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Keywords:

  • cardiorespiratory fitness;
  • insulin sensitivity;
  • insulin secretion;
  • adiposity;
  • youth

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Objective: We examined whether the relationship between cardiorespiratory fitness (CRF) and insulin sensitivity (IS)/secretion is independent of adiposity in healthy African-American (n = 65) and white (n = 57) youth.

Research Methods and Procedures: IS and β-cell function were evaluated by a 3-hour hyperinsulinemic-euglycemic and a 2-hour hyperglycemic (12.5 mM) clamp, respectively. Total fat was measured by DXA and abdominal fat with computed tomography. CRF (peak volume of oxygen) was measured using a graded maximal treadmill test.

Results: Independent of race, CRF was inversely (p < 0.05) related to total and abdominal fat, fasting insulin and first phase insulin secretion, and positively (p < 0.05) related to IS. When subjects were categorized into low (≤50th) and high (>50th) CRF groups, IS was significantly (p < 0.05) higher in the high compared with the low CRF group independently of race. Furthermore, first and second phase insulin secretion were lower (p < 0.05) in the high CRF group in comparison with the low CRF group in both races. However, in multiple regression analyses CRF was not (p > 0.05) an independent predictor of IS and acute insulin secretion after accounting for total adiposity.

Discussion: Our findings demonstrate that low CRF is associated with decreased IS compensated by higher insulin secretion in both African-American and white youth. However, this relationship disappears after adjusting for differences in adiposity, suggesting that the association between fitness and IS is mediated, at least in part, through fatness.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Epidemic increase in childhood obesity and its adverse health outcomes are of great public health concern in the United States. In adults, emerging evidence suggests that having a moderate to high cardiorespiratory fitness (CRF)1 is consistently associated with lower risks for many health outcomes such as the metabolic syndrome (1)(2), cardiovascular disease (3), and all-cause mortality (3)(4)(5). In some studies, these relationships are independent of fatness (2)(4). Despite the overwhelming evidence in adults, little is known about the role of CRF on health risks in youth. Gutin et al. (6) previously reported that fatness explained more of the variance in fasting insulin level than did fitness in adolescents. Ball et al. (7) have shown that CRF is not independently related to insulin sensitivity (IS) and secretion as measured by frequently sampled intravenous glucose tolerance test after accounting for total adiposity in overweight Hispanic youth. Conversely, recent evidence suggests that CRF is an independent predictor of insulin resistance (homeostasis model assessment) in a mixed racial sample of post-pubertal women (8). We examined the independent relationships between CRF and adiposity on IS and β-cell function using the gold standard methods and 3-hour hyperinsulinemic-euglycemic and 2-hour hyperglycemic clamp in healthy African-American and white youth.

Research Methods and Procedures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Subjects

Subjects consisted of healthy African-American (n = 65) and white (n = 57) youth, some of whom have been reported previously (9)(10)(11), who participated in studies to assess IS and its determinants in childhood. The subjects varied in age (8 to 17 years) and BMI (14 to 50 kg/m2). Study participants were recruited through newspaper advertisements in the greater Pittsburgh area, flyers posted in the city public transportation, and posters placed on campus. These Institutional Review Board-approved advertisements do not state the specific goals of the study but simply indicate that “healthy normal weight and overweight children and adolescents are needed for research studies that involve blood and body composition testing.” The investigation was approved by the Institutional Review Board and performed in the General Clinical Research Center (GCRC) of Children's Hospital of Pittsburgh. Parental informed consent and child assent were obtained from all participants before participation in accordance with the ethical guidelines of Children's Hospital of Pittsburgh. All participants were healthy as confirmed by physical examination and routine hematologic and biochemical tests. None of the subjects were taking medications or participated in structured regular physical activity. Pubertal development was assessed by physical examination according to Tanner criteria and was confirmed by measurement of plasma testosterone in men, estradiol in women, and dehydroepiandrosterone sulfate in both.

Body Composition

Total body fat was assessed by DXA. A single axial image (10-mm thickness) was obtained at the level of L4- L5 intervertebral disc space using a computed tomography to measure abdominal subcutaneous and visceral adipose tissue (12).

Measurement of β-Cell Function and IS

To evaluate β-cell function and IS, all participants underwent a hyperglycemic and a hyperinsulinemic-euglycemic clamp experiment on two separate occasions, except three boys (two African American and one white) who participated in a hyperglycemic clamp alone. The clamp measurements were randomized and separated by approximately 1 to 3 weeks. Subjects stayed in the GCRC the night before each clamp experiment, which was performed after a 10- to 12-hour overnight fast. During the clamp measurements, two catheters were inserted; after anesthetizing the skin with Emla cream, one was placed in a vein on the forearm for administration of glucose and insulin infusions, and the other was placed on the dorsum of the contralateral heated hand for sampling of arterialized venous blood. A 2-hour hyperglycemic clamp (12.5 mM) was performed from 9 to 11 am to evaluate first and second phase insulin secretion as described previously (11). On a separate visit, a 3-hour hyperinsulinemic-euglycemic clamp was performed from 9 to 12 am to measure IS as reported previously (13)(14). Briefly, plasma glucose was clamped at 5.6 mM with a variable rate infusion of 20% dextrose based on arterialized plasma glucose determinations every 5 minutes. The insulin-stimulated glucose disposal rate was calculated using the average exogenous glucose infusion rate during the final 30 minutes of the clamp. IS was calculated by dividing insulin-stimulated glucose disposal rate by the steady-state insulin levels during the last 30 minutes of the clamp.

Biochemical Measurements

Plasma glucose was measured by the glucose oxidase method with a glucose analyzer (YSI, Inc., Yellow Springs, OH), and the insulin concentration was determined by radioimmunoassay (11).

CRF

Peak volume of oxygen (Vo2peak) was measured using the Bruce multistage treadmill protocol (15) using standard open-circuit spirometry (Parvo Medics, Salt Lake City, UT). Vo2peak was attained when at least two of the following three criteria were achieved: a change in Vo2 of <2.1 mL/kg per minute with increasing exercise intensity at near-maximum higher treadmill stages, a respiratory exchange ratio in excess of 1.05, and/or heart rate >90% of the age-predicted maximum (220 − age). CRF was expressed relative to body weight (milliliters per kilogram per minute), which is the recommended index of individuals’ aerobic fitness for clinicians and health care professionals (16).

Statistical Analyses

Statistical procedures were performed using the SPSS/PC statistical program (version 13.0 for Windows; SPSS, Inc., Chicago, IL). To examine the influence of CRF on IS/secretion, subjects were categorized into low and high CRF groups using the 50th percentile of Vo2peak derived from all subjects (n = 122). Subject characteristics were examined by two-way ANOVA with race and CRF groups as the main effects. Spearman correlation coefficients were employed to determine the associations among Vo2peak, total adiposity, and metabolic profiles. The Mann-Whitney U tests were used to evaluate CRF group differences in IS/secretion. CRF group effects on IS/secretion were examined using analysis of covariance, with CRF group as the fixed factor, adjusting for age, pubertal status, and total adiposity. Multiple regression analyses were used to quantify the independent contribution of fitness and fatness to IS/secretion. Data are presented as means ± standard error.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Subject characteristics are shown in Table 1.

Table 1.  Subject characteristics
 African-AmericansWhites 
  • CRF, cardiorespiratory fitness; NS, not significant; VAT, visceral adipose tissue; ASAT, abdominal subcutaneous adipose tissue; Vo2peak, peak volume of oxygen. Data are presented as means ± standard error.

  • *

    Two-way ANOVA; significant effects of race, CRF, and race × CRF are shown, p < 0.05.

  • In African Americans, n = 40 and n = 23 in low and high CRF groups; in whites, n = 17 in low CRF group.

  • In African Americans, n = 39 and n = 23 in low and high CRF groups; in whites, n = 18 and n = 36 in low and high CRF groups.

 AllLow CRFHigh CRFAllLow CRFHigh CRFSignificance*
n654124571938 
Age (years)11.9 ± 0.311.8 ± 0.312.4 ± 0.411.7 ± 0.311.8 ± 0.511.7 ± 0.3NS
Sex (male/female)36/2917/2419/528/294/1524/14 
Tanner stage       
 I2115620614 
 II to V442618371324 
BMI (kg/m2)24.9 ± 1.127.0 ± 1.521.4 ± 1.222.6 ± 1.027.5 ± 2.020.2 ± 0.8CRF
Total fat (%)27.1 ± 1.732.6 ± 1.917.7 ± 2.326.2 ± 1.635.3 ± 2.822.2 ± 1.6CRF
VAT (cm2)32.7 ± 3.641.1 ± 5.018.4 ± 3.331.2 ± 3.741.4 ± 5.826.2 ± 4.5CRF
ASAT (cm2)233.1 ± 29.7314.7 ± 39.794.7 ± 24.3192.4 ± 26.9327.7 ± 56.2124.7 ± 22.0CRF
Fasting glucose (mg/dL)95.3 ± 0.795.5 ± 0.994.9 ± 1.296.4 ± 0.895.9 ± 1.396.7 ± 1.0NS
Fasting insulin (μU/mL)25.4 ± 2.129.6 ± 3.017.8 ± 1.521.8 ± 1.630.3 ± 3.717.7 ± 1.2CRF
Vo2peak (mL/kg per minute)29.8 ± 1.024.9 ± 0.738.2 ± 1.036.6 ± 1.227.7 ± 0.441.0 ± 1.3CRF, race

Relationships of CRF to Fatness and Insulin Resistance

Independent of race, Vo2peak was inversely (p < 0.05) related to percentage body fat and visceral fat (Figure 1). Furthermore, Vo2peak was positively (p < 0.05) related to IS and inversely (p < 0.05) related to first phase insulin in both races. All of these associations remained significant (p < 0.05) after controlling for age and pubertal status.

image

Figure 1. (Black circles) African Americans. (White circles) Whites. Associations among Vo2peak, adiposity, and IS/secretion.

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Comparisons of Low vs. High CRF on IS and β-Cell Function

Despite similar fasting glucose between the low and high CRF groups, fasting insulin was significantly (p < 0.05) lower in the high CRF in comparison with the low CRF independent of race (Table 1). In vivo IS was significantly higher (p < 0.05) in the high CRF in comparison with the low CRF group in both races (Figure 2 A and B). Furthermore, first and second phase insulin secretion was lower (p < 0.05) in the high CRF in comparison with the low CRF group in both African Americans and whites (Figure 3). However, the influence of high CRF on IS (Figure 2C and 2D), fasting insulin, and insulin secretion (data not shown) did not remain significant (p > 0.05) after adjusting for percentage body fat, age, and pubertal status.

image

Figure 2. (Black bars) Low CRF. (White bars) High CRF. Influence of fitness on IS in African Americans (A and C) and whites (B and D) before (upper) and after (lower) adjusting for age, pubertal status, and percentage adiposity.

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image

Figure 3. Plasma insulin (upper, A and B), and basal, first phase, and second phase insulin secretion (lower, C and D) in low vs. high CRF in African Americans (left) and whites (right) during a hyperglycemic clamp.

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Independent Contributions of Fitness and Fatness on IS and β-Cell Function

Multiple regression analyses revealed that race and pubertal status were independently (p < 0.05) related to IS and secretion as expected (Table 2). Furthermore, percentage body fat was independently (p < 0.05) related to fasting insulin, IS, and secretion (Table 2) after controlling for Vo2peak. For the dependent variable second phase insulin secretion, Vo2peak was inversely (p < 0.05) related. When multiple regression analysis was employed in normal-weight subjects (age- and sex-specific BMI <85th percentile) (17) alone, the results were similar to those observed in the total population: Vo2peak did not contribute (p > 0.05) to any of the metabolic variables, whereas percentage body fat was related to fasting insulin (p = 0.023) and IS (p = 0.067) after accounting for race, pubertal status, sex, and Vo2peak (data not shown).

Table 2.  Multiple regression analyses examining independent contributions of CRF and fatness to insulin sensitivity and β-cell function
Dependent variablesIndependent variablesβSEp
  1. CRF, cardiorespiratory fitness; SE, standard error; Vo2peak, peak volume of oxygen; IS, insulin sensitivity.

  2. All dependent variables were log-transformed to normalize their distribution. Race: 1, African Americans; 2, whites. Pubertal status: 1, prepubertal; 2, pubertal. Sex: 1, males; 2, females.

Fasting insulin (R2 = 0.61, p < 0.01)Race−0.0470.0330.156
 Pubertal status0.1330.033<0.001
 Sex0.0320.0320.315
 Vo2peak0.0000.0020.915
 Total fat (%)0.0110.002<0.001
IS (R2 = 0.73, p < 0.01)Race0.0840.0430.053
 Pubertal status−0.2210.044<0.001
 Sex0.0010.0420.985
 Vo2peak−0.0010.0030.764
 Total fat (%)−0.0200.002<0.001
First phase insulin (R2 = 0.52, p < 0.01)Race−0.1960.045<0.001
 Pubertal status0.1100.0460.018
 Sex−0.0280.0440.523
 Vo2peak−0.0050.0030.112
 Total fat (%)0.0090.002<0.001
Second phase insulin (R2 = 0.52, p < 0.01)Race−0.0330.0420.431
 Pubertal status0.1440.0430.001
 Sex−0.0270.0410.515
 Vo2peak−0.0070.0030.034
 Total fat (%)0.0100.002<0.001

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

We evaluated the relationship of CRF to IS and β-cell function in the context of body composition using the gold standard methods in healthy African-American and white youth. The primary findings of this study are that low CRF is associated with higher total and abdominal fat, and lower IS compensated by higher insulin secretion independent of race; and beneficial influence of high CRF on IS/secretion is abolished once adiposity is controlled for. These observations suggest that in the pediatric population, the effect of high CRF on IS and secretion may be mediated, in part, by decreased adiposity.

Boreham et al. (18) reported that the strength of the relationships between fatness and cardiovascular disease risk factors is greater than those observed between fitness and the same risk factors in a large sample of European boys and girls. In addition, Shaibi et al. (19) demonstrated that CRF is not independently associated with any individual components of the metabolic syndrome in overweight Hispanic youth. Our findings in a biracial sample of children and adolescents using the gold standard methods of examining IS and β-cell function extend the previous observations (6)(18)(19) and demonstrate that fatness is a stronger predictor of insulin resistance and hyperinsulinemia than fitness in youth. This observation differs from Kasa-Vubu et al. (8), who reported an independent effect of CRF on insulin resistance in a small sample of adolescent girls (n = 53). The different findings could be attributed to differences in the cohorts studied and methodology employed. In that study (8), the subjects examined includes young women (mean age, 18.7 ± 1.3 years) from various ethnic backgrounds (African American, white, Asian, and Hispanic white). Moreover, insulin resistance was evaluated by homeostasis model assessment, which is not a true measurement of in vivo IS.

Unlike several pediatric studies, some studies in adults reported an independent effect of CRF on major health outcomes. In men, fitness is associated with all-cause and cardiovascular disease-related mortality and the incidence of metabolic syndrome independent of fatness (2)(4). Although health risk measures examined are different between studies in children (i.e., disease risk factors) and adults (i.e., incidence of CVD or mortality), they provide substantial support for the beneficial influence of having a high aerobic fitness on obesity-related health risks independent of age.

Evidence suggests that lower aerobic fitness is independently related to greater adiposity gain in growing prepubertal children (20). During 3 to 5 years of follow-up, Johnson et al. (20) have shown that there is a significant inverse relationship between initial aerobic fitness and increasing adiposity during maturation, and this observation was similar for both African-American and white children. Given that childhood fitness predicts adulthood fitness (21) and that childhood obesity tracks well into adulthood obesity together with cardiovascular risk factors (21), regular physical activity should be an essential component of weight management in overweight youth to improve CRF and health risk factors.

Limitations of this study warrant mention. First, the cross-sectional design of the present study does not allow us to infer a causal relationship. Thus, intervention studies with serial measurements of fitness, total fat, and metabolic profiles are needed to confirm our observation. Second, due to small sample size, we could not examine whether gender influences the relationship between fitness and fatness on the metabolic risks.

In conclusion, our findings suggest that in youth, low CRF is associated with lower IS compensated by higher insulin secretion, and these relationships may be mediated, in part, by increased fatness. These findings reinforce the recommendation that youths adopt a physically active lifestyle to improve aerobic fitness and body composition for preventing childhood obesity and related health risks.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

This work was supported by the U.S. Public Health Service (Grants RO1-HD-27503 and K24-HD-01357), by GCRC (Grant MO1-RR-00084), and by Eli Lilly and Co. We thank the study participants and GCRC staffs. This work was presented at the Annual Scientific Meeting of the North American Association for the Study of Obesity (October 15–19, 2005, Vancouver, Canada).

Footnotes
  • 1

    Nonstandard abbreviations: CRF, cardiorespiratory fitness; IS, insulin sensitivity; GCRC, General Clinical Research Center; Vo2peak, peak volume of oxygen.

  • 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.

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  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
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