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Association between the Insulin Resistance of Puberty and the Insulin-Like Growth Factor-I/Growth Hormone Axis

Department of Pediatrics (A.M., J.S., A.S.) and School of Public Health (D.J., C.-P.H.), University of Minnesota, Minneapolis, Minnesota 55455; Department of Pediatrics (P.C.), University of California, Los Angeles, Los Angeles, California 90095; and Department of Public Health Sciences (R.P.), Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

Address all correspondence and requests for reprints to: Antoinette Moran, M.D., University of Minnesota Pediatric Department, Box 404, 516 Delaware Street SE, Minneapolis, Minnesota 55455. E-mail: moran001{at}umn.edu.

Abstract

To test the hypothesis that the relative insulin resistance of puberty is associated with changes in IGF-I levels, we compared IGF-I, IGF binding protein-3 (IGFBP-3), and IGFBP-1 levels to insulin resistance [M_lbm, milligrams glucose used per kilogram of lean body mass (LBM) per minute] measured during euglycemic, hyperinsulinemic clamp studies in 342 children and adolescents.

IGF-I levels rose and fell during the Tanner stages of puberty in a pattern that closely followed the rise and fall of insulin resistance. IGF-I levels were significantly related to M_lbm in boys (P = 0.0006) and girls (P = 0.02). IGF-I was significantly related to fasting insulin levels only in girls (P = 0.006; boys, P = 0.26), and this relation was significantly influenced in girls by body fat (P = 0.007), with the strongest association between IGF-I and fasting insulin seen in thin girls. IGFBP-1 correlated negatively with insulin resistance in both boys (P = 0.0004) and girls (P = 0.04), whereas IGFBP-3 correlated positively with insulin resistance in boys (P = 0.0004) but not girls (P = 0.85).

These data suggest that the GH/IGF-I axis is an important contributor to the insulin resistance of puberty.

TRANSIENT INCREASE in insulin resistance is a normal component of pubertal development (1, 2, 3, 4). Previous studies from this group using euglycemic clamps in 357 Minneapolis school children showed a pattern of increasing insulin resistance that began early in puberty and resolved by the end of puberty (1). The factors influencing these pubertal changes have not been clearly defined. Although insulin resistance in children is strongly related to body mass index (BMI), this relationship is independent of Tanner stage and sex, and the relative insulin resistance of puberty is not explained by differences in BMI or adiposity (1).

Important hormonal changes occur during pubertal development. Sex hormone levels are barely detectable in early childhood but increase to adult levels during puberty. Neither testosterone nor estradiol levels, however, have been shown to be associated with insulin resistance (2). Because levels of GH and IGF-I are higher during adolescence than in the prepubertal or adult years (5), it is possible that the insulin resistance of normal puberty might be related to the GH/IGF-I axis. Plasma IGF-I levels are primarily regulated by GH (6), and GH is a counterregulatory hormone known to be a potent insulin antagonist (7).

An association between IGF-I levels and glucose-stimulated insulin levels was reported in 14 adolescents (4), providing the first suggestion that IGF-I might be related to pubertal insulin resistance. A study of children in early puberty reported an inverse correlation between IGF binding protein-1 (IGFBP-1) levels and insulin resistance as measured by the minimal model (8), supporting this theory. Insulin resistance has not previously been compared with levels of IGF-I and its binding proteins at each Tanner stage to define the pattern of changes in this relation that occurs across the entire spectrum of normal puberty.

The present study of 342 youth was undertaken to test the hypothesis that the relative insulin resistance of puberty is intimately associated with increased IGF-I levels. Fasting IGF-I, IGFBP-3, and IGFBP-1 levels were compared with insulin resistance measured by euglycemic clamp studies in boys and girls at every Tanner stage of puberty, to determine the strength of this relation and whether the pattern of IGF-I changes across the pubertal stages resembles the pattern of insulin resistance changes during puberty.

Subjects and Methods

Subjects

This study was approved by the University of Minnesota Committee for the Use of Human Subjects in Research. Informed consent was obtained from parents, and informed assent from the children. Participant recruitment and methods have been previously described in detail (1, 9). The subjects were participants in a longitudinal study of the relation between insulin resistance and cardiovascular risk factors in children. Insulin clamps were completed in 357 participants (age, 13.0 ± 1.2 yr). Frozen fasting serum samples were available from 342 of the participants, and these form the cohort for the present report.

Body composition measurements

All participants attended a clinic dedicated to this study in which history and physical examination were performed by board-certified pediatricians. Children were divided into Tanner stages according to pubic hair development in boys and breast and pubic hair development in girls. In girls, the greater of the two values was used for statistical analysis so that pubertal maturation was not underestimated. Triceps and subscapular skinfold thickness were measured in duplicate to the nearest millimeter with Lange calipers and were used to predict percentage body fat using a regression equation developed specifically for this age group (10, 11).

Euglycemic clamps

Participants were admitted to the University of Minnesota Clinical Research Center after a 10- to 12-h overnight fast. An arm vein was cannulated for infusion of potassium phosphate, insulin, and dextrose. A contralateral vein was cannulated for blood sampling, and the hand was placed in a heated box (65 C) to arterialize venous blood. Insulin was infused at a rate of 1 mU/kg·min for 3 h, and plasma glucose was measured every 5 min. A variable infusion of 20% dextrose was used to maintain the serum glucose level at 100 mg/dl.

Analytical methods and calculations

Plasma glucose was measured immediately at the bedside with a Beckman Glucose Analyzer II (Beckman Instruments Inc., Fullerton, CA). Blood samples were collected on ice, centrifuged within 20 min, and frozen and stored at -70 C for up to 4 yr. IGF-I and IGFBP levels have previously been shown to be stable for at least 15 yr at -70 C (12). Insulin levels were determined within 1 wk of the clamp studies by RIA using a double antibody method. IGF-I, IGFBP-3, and IGFBP-1 assays were performed by ELISA (Diagnostic Systems Laboratories, Inc., Webster, TX) according to the manufacturer’s instructions. Insulin sensitivity (M) was calculated as the amount of glucose (milligrams per kilogram per minute) required to maintain euglycemia during the last 40 min of the clamp and expressed as M_lbm [milligrams of glucose infused per kilogram lean body mass (LBM) per minute]. A lower M_lbm value represents a greater degree of insulin resistance.

Data analysis

Means and SD values were computed within sex and Tanner stage categories. Pearson partial correlation coefficients were computed, adjusting for sex, Tanner stage, and race. Analyses by race were adjusted for sex and Tanner stage. Plots of mean IGF-I, IGFBP-1, and IGFBP-3 were made by Tanner stage, showing similarity of pattern between boys and girls. A further plot of IGF-I and M_lbm (the latter with inverted scale) was used to show the similarity of pattern of these two variables across Tanner stage, within each sex. Pairwise two-sample t tests were performed to compare Tanner stages within sex categories. Slopes were derived from linear regression of IGF-I or the binding proteins on either fasting insulin or M_lbm, percentage body fat, and their interaction (all as continuous variables), adjusted for sex, race, and Tanner stage. Parallel regressions were done for each of the binding proteins.

Results

Characteristics for boys and girls are presented in Table 1. As previously reported (1), BMI did not differ significantly between boys and girls at any stage of puberty, but girls had greater adiposity than boys (P = 0.0001). Lean mass and fat mass were related in girls (r = 0.56; P = 0.0001) but not boys (r = -0.02; P = 0.78), consistent with the observation that girls simultaneously gain LBM and fat body mass during puberty, whereas boys gain primarily LBM. Insulin resistance was greater in girls than boys (P < 0.0003), and this difference was only partially related to greater adiposity in girls (1). There were only three girls at Tanner stage 1, and findings for this subgroup are presented for completeness only.

Levels of IGF-I and its binding proteins (Table 2)

The cohort of girls had a slightly higher mean IGF-I level than boys (508 vs. 476 ng/ml; P = 0.053), but there were no significant differences between boys and girls at any Tanner stage. IGF-I levels rose steeply in early puberty in both sexes (Fig. 1) and peaked at Tanner stage (T) 4 (T3 vs. T1, T4 vs. T1, T3 vs. T2, T4 vs. T2; in girls, the maximum P value for these four comparisons was 0.02; in boys, the maximum P value was 0.06; Table 2). Levels fell significantly from T4 to T5 in both genders (P = 0.001). These findings were unchanged by further adjustment for BMI or body fat.

View larger version (19K): [in this window] [in a new window]   Figure 1. Changes in IGF-I and Mlbm from T1 to T5 in boys and girls. Note that the Mlbm axis is inverted to better show the similar pattern for IGT-I and insulin resistance. A lower Mlbm value indicates greater insulin resistance.

IGF-I correlated with its major carrier protein, IGFBP-3 (r = 0.25; P = 0.0001), but not with its short-term regulator IGFBP-1 (r = -0.08; P = 0.13) in both sexes. IGFBP-3 and IGFBP-1 were not significantly correlated (r = 0.05; P = 0.38). These relations were independent of percentage body fat.

Lipid levels, which have been previously reported in this cohort (9), were not related to IGF-I levels. Systolic (r = 0.12; P = 0.03) but not diastolic (r = 0.01; P = 0.85) blood pressure was related to IGF-I levels. These relations were independent of percentage body fat.

Relation of IGF-I and binding protein levels to insulin resistance

IGF-I was significantly related to M_lbm in both genders (girls, r = -0.18, P = 0.02; boys, r = -0.25, P = 0.0006), and there was no interaction between this relationship and percentage body fat in girls (P = 0.39) or boys (P = 0.42). The pattern of change in M_lbm was inverse to the IGF-I pattern during puberty in both sexes, i.e. changes in IGF-I closely followed the changes in insulin resistance (Fig. 1).

IGF-I was significantly related to fasting insulin in girls (r = 0.22; P = 0.006) but not boys (r = 0.08; P = 0.26). The strength of the correlation between IGF-I and fasting insulin was strongly related in girls to percentage body fat (P = 0.007), and was not significantly related to LBM (P = 0.10). As noted in Fig. 2, the association between IGF-I and fasting insulin was strongest in girls with a low percentage body fat and steadily decreased as percentage body fat increased. In contrast, this association was not related to percentage body fat in boys (P = 0.55).

View larger version (28K): [in this window] [in a new window]   Figure 2. Estimated slope of fasting IGF-I vs. fasting insulin, according to percentage body fat, derived from a regression model containing the interaction of fasting insulin and percentage body fat.

IGF-I levels did not differ between white and black subjects, but whites had significantly higher levels of IGFBP-3 (P = 0.001) and marginally higher levels of IGFBP-1 (P = 0.06). Further adjustment for percentage body fat or BMI did not alter these relationships.

Discussion

This study of 342 normal youth shows that IGF-I levels in boys and girls rise and fall during the course of puberty in concert with the well recognized rise and fall in insulin resistance. IGFBP-3, the primary carrier protein of IGF-I, correlates positively with insulin resistance, whereas IGFBP-1, which is inhibited by insulin, correlates inversely with insulin resistance. This is the first study to compare insulin resistance to IGF-I and its binding proteins at each Tanner stage, to define the pattern of changes in this relation that occurs across the entire spectrum of normal puberty. The data suggest that physiological elevation of the IGF-I/GH axis contributes to the relative insulin resistance of normal puberty.

Puberty is associated with a rise in GH, increased sex steroid secretion, and increased insulin levels. All of these factors may contribute to the rise in IGF-I and IGFBP-3 levels and may operate synergistically to enhance growth. GH has both anabolic and diabetogenic effects, and the rise in IGF-I seen during puberty may be a physiological balancing factor to the effects of GH. In both prepubertal and pubertal children, mean 24-h GH levels correlate with insulin resistance and insulin secretion as measured by clamp studies (3). Increased insulin secretion suppresses hepatic IGFBP-1 production. This, in turn, would be expected to increase the availability of bioactive IGF-I to further stimulate somatic growth. Thus, insulin, GH, IGF-I, and the IGFBPs may act together to promote growth.

The current data show that the association of IGF-I with fasting insulin differs between the sexes and appears to be related to adiposity in girls. The significant relation between fasting insulin and IGF-I was strongest in thin girls and decreased with increasing percentage body fat. This may suggest that fasting insulin levels rise in response to increasing body fat until a maximal influence of fasting insulin on IGF-I is exceeded and a plateau effect reached, thus giving the appearance of a lessening effect with increasing fatness. In boys, however, there was no significant relationship between IGF-I and fasting insulin and no effect of percentage body fat on this interaction. Although there is no clear explanation for this, the sex-specific patterns may be related to differences in hormonal milieu, in body fat distribution, or in the ratio between body fat and LBM. Deep visceral fat, which was not specifically measured in the current study, may have the greatest effect on insulin resistance.

In contrast to fasting insulin, the significant relation between IGF-I and M_lbm in both sexes was independent of adiposity. Insulin resistance (M) is an independent, primary component of puberty that is only weakly correlated with fatness (r = 0.2), whereas hyperinsulinemia, in addition to increasing in response to insulin resistance, is more highly dependent on the level of body fatness (r = 0.4). We have previously shown that fasting insulin and M_lbm differ in their relation to cardiovascular risk factors in this population (9).

Investigation into the effect of ethnicity on IGF-I and its binding proteins has produced conflicting results (13, 14, 15, 16, 17). There were no significant differences in IGF-I or its relation to fasting insulin or insulin resistance between black and white children in this study. IGFBP-1 and IGFBP-3 were lower in the black children in the current cohort. Lower IGFBP-1 levels have been previously reported in black girls (13, 14, 15), whereas IGFBP-3 levels have been reported to be either no different between black and white children (13, 14) or lower in black children (15) and black men (17, 18). The potential implications of this in terms of body composition or insulin sensitivity are unclear.

In conclusion, IGF-I levels rose and fell in a pattern that was similar to the rise and fall of insulin resistance across the Tanner stages of puberty. These data suggest that the GH/IGF-I axis contributes to the insulin resistance of puberty.

Acknowledgments

Footnotes

This project was supported by National Institutes of Health Grants HL 52851 and M01-RR-00400 (to the General Clinical Research Center).

Abbreviations: BMI, Body mass index; IGFBP, IGF binding protein; LBM or lbm, lean body mass; M_lbm, milligrams of glucose used per kilogram of lean body mass per minute; T, Tanner stage of puberty.

Received April 1, 2002.

Accepted July 12, 2002.

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