The prevalence of childhood overweight and obesity has been rising in the Western world during the past two decades (14,20) and tracks into adulthood, leading to serious health consequences (35). The adverse effects of obesity on health start early in life, however, and health risks such as impaired glucose tolerance, insulin resistance, and type II diabetes accompany a high degree of fatness in children (29,31). In fact, the most frequently found risk factors for type II diabetes in children are puberty, obesity, and insulin resistance (15).
Body fatness is positively associated with insulin resistance in adults, but it is also well established that aerobic fitness (fitness) has the opposite action (6,27) through its beneficial effects on glucose homeostastis and insulin sensitivity. Fitness can even counteract the negative effects that fatness has on health in adults (i.e., being fit and fat is not worse for health than being unfit and thin) (7,34), but this counteraction is not as clear in children (13). The relation of fitness to insulin resistance and the fitness-fatness interactions are also not as well characterized in children. Studies conducted in late adolescence report a negative association between fitness and insulin resistance after controlling for fatness (17,21), whereas studies in children have reported that fitness is not related to insulin resistance independently of fatness (3,16,28). However, some of these studies have used overweight children with family history of diabetes (3,28), and it is known that normal-weight children do not share similar patterns of the metabolic syndrome as do their overweight peers (9). The relationship between fitness and insulin resistance over a wider range of body composition in children, therefore, is unknown. The previous studies have also grouped children of various ages into one group (3,16,22,28), which makes it impossible to identify any potential differences in the effects of fitness on insulin resistance between children and adolescents.
The purpose of this study was to explore the relations of fitness and fatness and their interactions to insulin resistance in two distinct, population-based groups of children and adolescents. We hypothesized that, similar to previous findings in children, fitness would not be associated with fasting insulin levels independently of body fatness among mostly prepubertal children, but the relation in mostly postpubertal adolescents would be in accordance with published reports in late adolescence and adulthood. Furthermore, we hypothesized that among fit children and adolescents, fasting insulin would not differ across fatness categories (i.e., fit and fat children and adolescents would not differ in fasting insulin from their fit and lean counterparts).
A total of 207 randomly selected healthy 9-yr-old (47 boys, 56 girls) and 15-yr-old (53 boys, 51 girls) Icelandic children and adolescents participated in this study. They came from 18 primary or lower secondary schools in Iceland that were randomly selected on the basis of the national and geographical distribution of the Icelandic population. This sample was a subsample from a larger, population-based epidemiological study investigating the lifestyle of 9- and 15-yr-old Icelandic children (20). The protocol in that study and, therefore, the present one was modeled after the protocol used in the European Youth Heart Study (1,4,33). Written informed consent was obtained from the children's parents, as well as an assent from the children themselves. The National Bioethics Committee in Iceland approved the study (VSNa2003060014/03-12/BH/-).
Body size and composition.
Standing height was measured to the nearest millimeter with a transportable stadiometer (Seca 220, Seca Ltd., Birmingham, UK), and body mass was determined to the nearest 0.1 kg (Seca 708, Seca Ltd., Birmingham, UK), using standard procedures. Body mass index (BMI) was calculated as body mass (kg) divided by height (m) squared. Skinfold thickness was measured with a skinfold caliper (Lange, Beta Technology Incorporated, Cambridge, MD) in four places (subscapular, triceps, biceps, suprailiac), on the left side of the body (12), three times. The average of the two closest measurements was calculated, and the sum (mm) of the four skinfolds (SKF) was used for analysis. Waist circumference was measured two times at the umbilical level to the nearest millimeter, and the mean value divided by height to the 0.9282 power (waistadj) was used for analysis. We chose to divide the waist circumference by height because taller children tend to have larger waist circumference, and waist-to-height ratio is a better predictor of cardiovascular disease risk than waist circumference in children (18). We divided by height to the 0.9282 power because raising height to that exponent abolished the relationship between height and the adjusted waist circumference in the whole population-based sample. Sexual maturity was assessed by the participants with the aid of pictures, using Tanner's (30) five-stage scale for breast development in girls and pubic hair in boys.
Fitness (W·kg−1) was assessed on a Monark 839E (Monark Exercise AB, Vansbro, Sweden) electronically braked cycle ergometer, as previously described (2,33). The importance of a maximal effort was stressed, but the children were also told they could stop cycling at any time. Children who did not reach a heart rate of 185 bpm during the test were excluded from the analysis. The absolute and relative maximal power output from this cycle ergometer test correlates very well with measured absolute (r = 0.98) and relative (r = 0.90) peak oxygen uptake in children and adolescents (2).
Blood samples were taken in the morning after a 12-h fast from the antecubital fossa by a pediatrician at the Landspitali University Hospital, using the Vacutainer system with two 4-mL serum gel vials and one 2-mL EDTA vial. Information and guidelines about blood sampling were given to the children and their parents, and to ensure fasting, the children were asked at the hospital if they had eaten anything in the morning or during the night. The 9-yr-old children were given two EMLA (Albertslund, Denmark) medicated band-aids with anesthesia (lidocaine prilocaine), one for each arm, to anesthetize the area from which blood would be drawn. Fasting insulin, an indicator of insulin resistance, was measured at the Landspitali University Hospital Laboratory with ECLIA (Electrochemiluminescence immunoassay) on an automatic analyzer (Modular Analytics E170, Roche Diagnostics, Basel, Switzerland). The University Hospital Laboratory has a coefficient of variation of 4.2% for the insulin assay.
Statistical analysis was performed with SPSS 14.0.0 (Chicago, IL). The variables were inspected for normality, and all analyses were conducted within age groups. Fasting insulin was positively skewed, and the body composition variables were also slightly positively skewed. Therefore, these variables were log10 transformed for all statistical analysis, but the untransformed values are represented in text, tables, and figures for more meaningful comparisons. Independent-sample t-tests were used to assess gender differences in subject characteristics. Partial correlational analyses adjusted for sexual maturity and gender were used to determine the relationship between fasting insulin and A) body composition (one variable at a time), with further adjustments for fitness and body composition variables not being tested; and B) fitness, with additional adjustment for body composition variables. To further explore the interactive effects of fitness and fatness on fasting insulin, the sample was divided (within age groups) on the median (Table 1) of the body composition variables (high fatness vs low fatness) and on the median of fitness (high fitness vs low fitness), and a two-way ANOVA was used to test for the presence of a fitness-fatness interaction. Then, on the basis of the median divisions, four groups were formed: A) fitter and leaner children (high fitness, low fatness), B) fitter and fatter children (high fitness, high fatness), C) unfitter and leaner children (low fitness, low fatness), and D) unfitter and fatter children (low fitness, high fatness), and planned contrasts (one-way ANOVA) were used to compare the fitter and leaner children on one hand, and the unfitter and fatter children on the other, with other fitness-fatness groups of children. The data are presented as means and SD. Significance was accepted at an α level of 0.05.
The subject characteristics are presented in Table 1. The 15-yr-old boys were taller, heavier, and had lower waistadj than the 15-yr-old girls, who, in turn, had higher SKF. Similarly, the 9-yr-old girls had higher SKF than their counterparts, and the boys in both age groups were more fit than the girls. About 19% of the 15-yr-olds and 23% of the 9-yr-olds were classified as overweight (8). Approximately 98% of the 9-yr-old children were in Tanner stages 1 or 2 (N = 39/62), and about 97% of the 15-yr-olds were in stages 4 and 5 (N = 79/22), with the remaining children in both age groups being in stage 3 (N = 2 and 3, respectively).
The three measures of fatness (BMI, waistadj, and SKF) were highly correlated with each other, both among the 9-yr-old (r = 0.82-0.88, all P < 0.001) and 15-yr-old (r = 0.81-0.87, all P < 0.001) children, after adjusting for gender and sexual maturity. The body composition measures, controlled for gender and sexual maturity, all correlated similarly with fasting insulin in both age groups (Table 2). The relation between SKF, an estimate of total body fat, and fasting insulin remained significant after further adjustment for waistadj (r = 0.20), but it was abolished when controlling for BMI (r = 0.14) among the 9-yr-old children. Similarly, the associations between BMI and fasting insulin and waistadj and fasting insulin were nonsignificant after adjusting for the other body composition variables. Among the 15-yr olds, waistadj, an index of central fatness, was significantly correlated with fasting insulin after adjusting for BMI (r = 0.22), but not when controlling for SKF (r = 0.17), and neither SKF nor BMI were significantly related to fasting insulin after controlling for the other body composition variables. In both age groups, higher levels of fatness were associated with greater fasting insulin levels.
Fitness and the body composition measures were inversely correlated among the 9-yr-olds (r = −0.60 to −0.68, all P < 0.001) and 15-yr-olds (r = −0.52 to −0.64, all P < 0.001). Fitness was also negatively associated with fasting insulin in both age groups (Table 2). Fitness did not change the significance of the relationship between the body composition variables and fasting insulin among the 9-yr-old children (i.e., all measures of fatness remained significantly related to fasting insulin after controlling for fitness). However, among the 15-yr-olds, only waistadj maintained a significant correlation (r = 0.24) with fasting insulin after controlling for fitness. Once fitness was adjusted for the body composition variables, all relations between fitness and fasting insulin were abolished except when controlling for BMI (r = −0.20) among 15-yr-old adolescents. Fatness can, therefore, explain a part of the variance in fasting insulin that is not explained by fitness among the 9-yr old children (Fig. 1). On the other hand, only central fatness explains a part of the variance in fasting insulin independent of fitness among the 15-yr-olds.
There were significant interactions in fasting insulin between all sexual maturity-adjusted estimates of fatness and fitness (both divided on the median) groupings among the 9-yr-old children (P = 0.015-0.017), but no such interactions existed for the 15-yr-old group (P = 0.227-0.492). For the adolescents, the main effects of waistadj (P = 0.009) and BMI (P = 0.015) were significant across fitness groups, but SKF (P = 0.096) was not, and the main effects of fitness across fatness groups were nonsignificant (P = 0.160-0.208). Among the 9-yr-olds, the children in the unfitter and fatter group were significantly different in fasting insulin from the children in the other three groups, regardless of the body composition method used to classify high and low fatness (Fig. 2A). In contrast, the fitter and fatter group did not differ from the fitter and leaner group. Similarly, the fitter and fatter group did not differ in fasting insulin from the fitter and leaner group among the 15-yr-old adolescents (Fig. 2B). Furthermore, SKF, BMI, and waistadj correlated significantly with fasting insulin after adjusting for sexual maturity and gender among the 9-yr-old (r = 0.54, 0.51, and 0.51, respectively, all P < 0.001) and 15-yr-old (r = 0.31, 0.32, and 0.35, respectively, P = 0.011-0.028) children who were below the median on fitness, whereas the correlations were nonsignificant (r = 0.04-0.18, P = 0.217-0.768) in children in both age groups who were above the median on fitness.
The major finding of this study is that fatness has a greater association than fitness with fasting insulin levels in 9-yr-old children, whereas estimates of total body fat are not related to fasting insulin after adjusting for fitness among 15-yr-old adolescents. However, in both age groups, fasting insulin of children who were above the median in fitness did not differ across levels of fatness. A secondary finding of this study is that the relation of central fatness to fasting insulin is more independent of confounders than is the relation of total body fat to fasting insulin in adolescents, but the opposite is true for children. To our knowledge, this is the first study to explore the fitness-fatness association to fasting insulin concentration in two distinct, population-based groups of children and adolescents. Previous studies in children have used overweight, unfit children, often with family history of diabetes (3,28); lumped children of various ages and sexual maturity into one group (3,16,22,28); or studied one group in late adolescence (17) to address this dilemma.
The sample for this study was randomly selected from a large epidemiological study based upon the national and geographical distribution of the Icelandic population that included approximately 10% of all 9- and 15-yr-old children in Iceland (20). The subsample for this study did not differ from the larger study, although the relative number of overweight children was slightly higher (20). Furthermore, we have shown that these children are very similar in fitness and fatness to other Scandinavian and European children (2). Therefore, we are confident that our sample is a good representation of the whole population.
It is well established in adults that fatness is positively associated with insulin resistance (6,27). Similarly, in children and adolescents, higher levels of fatness generally translate into greater insulin resistance (3,16,17,22,23,31). Our results agree with these published findings; all estimates of fatness were positively correlated with insulin resistance as assessed by fasting insulin (Table 2). Fitness was also negatively associated with insulin resistance (i.e., fasting insulin) in both age groups, a finding that has been reported in children, adolescents, and adults (3,6,16,17,21,27,28).
Adjustment for fitness did not change the relation between fatness and fasting insulin among 9-yr-old children. However, among 15-yr-old adolescents, waistadj was the only fatness estimate to be related to fasting insulin independent of fitness. Fitness was not associated with fasting insulin after adjustment for the measures of fatness among the 15-yr-olds, except for BMI, which might be because BMI is a poorer estimate of total body fat than SKF and is also a surrogate of lean body mass. Similarly, fitness was not a predictor of fasting insulin independent of body composition in 9-yr-olds. Our findings are in contrast with the findings in adults (6,27) but in agreement with findings in a group of overweight children and adolescents with family history of diabetes (3,28) and a group of young (7- to 11-yr-old) children (16). All these findings suggest that either the relation of fitness to insulin resistance is channeled through body composition among 9-yr-old children, or that fatness simultaneously and independently affects insulin resistance and fitness (Fig. 1). Among 15-yr-olds, however, the relation of fitness to fasting insulin seems to be more through central fatness than total body fat, which, in addition to waistadj having a relation with fasting insulin that is independent of conventional epidemiological estimate of total body fat (BMI), indicates that central fatness has a greater influence on insulin resistance among the 15-yr-olds than total body fat. Along those lines, central fatness has been shown to be related to insulin resistance independent of total body fat in young adolescents and adults, whereas total body fat was not related to insulin resistance independent of central fatness (23,27).
The existing literature indicates that fitness does not play a major role in determining insulin resistance in children but does have an independent role among adults (3,6,16,27,28). Because fitness is not strongly affected by physical activity in children (1,10), but physical activity affects fitness among adults (32,36), it could be proposed that the effects of fitness on insulin resistance in adults could be, in part, attributable to physical activity. Although more difficult to objectively measure, physical activity is negatively associated with insulin resistance in adults (19,24) and children (1,22), even after controlling for total body fat (4). At some time point during adolescence and puberty, physical activity begins to affect fitness, and, therefore, fitness may begin to impact insulin resistance. In late adolescence, fitness already positively correlates with insulin resistance after adjusting for body fat, as it does in adults (17,21). A unique aspect of the present study was the attempt to tease out the difference in the fitness-fatness association to insulin resistance between mostly prepubertal (9-yr-olds) and mostly postpubertal (15-yr-olds) children. In this study, the relation of fitness to fasting insulin when adjusted for fatness was clearly stronger in the older age group; thus, this relation is in a transition from being none in children to being mild-to-moderate in adults. Other studies have not been able to test this possible change in the relation during middle adolescence, because they have lumped in one group children of various ages across childhood and adolescence (3,28).
Despite the lack of an independent relation of fitness to insulin resistance in the present and in previous studies in children (3,16,28), and the weak association in adolescents in this study, training studies in 9- to 15-yr-old overweight girls have found improvements in fitness along with increases in insulin sensitivity without changes in body weight or body fat (25). Similarly, in a randomized controlled study of 12-yr-old obese children, Carrel et al. (5) found that training improved fitness, along with an increase in insulin sensitivity, without changes in BMI. These training studies suggest that fitness may play some role independent of fatness. Therefore, we created four groups of children split on the median of fitness and the three fatness measures (fitter and leaner children, fitter and fatter children, unfitter and leaner children, unfitter and fatter children) to simultaneously assess the interactive effects of fitness and fatness on fasting insulin levels. The fitter and fatter children did not differ from the fitter and leaner children in fasting insulin in either age group, and no relation was found between body composition and fasting insulin in children above the median in fitness, suggesting that as long as the children and adolescents are fit, a greater fatness level does not significantly worsen fasting insulin. These results are in contrast with the findings of Gutin et al. (17), who reported that fasting insulin remained high in adolescents with high fatness regardless of their fitness level, and that increasing fatness within fitness levels resulted in higher fasting insulin. Similarly, high-BMI/high-fit 9- to 18-yr-old boys had a worse composite risk factor for cardiovascular disease than did low-BMI/low-fit or low-BMI/high-fit boys, but low-BMI/low-fit girls of the same age did not differ from the high-BMI/high-fit girls (13). Both these studies (13,17) used a submaximal exercise test to estimate fitness, and Eisemann et al. (13) grouped children and adolescents of various ages into one group; these differences might explain some of the disagreement between these studies and the present results. The protective effects of being fit while being fat (fit and fat) against various lifestyle-related diseases have been established in adults (7,34), but we are unaware of any other data in children indicating that fat and fit children are not different on health risk factors compared than fit and lean children.
Because of the cross-sectional design of this study, cause and effect cannot be established; although fatness is a risk factor for insulin resistance, high insulin could cause higher fatness through its anabolic effects. Furthermore, it is unknown whether the fitness and fatness are on the same causal chain (i.e., low fitness increasing fatness, which then increases insulin resistance), as has been suggested for physical activity (4), or whether these risk factors are parallel (competing), as fit-but-fat data in adults indicate (7,34). Nevertheless, the associations in this study consistently suggest that fatness may play a more important role than fitness for insulin resistance, especially in lower-fit children. The lack of association between fatness and fasting insulin in higher-fit children also indicates that the fatness and fitness risk factors are parallel and counteract each other. However, further longitudinal studies on the impact of childhood fatness and fitness on the later health of apparently healthy children are needed.
The mechanisms for the beneficial effects of fitness on insulin resistance are most likely related to training (physical activity). Exercise can reduce fasting insulin and improve insulin sensitivity through enhanced glucose transport into muscle cells for storage to replace glycogen used during exercise (26), and by increasing the ability of the muscles to metabolize glucose (11). The mechanisms underlying these effects involve upregulation of key proteins in the insulin cascade, such as insulin-receptor substrates, phosphor-inositol-3-kinase, and glucose-transporting proteins (37). Other mechanisms are upregulation of the rate-limiting enzymes: hexokinase, citrate synthase, and glycogen synthase, which would help maintain the concentration gradient when glucose-transporting proteins are embedded on the cell membrane (37). Exercise training, along with increases in fitness, may also increase the fat-free mass (mainly muscle mass) (25), which, theoretically, should allow more transport of glucose from the blood into the muscles.
We conclude that total body fat has a greater association with fasting insulin in 9-yr-olds, whereas central fatness is more independently related to fasting insulin among 15-yr-olds in two distinct, population-based groups of children and adolescents. Fatness has a greater association with fasting insulin than fitness, especially among the 9-yr-olds; however, fitness attenuates the adverse relation of fatness to fasting insulin in 15-yr-old adolescents but does not change it in 9-yr-old children. In both age groups, being fitter and fatter does not result in greater fasting insulin than being fitter and leaner, and fatness is primarily associated with fasting insulin in lower-fit children.
The authors would like to thank Katla Sóley Skarphéðinsdóttir, Kristján Þór Magnússon, and Gry Skæveland for invaluable help during the data collection. This study was supported by research grants from the Icelandic Centre for Research.
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