipid and Insulin Levels in Obese Children: Changes with Age and Puberty

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1 Risk Factors and Chronic Disease Lipid and Insulin Levels in Obese Children: Changes with Age and Puberty Orit Pinhas-Hamiel,* Liat Lerner-Geva,* Nancy M. Copperman, and Marc S. Jacobson Abstract PINHAS-HAMIEL, ORIT, LIAT LERNER-GEVA, NANCY M. COPPERMAN, AND MARC S. JACOBSON. Lipid and insulin levels in obese children: changes with age and puberty. Obesity. 2007;15: Objective: The goal was to describe the lipid profile and insulin changes seen in obese children and adolescents at different stages of puberty. Research Methods and Procedures: A cross-sectional study was conducted by chart review of 181 obese (BMI 95th) children and adolescents 5 to 17 years of age, who were referred to the Center for Atherosclerosis Prevention for cardiovascular risk reduction from January 2003 through December Results: Eighty (44.2%) subjects were 12 years of age, and 101 (55.8%) were 12 years. Severity of obesity as expressed by BMI standard deviation score did not differ between these age groups. A significant difference with lower serum levels of total cholesterol, non-high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol was seen with older age and with advancing sexual maturity rating. Triglycerides, very-low-density lipoprotein cholesterol, and lipoprotein(a) levels remained elevated across age and pubertal stages. Insulin levels and insulin resistance as expressed by homeostasis model assessment were significantly higher with older age. Similar trends were observed both in obese boys and obese girls during puberty. Discussion: The most striking findings of this study are that in the 5- to 17-year-old obese population, the combination Received for review December 12, Accepted in final form March 6, The costs of publication of this article were defrayed, in part, by the payment of page charges. This article must, therefore, be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. *Pediatric Endocrinology and Diabetes Unit, Safra Children s Hospital, Sheba Medical Center, Ramat-Gan, Tel-Aviv University, Israel; and Center for Atherosclerosis Prevention, Division of Adolescent Medicine, Schneider Children s Hospital, New Hyde Park, New York. Address correspondence to Marc S. Jacobson, Division of Adolescent Medicine, Schneider Children s Hospital, 410 Lakeville Road, Suite 108, New Hyde Park, NY Jacobson@lij.edu Copyright 2007 NAASO of elevated triglycerides and very-low-density lipoprotein cholesterol and low high-density lipoprotein cholesterol levels place them at greater cardiovascular risk than their non-obese peers, even when the changing patterns of lipids and lipoproteins seen during pubertal maturation are accounted for. Key words: high-density lipoproteins, lipids, puberty, triglyceride, insulin Introduction The primary dyslipidemia seen in obesity is characterized by increased triglycerides (TGs), 1 decreased high-density lipoprotein cholesterol (HDL-C) levels, and abnormal lowdensity lipoprotein cholesterol (LDL-C) composition (1). Elevated levels of LDL-C and decreased levels of HDL-C have long been recognized as important risk factors for cardiovascular disease (CVD). The atherosclerotic process begins very early in life, and although clinical manifestations of CVD do not usually emerge until middle age, current evidence shows that obese children suffer from abnormalities of the cardiovascular system during childhood and adolescence (2). Children who are at risk for the development of accelerated atherosclerosis in early adult life may need early treatment. Complicating the interpretation of lipid parameters of risk in this age group are the various changes in serum lipids that accompany the hormonal changes of puberty. The changes of lipid levels during puberty differ between male and female adolescents and may account for some of the sexual dimorphism in cardiovascular risk in adults. In normal-weight subjects, total cholesterol (TC), LDL-C, and non-high-density lipoprotein cholesterol (NHDL-C) levels decrease in both sexes during puberty. HDL-C concentrations decrease 1 Nonstandard abbreviations: TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; CVD, cardiovascular disease; TC, total cholesterol; NHDL-C, non-high-density lipoprotein cholesterol; SDS, standard deviation score; VLDL-C, very-low-density lipoprotein cholesterol; LP(a), lipoprotein (a); HOMA, homeostasis model assessment. OBESITY Vol. 15 No. 11 November

2 among boys during adolescence, but remain the same in girls (3). Puberty is associated with an increase in TGs level in both sexes (3,4). In children with heterozygous familial hypercholesterolemia, lipid levels vary in relation to pubertal stages (5). TC levels are lower among both boys and girls at pubertal Stages 3 to 5 compared with Stages 1 and 2. LDL-C and HDL-C levels are significantly lower among the older boys, suggesting that the disease does not alter the natural course of puberty on lipoproteins. It is important to establish the natural course of the lipid profile in obese children during puberty because they are at increased risk for CVD and dyslipidemia. Questions of whether obese children enjoy the same spontaneous improvement in lipid profile during puberty or whether obesity overrides puberty and, therefore, exposes them to increased risk remain unanswered. Our aim was to study the association between sexual maturation and plasma lipid and lipoprotein levels in obese children during adolescence. Research Methods and Procedures Study Population After approval by the institutional review board of the North Shore LIJ Health System, a chart review was conducted on 198 consecutive obese children and adolescents, age 5 to 17 years, who were referred to the Center for Atherosclerosis Prevention for cardiovascular risk reduction. Anthropometric measurement of height and weight in each child were obtained at the first visit using standard techniques. BMI was calculated as the weight in kilograms divided by the height in meters squared. Obesity was defined as BMI above the 95th percentile for age and gender [ standard deviation score (SDS)] according to the Centers for Disease Control and Prevention (CDC) (Epi info 2000) (6). Patients using medication, with eating disorders, or with obesity secondary to genetic disorders were excluded (n 17). Patients were divided into two age groups according to Srinivasan et al. (7), a younger age group with subjects 5 to 11 years old and an older age group with subjects 12 to 17 years old. The rationale for the division into these two age groups was so that our findings would be easy to compare to those of the Bogalusa Heart Study. The pubertal developmental stage was determined according to the method of Marshall and Tanner (8,9). Data on pubertal staging were missing in 35 subjects (19.3%). Therefore, for the age and sex comparisons, the number of subjects was 181, whereas for the for the sexual maturity rating comparisons, the number of subjects was 146. The proportion of missing data was similar in boys and girls (p 0.12) and in both age groups (p 0.2). Subjects without missing data were categorized into three groups: prepubertal (Tanner Stage 1, n 41), early puberty (Tanner Stages 2 3, n 40), and advanced puberty (Tanner Stages 4 5, n 65). Laboratory Analysis Participants were instructed to fast for 12 hours before venipuncture, and compliance was determined by interview on the morning of the examination. Lipoprotein analysis was by the vertical auto profile test for cholesterol levels (Quest Diagnostics, Inc., Lyndhurst, NJ). TC, LDL-C, HDL-C, TGs, very-low-density lipoprotein cholesterol (VLDL-C), and lipoprotein (a) [LP(a)] were measured. NHDL-C was calculated by TC HDL-C. Insulin was measured in radioimmunoassay (Quest Diagnostics, Inc). Homeostasis model assessment (HOMA) index was calculated as: fasting insulin concentration (microunits per milliliter) fasting glucose concentration (millimolar)/22.5, assuming that normal young subjects have an insulin resistance of 1. Statistical Analyses Descriptive statistics are presented as frequencies and percentages for categorical variables and as the mean values SD for continuous variables. Because of the skewed distribution, TG levels are presented as median and interquartile range and were log-transformed before statistical testing. Categorical variables were compared using the 2 test. Two-way ANOVA with sex, age groups ( 12 and 12 years), and their interaction term was used to test differences in continuous variables between age groups and similarity of these differences for boys and girls. Two-way ANOVA with sex, Tanner group (1, 2 3, 4 5), and their interaction term was performed to check differences and linear trends in lipid levels among the three pubertal staging groups and the similarity of these differences in boys and girls. All tests were two-sided, and p values 0.01 were considered statistically significant. Statistical analyses were performed with SAS version 9.1 (SAS Institute, Inc., Cary, NC). Results The study group comprised 181 children and adolescents 5 to 17 years of age, all obese with BMI SDS Seventy-eight (43.1%) were boys with a mean age of years, and 103 (56.9%) were girls with a mean age of years (p 0.95). Eighty (44.2%) subjects were 12 years, and 101 (55.8%) were 12 years. There was no difference in distribution of age groups between boys and girls (46.6% of boys and 41.0% of girls were younger than 12 years; p 0.45). The distribution of pubertal stages in boys and girls was similar (data not shown; p 0.2). Six subjects (2.6%) were Asian, 14 (6.2%) were African-American, 17 (7.5%) were Latin American, 123 (54%) were white, and 23 (10.8%) were Caribbean, Native American, or of mixed ethnicities. The clinical population was heterogeneous, and no one group represented a large enough proportion of our subjects to allow us to study or comment on ethnic variability in lipids or insulin OBESITY Vol. 15 No. 11 November 2007

3 Table 1. Risk factor comparison* between different age groups 5 to 11 years old (N 80) 12 to 17 years old (N 101) p BMI SDS TC (mg/dl) NHDL-C (mg/dl) LDL-C (mg/dl) HDL-C (mg/dl) TG (mg/dl) 121 (76 to 141) 120 (87 to 176) 0.97 VLDL-C (mg/dl) LP(a) (mg/dl) Glucose (mg/dl) Insulin ( U/mL) HOMA SDS, standard deviation score; TC, total cholesterol; NHDL-C, non-high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglyceride; VLDL-C, very-low-density lipoprotein cholesterol; LP(a), lipoprotein (a); HOMA, homeostasis model assessment. * Two way ANOVA. Severity of obesity as expressed by mean BMI SDS did not differ between the age groups (Table 1). A significant difference in serum levels of TC, NHDL-C, LDL-C, and HDL-C was seen between the two age groups, with higher levels in the older age group as compared with the younger age group. TG, VLDL, and LP(a) were similar in the different age groups. Insulin levels and insulin resistance as expressed by HOMA were higher in the older age group. There was no difference in degree of obesity or in lipid or insulin levels between boys and girls (Table 2). Looking at the interaction between both gender and age groups on lipid profile, lower levels of TC, NHDL-C, LDL-C, and HDL-C levels with age were observed in both boys and girls (Table 2). TG, VLDL-C, and LP(a) did not differ in the two age groups for either boys or girls. Insulin levels and HOMA were significantly higher in the older age group in boys but not in girls. Table 3 presents lipid and insulin profiles by sexual maturity rating stage. There were lower levels of TC, NHDL-C, LDL-C, and HDL-C with advanced stages of puberty. TG, VLDL-C, and LP(a) levels were similar in different stages of puberty. As seen in Figure 1, in TGs, no linear trend was observed. Discussion As the epidemic of childhood obesity progresses, pediatricians are increasingly faced with patients with elevated levels of cardiovascular risk. The present study provides cross-sectional data on the distribution and association between lipid levels and age in obese children and adolescents throughout puberty. We found that age was inversely correlated to TC, NHDL-C, LDL-C, and HDL-C as demonstrated in normal-weight children. Similar inverse correlation was observed with advancing sexual maturity rating. However, TG, VLDL-C, and LP(a) did not change across age and puberty in this obese population as would have been expected. These trends were evident both in obese boys and obese girls during puberty. The most striking findings of this study are that in the 5- to 17-year-old obese population, the combination of elevated TGs, VLDL-C, and low HDL-C levels place them at greater cardiovascular risk than their non-obese peers, even when the changing patterns of lipids and lipoproteins seen during pubertal maturation are accounted for. The mean HDL-C level in obese boys 5- to 11-years-old was 46 mg/dl, much lower than the reported mean 54 mg/dl in a study of 9- to 11-year-old non-obese boys (10). A further 15% decrease in HDL-C level to 39 mg/dl was seen in the 12- to 17-year-old group. In girls, a similar trend was observed: HDL-C was 5% lower in the 12- to 17-year-old group than in the younger group (45 vs. 43 mg/dl compared with 51 vs. 52 mg/dl reported in normal-weight subjects) (10). Interestingly, in normal-weight girls, HDL-C levels remained unchanged (3,11). The lower levels in HDL-C were prominent in boys mainly at Stages 4 and 5 of puberty, whereas in girls they were prominent from the beginning of puberty. Morrison et al. found that in a group of prepubertal OBESITY Vol. 15 No. 11 November

4 Table 2. Risk factor interaction between age groups and gender 5 to 11 years old (N 48) Boys 12 to 17 years old (N 55) 5 to 11 years old (N 32) Girls 12 to 17 years old (N 46) Age sex interaction* (p) BMI SDS TC (mg/dl) NHDL-C (mg/dl) LDL-C (mg/dl) HDL-C (mg/dl) TG (mg/dl) VLDL-C (mg/dl) LP(a) (mg/dl) Glucose (mg/dl) Insulin ( U/mL) HOMA SDS, standard deviation score; TC, total cholesterol; NHDL-C, non-high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglyceride; VLDL-C, very-low-density lipoprotein cholesterol; LP(a), lipoprotein (a); HOMA, homeostasis model assessment. * Two-way ANOVA. male subjects, HDL-C decreased from a mean level of 57 mg/dl in prepubertal boys to 48 mg/dl in late puberty. This decrease in concentrations of HDL-C was parallel to the increase in free testosterone (12,13). TGs were high in obese prepubertal subjects compared with studies of normal-weight children. Puberty in normalweight subjects is associated with an increase in TGs level in both sexes (3,4). TGs increased from a mean of 64 mg/dl in prepubertal boys to 74 mg/dl in late puberty (13). Although TGs of obese children in our study were not different in different stages of puberty, the levels were consistently high. Because VLDL content is mainly TGs, it is not surprising that levels in obese subjects show similar pattern to those of TGs. Table 3. Lipid and insulin profiles at different stages of puberty Tanner 1 (n 41) Tanner 2 3 (n 40) Tanner 4 5 (n 65) p for linear trend TC (mg/dl) NHDL-C (mg/dl) LDL-C (mg/dl) HDL-C (mg/dl) TG (mg/dl) 144 (88 to 194) 130 (92 to 173) 120 (87 to 185) 0.72 VLDL-C (mg/dl) LP(a) (mg/dl) Insulin ( U/mL) HOMA TC, total cholesterol; NHDL-C, non-high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglyceride; VLDL-C, very-low-density lipoprotein cholesterol; LP(a), lipoprotein (a); HOMA, homeostasis model assessment OBESITY Vol. 15 No. 11 November 2007

5 Figure 1. Lipid levels in different stages of puberty, males (closed triangles and solid lines) vs. females (open squares and dotted lines). TC levels in obese children were significantly lower in the older age group, a 14% difference in boys and 7% difference in girls. In normal-weight boys, TC declines by 10% to 20% during puberty (12 to 16 years of age) (4). This is similar to the age- and sex-related patterns noted in Bogalusa and in the recent National Health and Nutrition Examination Study data (14). In normal-weight girls, the picture is controversial. Some studies show that TC decreases in plasma during adolescence (3,15), and others observe no change (16). The lower lipid and lipoprotein OBESITY Vol. 15 No. 11 November

6 levels with age and pubertal development in our study are, thus, comparable with the expected decline seen from age 12 to 17, which then rapidly begin to rise by age 20 (14). NHDL-C is considered a better screening tool than LDL-C for the assessment of CVD risk in adults because it includes all classes of atherogenic lipoproteins (7,17). A 14% lower mean NHDL-C level was observed in obese boys 12- to 17-years-old, compared with the 5- to 11-yearold group. The majority of the difference in NHDL-C was in the later stage of sexual maturation as judged by Tanner stage. This pattern was similar to the pattern reported in normal-weight boys. Similarly, an 8% change was observed in obese girls. Because the mean is also seen to decrease with age and Tanner stage in non-obese adolescents, this should not be assumed to be a decline in risk. A 16% difference was observed in mean LDL-C level in obese boys, when comparing the younger with older age groups. In girls, a 5% difference was found between the young age group and the 12- to 17-year-old group. This trend was similar to the reported decrease in normal-weight boys and girls (3,18). The mean level of LDL-C of obese prepubertal children was 137 mg/dl, which is above the upper limit of LDL-C for healthy children. Serum LP(a) is an independent risk factor for premature coronary artery disease. In normal-weight children, LP(a) serum levels remain fairly constant throughout puberty (19). A similar pattern was observed in LP(a) serum levels in obese children during sexual maturation (Table 3). Pubertal insulin resistance has been well documented; previous cross-sectional reports consistently show that pubertal development is associated with a 25% to 30% reduction in insulin sensitivity. The fall in insulin sensitivity during puberty is associated with a compensatory increase in insulin secretion (20). Indeed, our data show that insulin levels in obese children were higher with age and pubertal maturity, although the degree of obesity did not change, reflecting the increase of insulin levels during puberty. Similarly, insulin resistance, as expressed by HOMA, was higher than that reported in normal-weight children, and further increase occurred with age and pubertal stages. Hyperinsulinism is the key factor for the metabolic syndrome and may be associated with the sustained levels of TGs and low HDL-C in obese children during puberty (21). Although a causal relation between hyperinsulinemia/insulin resistance and the clustering of lipid abnormalities cannot be drawn from our study, correlation with the degree of insulin resistance and lipid abnormalities (elevated serum LDL-C and TGs, and reduced HDL-C levels) in obese adolescents has been demonstrated by Steinberger et al. (22). In assessing the results of this study, a number of limitations should be considered. First, it is a cross-sectional rather than longitudinal study. Second, it is a referral population, not a randomly selected community sample. Third, our data are based on an ethnically heterogeneous clinical population, and the observed results may not be generalizable to specific ethnic groups. Finally, the relatively small number of subjects in each sexual maturity rating group may have increased the variability seen in those comparisons. Taken together, these results showed that lower TC and LDL-C were seen at higher levels of sexual maturation in the obese. Although TG levels did not change during puberty, their elevated levels, together with the decrease in HDL-C seen in obese children during puberty, further contribute to metabolic risk and leave obese children at higher risk for CVD. The pathogenesis of the dyslipidemia of obesity seems to be closely related to insulin resistance in obese individuals. 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