Twenty-four hour growth hormone and leptin secretion in active postpubertal adolescent girls: impact of fitness, fatness, and age at menarche

CONTEXT: GH is strongly related to body composition, physical activity, and pubertal progression. Adolescent girls decrease physical activity during puberty, whereas their weight increases. Because leptin is a good index of energy balance in active young women, we hypothesized that leptin is related to GH secretion in this population while taking into account fitness, fatness, and age at menarche. METHODS: We measured body composition and maximal oxygen consumption (VO(2)max) in 37 postpubertal adolescent girls aged 16-21 yr. GH was sampled every 10 min and leptin hourly for 24 h. We first analyzed 6-h time blocks by repeated measures for GH and leptin, with body mass index (BMI), percent body fat, and VO(2)max as covariates for the entire group and a lean subgroup. The deconvolution method was used to characterize GH pulsatility from individual time points. RESULTS: GH varied through the day (P < 0.0001), with the highest concentrations overnight. BMI, percent body fat, and VO(2)max were related to GH concentrations in the entire group, whereas leptin predicted GH in the entire group as well as the lean subgroup of girls. Higher leptin was related to lower GH concentrations (P = 0.011), regardless of time. A log leptin level increase by 1 unit decreased GH by 27%. Pulsatility characteristics showed a 1-yr increase of age at menarche increasing total GH input by 20% (P = 0.0035) independently from BMI. CONCLUSION: In postpubertal adolescent girls, leptin is related to GH concentration across the lean to overweight BMI spectrum. GH pulsatile secretion was greater in girls with later age at menarche.     

Ghrelin concentrations in healthy children and adolescents

OBJECTIVE: In addition to its regulation by GH releasing hormone (GHRH) and somatostatin, release of GH from the pituitary is modulated by a third factor, ghrelin, which is expressed in high concentration in the stomach and is present in the circulation. Ghrelin has also been shown to cause weight gain by increasing food intake and decreasing fat utilization. Ghrelin is a potential candidate hormone to influence nutrient intake and growth. Its role through normal childhood and adolescence has not been fully defined. DESIGN: Cross-sectional study in 121 healthy children (65 male, 56 female) aged 5-18 years, in whom height, weight, body mass index (BMI), pubertal status and measurements of IGF-I, IGFBP-3, IGFBP-1 and leptin were available. METHODS: Serum ghrelin concentrations have been measured in radioimmunoassay (RIA; Phoenix, AZ, USA) that detects active and inactive human ghrelin. Relationships between ghrelin and anthropometric data and growth factors were assessed by correlation and regression analyses. RESULTS: Ghrelin was detected in all samples, with a median concentration of 162 pg/ml, range 60-493 pg/ml. Prepubertal children had higher ghrelin concentrations than those in puberty [218 pg/ml (n = 42) and 157 pg/ml (n = 79), P < 0.001], with significant negative correlations between ghrelin and age (rs = -0.39, P < 0.001) and pubertal stage (rs = -0.42, P < 0.001). The decrease in ghrelin with advancing pubertal stage/age was more marked in boys than girls. In the whole group, ghrelin was negatively correlated to BMI SD (rs = -0.24, P = 0.006) and to weight SD (rs = -0.24, P = 0.008) but not height sds. Ghrelin was also negatively correlated to IGF-I (rs = -0.48, P < 0.001), IGFBP-3 (rs = -0.32, P < 0.001) and leptin (rs = -0.22, P = 0.02) but not IGF-II. It was positively related to IGFBP-1 (rs = +0.46, P < 0.001). In stepwise multiple regression, 30% of the variability in ghrelin through childhood could be accounted for by log IGF-I (24%) and log IGFBP-1 (6%). CONCLUSIONS: The fall in ghrelin over childhood and with puberty does not suggest that it is a direct growth-promoting hormone. However in view of the negative relationship with IGF-I and the positive relationship with IGFBP-1, this fall in ghrelin could facilitate growth acceleration over puberty.     

Serum levels of growth hormone binding protein in children with normal and precocious puberty: relation to age, gender, body composition and gonadal steroids

AIM: To study the regulation of GHBP serum levels by gonadal steroids in normal and precocious puberty. STUDY PROTOCOL: We studied GHBP levels in relation to age, sex, pubertal maturation, body composition as well as to circulating IGF-I and gonadal steroid levels in 320 healthy children. Furthermore, we studied the regulation of circulating GHBP in 33 girls with central precocious puberty before and during gonadal suppression with GnRH agonist. METHODS: GHBP was determined by a time-resolved fluoroimmunoassay (GHBP TR-FIA) based on a commercially available immunoassay for GH, the DELFIA GH assay. RESULTS: In healthy children GHBP levels were significantly higher in normal girls compared with boys, and there was no significant increase in GHBP in puberty in both sexes. GHBP levels did not correlate with height (SDS), age, pubertal stage, IGF-I or testosterone/oestradiol levels in boys and girls, respectively. There were significant correlations between BMI and GHBP in boys and girls (R 2 = 0.14 and R 2 = 0.12, both P < 0.0001). Furthermore, GHBP correlated highly significantly with the percentage body fat, determined by BIA in 43 healthy girls (R 2 = 0. 40, P < 0.0001). GHBP levels were significantly higher in girls with central precocious puberty (CPP) (1.31 SDS (1.26), mean (SD)) compared to prepubertal controls (P < 0.0001), and above + 2 SD in 10 out of 33 patients. In girls with CPP, GHBP correlated inversely with oestradiol before treatment (R 2 = 0.26, P < 0.01) and there was a tendency towards a positive correlation with BMI (R 2 = 0.13, P = 0.078). By contrast, there were no signficant correlations between GHBP and IGF-I or height SDS. Gonadal suppression with GnRH agonist treatment caused a transient significant increase of 0.57 SD after 2 months of treatment (P < 0.001), but decreased to baseline levels hereafter. CONCLUSION: We conclude that in children, as in adults, body fat is the primary determinant for the circulating level of GHBP, and that the difference in body fat is probably the main factor for the higher levels of serum GHBP in girls compared with boys, as well as for the negative influence of testosterone levels in boys and of oestrogen levels in girls. The elevation in GHBP levels observed in girls with central precocious puberty is probably due their higher body fat content.     

Serum insulin-like growth factor (IGF)-I and IGF-binding protein-1 in elderly people: relationships with cardiovascular risk factors,body composition,size at birth,and childhood growth

The IGF system is important in regulation of fetal and childhood growth. In later life, IGF-I and IGF-binding protein-1 (IGFBP-1) have been implicated in the pathogenesis of arteriosclerosis. They are, thus, potential candidates in explaining the link between early growth and adult cardiovascular disease. We measured fasting serum IGF-I and IGFBP-1 concentrations in 394 men and women from a cohort of 7086 individuals, born between 1924 and 1933 in Helsinki, Finland, whose weight and height were recorded at birth and from 7 to 15 yr of age. They also underwent clinical examination, including measurement of body fat using bioimpedance, blood pressure, glucose tolerance, and plasma insulin and fibrinogen concentrations. Serum IGF-I was positively correlated with fasting glucose (r = 0.10, P = 0.06) and fibrinogen (r = 0.19, P = 0.0001) concentrations and blood pressure (systolic and diastolic r = 0.10, P 相似文献   

Fitness, training, and the growth hormone-->insulin-like growth factor I axis in prepubertal girls

We recently demonstrated that a brief endurance type training program led to increases in thigh muscle mass and peak oxygen uptake (VO(2)) in prepubertal girls. In this study, we examined the effect of training on the GH-->insulin-like growth factor I (GH-->IGF-I) axis, a system known to be involved both in the process of growth and development and in the response to exercise. Healthy girls (mean age 9.17 +/- 0.10 yr old) volunteered for the study and were randomized to control (n = 20) and training groups (n = 19) for 5 weeks. Peak VO(2), thigh muscle volume, and blood samples [for IGF-I, IGF-binding proteins (IGFBP)-1 to -6, and GHBP] were measured. At baseline, IGF-I was significantly correlated with both peak VO(2) (r = 0.44, P < 0.02) and muscle volume (r = 0.58, P < 0.004). IGFBP-1 was negatively correlated with muscle volume (r = -0.71, P < 0.0001), as was IGFBP-2. IGFBP-4 and -5 were significantly correlated with muscle volume. We found a threshold value of body mass index percentile (by age) of about 71, above which systematic changes in GHBP, IGFBP-1, and peak VO(2) per kilogram were noted, suggesting decreases in the following: 1) GH function, 2) insulin sensitivity, and 3) fitness. Following the training intervention, IGF-I increased in control (19.4 +/- 9.6%, P < 0.05) but not trained subjects, and both IGFBP-3 and GHBP decreased in the training group (-4.2 +/- 3.1% and -9.9 +/- 3.8%, respectively, P < 0.05). Fitness in prepubertal girls is associated with an activated GH-->IGF-I axis, but, paradoxically, early in a training program, children first pass through what appears to be a neuroendocrine state more consistent with catabolism.     

Age-related changes in fat deposition in mid-thigh muscle in women: relationships with metabolic cardiovascular disease risk factors

OBJECTIVE: To determine if fat deposition within mid-thigh muscle, represented by low density lean tissue density, is associated with age, low physical fitness, hyperleptinemia, hyperinsulinemia and dyslipidemia in women. SUBJECTS: Seventy-two women aged 18-69y with a wide range of total body fat (10-55%) and maximal aerobic capacity (VO2max: 17-61 ml/kg(-1)/min(-1)). MEASUREMENTS: Mid-thigh muscle, mid-thigh fat, low density lean tissue, intra-abdominal adipose tissue (IAAT) and subcutaneous abdominal fat (by computed tomography, CT), fat mass (FM) and fat-free mass (FFM) (by dual energy x-ray absorptiometry, DEXA), plasma insulin and leptin (by radioimmunoassay, RIA) and lipoprotein lipid profiles (by enzymatic methods). RESULTS: VO2max declined with age (r=-0.59, P<0.0001) while IAAT and subcutaneous abdominal fat increased with age (r=0.68, r=0.57, r=0.63, P<0.0001). Mid-thigh low density lean tissue correlated with age (r=0.52), VO2max (r=-0.56), FFM (r=0.35), fat mass (r=0.68), IAAT (r=0.66) and subcutaneous abdominal fat (r=0.67, all P<0.005). Mid-thigh low density lean tissue also correlated with fasting plasma leptin, insulin, triacylglycerol (TG), total cholesterol (TC) and low-density-lipoprotein cholesterol (LDL-C) levels (r=0.44, 0.34, 0.41, 0.50, 0.53, respectively, all P<0.005), but not after controlling for body fat and age. Subcutaneous abdominal fat, IAAT, FFM and age were independent predictors of low density lean tissue (P<0.05). CONCLUSIONS: Mid-thigh low density lean tissue is directly related to age and adiposity. Furthermore, it appears that fat accretion in skeletal muscle adversely influences plasma insulin and lipoprotein metabolism in women, but not independently of total adiposity and age.     

Association between the insulin resistance of puberty and the insulin-like growth factor-I/growth hormone axis

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.     

Lipoprotein subfractions in women athletes: effects of age, visceral obesity and aerobic fitness

OBJECTIVE: To examine whether lipoprotein subfractions are associated with age-related changes in visceral obesity and maximal aerobic fitness in women athletes. SUBJECTS AND MEASUREMENTS: Body composition was measured using dual energy X-ray absorptiometry (DEXA) and a single slice computed tomography (CT) scan of the abdomen of 39 women athletes (age: 18-69y, body mass index (BMI): 19-24 kg/m2). Lipoprotein lipids were measured in plasma drawn after a 12 h fast using nuclear magnetic resonance (NMR) spectroscopy, which quantifies lipoprotein subfractions by the spectroscopic differences exhibited by lipoprotein particles of various sizes. RESULTS: Total cholesterol (r=0.42; P<0.01) and low-density lipoprotein cholesterol (LDL-C) (r=0.32; P=0.05) correlated positively with age, even after adjustment for age-related decreases in maximal aerobic fitness (VO2 max) and increases in the intra-abdominal fat area. There were no relationships between any of the lipoprotein subfractions or sizes with age. Very-low-density lipoprotein (VLDL) size and VLDL2-TG correlated with total fat mass (r = 0.40 and r= -0.43, respectively; P < 0.05) and with intra-abdominal fat area (r = -0.47 and r = 0.43, respectively; P < 0.01), but not independently of total fat mass. Total cholesterol and LDL-C were negatively related to maximal aerobic fitness (VO2max) (r = -0.37 and r = -0.33, respectively; P < 0.05), while low-density-lipoprotein (LDL) size was positively related to VO2max (r = 0.35, P < 0.05). CONCLUSIONS: These results suggest that age-associated changes in lipoprotein concentrations are probably, in part, due to primary aging, rather than age-related changes in abdominal obesity and aerobic fitness.     

Serum concentrations of free and total insulin-like growth factor-I, IGF binding proteins -1 and-3 and IGFBP-3 protease activity in boys with normal or precocious puberty

OBJECTIVE  Circulating IGF-I and IGF binding protein-3 (IGFBP-3) levels both increase in puberty where growth velocity is high. The amount of free IGF-I is dependent on the IGF-I level and on the concentrations of the specific IGFBPs. Furthermore, IGFBP-3 proteolysis regulates the bioavailability of IGF-I. However, the concentration of free IGF-I and possible IGFBP-3 proteolytic activity in puberty has not previously been studied.
SUBJECTS AND MEASUREMENTS  We investigated serum levels of easily dissociable IGF-I concentrations and ultrafiltrated free IGF-I levels by specific assays in 60 healthy boys and in 5 boys with precocious puberty before and during GnRH agonist treatment. In addition, total serum IGF-I, IGFBP-1 and IGFBP-3 levels as well as IGFBP-3 protease activity were determined.
RESULTS  Free (dissociable and ultrafiltrated) IGF-I concentrations were significantly higher in pubertal boys than in prepubertal children and correlated significantly with the molar ratio between IGF-I and IGFBP-3 ( r =0.69, P <0.0001 and r =0.54, P =0.0008, respectively) and inversely with IGFBP-1 ( r =−0.47, P <0.0001 and r =−0.43, P =0.0003, respectively). Multiple regression analysis suggested that IGFBP-3 level, and not IGFBP-1, was the major determinant of the free IGF-I serum level in normal boys. Free IGF-I levels were elevated in boys with precocious puberty and decreased during GnRH treatment. IGFBP-3 proteolysis was constant throughout puberty (mean 20%).
CONCLUSIONS  We conclude that easily dissociable and ultrafiltrated free IGF-I serum levels are increased in boys with normal and precocious puberty and suggest that the increased free IGF-I serum concentration in puberty primarily reflects changes in total concentrations of IGF-I and IGFBPs secondary to increased GH secretion, but that it is not influenced by changes in IGFBP-3 proteolysis.     

Aortic augmentation index is inversely associated with cardiorespiratory fitness in men without known coronary heart disease

BACKGROUND: We investigated whether the aortic augmentation index (AIx), a measure of arterial wave reflection and stiffness, is associated with cardiorespiratory fitness in men without known coronary heart disease (CHD). METHODS: Asymptomatic men (n = 201, mean age 51 +/- 9.2 years) referred for a screening exercise electrocardiogram (ECG) underwent applanation tonometry to obtain radial artery pulse waveforms, and an ascending aortic pressure waveform was derived by a transfer function. The AIx is the difference between the first and second systolic peak of the ascending aortic pressure waveform, expressed as a percentage of the pulse pressure. Cardiorespiratory fitness was assessed by maximal oxygen consumption (VO2max mL/min/kg) during a symptom-limited graded exercise test. Multivariable regression analyses were used to identify significant independent determinants of AIx and of VO2 max. RESULTS: Diabetes was present in 2.5% of subjects, 34.8% had history of smoking, and 29% were hypertensive. Mean (+/- SD) AIx was 19.9% +/- 9.0% and mean VO(2 max) was 33.9 +/- 6.4 mL/min/kg. In a multivariable linear regression model, AIx was positively associated with age, hypertension, and history of smoking and inversely with heart rate, height, and body mass index (BMI). The VO2 max was significantly inversely related to AIx after adjustment for age, heart rate, height, and BMI (r = -0.22, P = .002), after further adjustment for CHD risk factors (total cholesterol, HDL-cholesterol, history of smoking, diabetes, hypertension) (P = .006), and after additional adjustment for behavioral factors (physical activity score, alcohol intake, and percent body fat) (P = .022). CONCLUSIONS: These findings indicate that AIx, a measure of arterial wave reflection and stiffness, is inversely associated with cardiorespiratory fitness in men without CHD.     

Serum IGF-I and IGFBP-3 concentrations do not accurately predict growth hormone deficiency in children with brain tumours

OBJECTIVE: The growth hormone (GH)-dependent growth factors insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) may be superior to provocative GH testing in diagnosing GH deficiency (GHD) in children. In adults with brain tumours (BT) and GHD, however, provocative GH testing more accurately reflects GHD than either IGF-I or IGFBP-3. We assessed growth factor levels in children with GHD due to BT with respect to brain tumour type, pubertal stage, growth velocity, bone age delay, and body mass index (BMI). DESIGN: Retrospective case review of all patients followed at our centre with GHD following treatment of BT. PATIENTS: 72 children (51 M, 21 F) with BT diagnosed with GHD by clinical and auxological criteria, including provocative GH testing, in whom pre-GH treatment IGF-I and IGFBP-3 levels were obtained. MEASUREMENTS: Auxological data, including height, weight, growth velocity, and pubertal stage; and biochemical data, including GH response to provocative GH testing and pre-GH treatment serum IGF-I and IGFBP-3 concentrations. RESULTS: IGF-I levels were normal (above -2 SD) in 19 of 70 children (27%), and IGFBP-3 levels were normal in 21 of 42 (50%). In children with GHD, pubertal stage correlated significantly with both IGF-I (r = 0.328, p < 0.006) and IGFBP-3 (r = 0.364, P < 0.02). Normal IGF-1 levels were found in 1/15 children with craniopharyngioma (Cranio) (7%), 10/30 with primitive neuroectodermal tumours (PNET) (33%), and 5/12 children with hypothalamic/chiasmatic glioma (HCG) (42%) (P < 0. 05). IGFBP-3 levels were normal in 4/13 Cranio patients (31%), 8/15 PNET patients (53%), and 6/8 HCG patients (75%) (P = ns). Tanner staging varied significantly among tumour types: mode = 1 for Cranio and PNET vs. mode = 3 for HCG (P < 0.03). BMI did not differ between patients with low vs. normal growth factor levels. CONCLUSIONS: Low IGF-I levels were more predictive of growth hormone deficiency than low IGFBP-3 levels in our brain tumour patients, but both were poor predictors of growth hormone deficiency in children with hypothalamic-chiasmatic glioma and in pubertal children. Serum IGF-I and IGFBP-3 levels, therefore, do not always reflect growth hormone deficiency in children with brain tumours, particularly in those with hypothalamic-chiasmatic glioma or those already in puberty.     

Influence of catch-up growth on IGFBP-2 levels and association between IGFBP-2 and cardiovascular risk factors in Korean children born SGA

Small for gestational age (SGA) at birth and postnatal growth pattern may have an impact on insulin resistance and body composition in their later life. Emerging evidence has indicated that insulin-like growth factor binding protein-2 (IGFBP-2) may be related to insulin sensitivity. The aim of this study was to evaluate insulin resistance and IGFBP-2 levels in SGA children, and to identify the effect of catch-up growth on IGFBP-2 concentration. Serum IGFBP-2 levels were measured in 103 Korean SGA children including 49 prepubertal and 54 pubertal subjects. Anthropometric values, fasting serum levels of metabolic parameters and insulin sensitivity indices were determined. Each prepubertal or pubertal group was subgrouped based on height or weight catch-up growth. The subgroups with weight catch-up showed higher values of BMI, body fat mass, percent body fat, and total cholesterol. Particularly in pubertal children, IGFBP-2 concentration was lower in the subgroup with weight catch-up. Catch-up growth in height did not affect insulin resistance and metabolic parameters. IGFBP-2 levels were inversely correlated with BMI, body fat mass, percent body fat, insulin and leptin levels in both prepubertal and pubertal groups. Additionally in the pubertal group, systolic blood pressure, cholesterol levels were related to IGFBP-2. A strong relationship between IGFBP-2, the insulin sensitivity index, and some cardiovascular risk factors was observed in children born SGA, suggesting that IGFBP-2 might be a promising marker for early recognition of insulin resistance, particularly in children with weight catch-up.     

Role of body fat distribution in the decline in insulin sensitivity and glucose tolerance with age.

The relationships of body composition and physical fitness [maximal aerobic capacity (VO2max)] to the decline in insulin sensitivity with age were examined in healthy older (47-73 yr; n = 36) and young (19-36 yr; n = 13) men. In 18 older men with normal glucose tolerance (OGTT), glucose disposal rates (M) during hyperinsulinemic euglycemic clamps correlated negatively with the waist to hip ratio (WHR; r = -0.77; P < .001) and percent body fat (r = -0.46; P < 0.05) and positively with VO2max (r = 0.54; P < 0.05), but not with age. Similar relationships existed in the 36 older men with a spectrum of OGTT responses; however, only WHR was independently related to M (r2 = 0.32; P < 0.01). In the older men with normal OGTT, M (mean +/- SEM, 7.88 +/- 0.43 mg/kg fat-free mass.min) was not different from that in the young men (8.56 +/- 0.47; P = NS). Furthermore, in older and young men with normal OGTT matched for WHR, percent fat, or VO2max, glucose disposal was comparable at sequential 15-min intervals during the clamp and in its relationship to insulin concentrations at the tissue level (multicompartmental analysis). In contrast, despite higher steady state plasma insulin levels during the clamp, M was significantly lower in the older men with a higher WHR, greater percent fat, lower VO2max, or impaired OGTT. Thus, in healthy older men up to the age of 73 yr, insulin sensitivity and glucose tolerance are affected primarily by the regional body fat distribution, not age, obesity, or VO2max.     

Reference values for insulin-like growth factor-binding protein-3 (IGFBP-3) and the ratio of insulin-like growth factor-I to IGFBP-3 throughout childhood and adolescence

To facilitate the diagnosis of GH deficiency and monitor GH therapy, we constructed two reference models to allow comparison of serum IGF binding protein (IGFBP)-3 concentrations and IGF-I to IGFBP-3 ratios among children throughout childhood and adolescence. This report presents equations for determining the sd score of IGFBP-3 and IGF-I to IGFBP-3 measurements for individual patients. The data set contains serum values from 468 healthy children and adolescents (232 males, 236 females; ages 1.1-18.3 yr) whose height, weight, and body mass index were within +/- 3 sd of means. Puberty was classified according to breast development (B) and testicular volume into pre-, early, mid-, and late puberty. The values of IGFBP-3 and IGF-I to IGFBP-3 ratios were log transformed, and multiple linear regression analysis was used to identify models for converting serum concentrations into sd scores. The models include the variables of age, gender, and puberty and take into account the interactions among these variables. The best linear models explain 42% of the variation in serum IGFBP-3 concentrations and 50% of the variation in serum IGF-I to IGFBP-3 concentrations. The relationship between age and log(IGFBP-3) was positive for boys in pre-, early, and midpuberty. In late puberty, values were higher than earlier in puberty, and there was a negative relationship with age. For girls the relationship between age and log(IGFBP-3) also was positive in pre- and early puberty, with larger effect for girls older than 8 yr. Values for girls in midpuberty were relatively constant, and in late puberty values were higher than earlier in puberty, and there was a negative relationship with age. The relationship between age and log(IGF-I to IGFBP-3 ratio) was positive for boys in pre-, early, and early midpuberty (volume = 9-14 ml). In late midpuberty (volume = 15-19 ml), the relationship between age and IGF-I to IGFBP-3 ratio was negative. In late puberty, values were relatively constant and higher than earlier in puberty. For girls in prepuberty, the relationship with age was positive, with a larger effect in girls older than 8 yr. In early puberty, the girls' values were relatively constant. In early midpuberty (B = 3), log(IGF-I to IGFBP-3 ratio) values were higher for girls than boys of the same age. In late midpuberty (B = 4), the relationship with age was negative, and in late puberty values were relatively constant and higher than earlier in puberty.     

Insulin-like growth factor binding protein-3 in normal pubertal girls.

IGFBP-3 concentrations rise in the second decade of life. To test the hypothesis that the stage of pubertal development, independent of chronological age, was associated with these increases we measured serum IGFBP-3 concentrations by radioimmunoassay in 324 sixth and seventh grade girls (12.3 +/- 0.7 years) at the beginning of a multisite school-based health curriculum. The mean (+/- SD) serum IGFBP-3 among the 242 girls with complete data was 4.0 +/- 0.7 mg/l. Pubertal stage was significantly associated with IGFBP-3 (p less than 0.0001, ANOVA). Mean concentrations rose from 3.5 +/- 0.7 mg/l among those with the earliest pubertal stages to 4.2 +/- 0.7 mg/l among the mature girls. IGF-I and IGFBP-3 concentrations were significantly correlated (Spearman's r = 0.43, p less than 0.0001). After controlling for the association between pubertal development and IGFBP-3 concentrations, only the waist/hip ratio, among the various measures of body composition, was significantly associated with IGFBP-3 concentration (Spearman's r = -0.23, p = 0.0002). Likewise, none of the measures of nutrition: intake of total calories, protein, fat and carbohydrate; serum iron; red cell mean corpuscular volume; or cholesterol; were significantly associated with IGFBP-3 concentrations. There was, however, a small, but significant association between IGFBP-3 concentrations and both serum transferrin and blood hemoglobin concentrations. Pubertal stage has a significant impact on IGFBP-3 concentrations and those attempting to utilize IGFBP-3 concentrations during adolescence should be cognizant of the subject's pubertal stage.     

Relationship of obesity and physical fitness to cardiopulmonary and metabolic function in healthy older men

The relationship of obesity and physical fitness (VO2max) to cardiopulmonary and metabolic function was examined in 132 healthy obese, nonsmoking men age 45-79. Obese men with higher VO2max had lower % body fat and waist-to-hip ratio (WHR) than obese men with low VO2max. The obese subjects with high WHR (upper body fat distribution) had higher systolic blood pressure, hyperinsulinemia and impaired glucose tolerance, lower high density lipoprotein cholesterol (HDL-C), and higher triglyceride (TG). VO2max (ml/kg FFM.min) was lower in the older men (r = -0.54, p less than .001), and 32% of the variation was accounted for by age and the one-second forced expiratory volume. Although pulmonary function was normal, 50% of the variability was predicted by age, height, and VO2max or WHR. Glucose tolerance and insulin correlated better with VO2max and indices of body composition than with age, while plasma TG and HDL-C correlated with body composition, not VO2max or age. Thus, while age affects the cardiopulmonary and metabolic function of obese older men, physical inactivity, obesity, and an abdominal body fat distribution (increased WHR) contributed significantly to their reductions in physiological function.     

Decreased serum levels of acid-labile subunit in patients with anorexia nervosa.

One of the observations in malnutrition is that serum insulin-like growth factor (IGF)-I levels are decreased, and this decrease is associated with an altered profile of IGF binding proteins (IGFBPs). In human circulation, IGFs are mostly present as an approximately 150-kDa ternary protein complex consisting of IGFs, IGFBP-3, and acid-labile subunit (ALS). In the present study, to clarify the effect of nutrition on serum ALS levels, we investigated 33 patients with anorexia nervosa. Serum levels of ALS were measured by RIA. Furthermore, we measured serum IGF-I, IGF-II, IGFBP-2, and IGFBP-3 levels in the patients. From these data, we investigated which was the best predictor of body mass index (BMI) as a nutritional status marker. In the patients with anorexia nervosa, the serum ALS levels ranged from 0.7-16.9, with a mean of 10.6 +/- 0.7 mg/L, and the levels were significantly lower than those of normal subjects (13.8 +/- 0.8 mg/L, P < 0.05). Serum ALS levels positively correlated with BMI (r = 0.41, P < 0.05), and the levels increased during treatment. The serum IGFBP-2 levels in the patients were increased (871 +/- 91 microg/L), and the levels inversely correlated with BMI (r = -0.52, P < 0.01). The serum IGF-I and IGFBP-3 levels were low (152 +/- 14 microg/L and 2.56 +/- 0.12 mg/L, respectively), and the levels positively correlated with BMI (r = 0.46, P < 0.01; and r = 0.39, P < 0.05, respectively). The serum IGFBP-2, IGF-I, and IGFBP-3 levels returned toward normal ranges as BMI in the patients improved during treatment. Serum IGF-II levels did not correlate with BMI (r = 0.24, P = 0.17). Stepwise regression analysis revealed that serum IGFBP-2 was the best marker of BMI among these variables. The present study suggested that ALS was regulated by nutritional status, the same as IGF-I, IGFBP-2 and IGFBP-3; but the serum IGFBP-2 was the best predictor of BMI as nutritional status marker among the parameters in patients with anorexia nervosa.     

Hormonal determinants of regional body composition in adolescent girls with anorexia nervosa and controls

We have previously demonstrated that girls with anorexia nervosa (AN) have higher levels of GH and cortisol and lower levels of estradiol than healthy adolescents. The effects of endocrine alterations on regional body composition in AN, however, have not been reported. We, therefore, enrolled 23 adolescent girls with AN and 20 healthy girls of comparable maturity in a study examining regional body composition. Levels of estradiol and IGF-I, as well as measures of GH and cortisol concentration (using cluster analysis of data obtained from frequent sampling q30' for 12 h overnight) were examined to determine hormonal determinants of regional body composition in adolescent girls with AN and controls. Girls with AN were followed for 1 yr and examined again at weight recovery (10% increase in body mass index) (n = 11). Percent trunk fat and trunk to extremity fat ratio (T/E fat) were significantly reduced in girls with AN compared with healthy adolescents (P = 0.001 and 0.01, respectively). Percent trunk lean mass and trunk to extremity lean mass ratio (T/E lean) were higher in AN than in controls (P = 0.01 and 0.009); percent extremity lean mass was lower in AN (P = 0.009). In healthy controls, total area under the curve (AUC) for GH correlated inversely with percent trunk fat and T/E fat (r = -0.66, P = 0.002 and r = -0.62, P = 0.003). Similar correlations were observed between other measures of GH concentration (mean and nadir) and percent trunk fat and T/E fat. No relationship was observed between GH concentration and regional lean mass or between cortisol concentration and regional body composition. In contrast, GH concentration did not predict regional body composition in adolescents with AN on regression analysis. However, nadir cortisol concentration correlated inversely with percent extremity lean mass (r = -0.49; P = 0.02) and positively with percent trunk lean mass and T/E lean (r = 0.48, P = 0.03; and r = 0.49, P = 0.02) in girls with AN. A similar trend was observed between other measures of cortisol concentration (mean cortisol and AUC) and percent trunk lean mass and T/E lean in AN. Trunk fat was lowest in girls with AN who had high GH but low cortisol levels (based on median values), whereas some preservation of trunk fat was observed in girls with low GH and high cortisol levels. Weight recovery occurred in seven of 11 girls with low GH and high cortisol values; however, only two of the nine girls with high GH and low cortisol recovered weight. High GH with lower cortisol levels may thus be a marker of greater severity of AN. Our results suggest that in healthy controls, GH concentration predicts regional body composition and favors a redistribution of body fat such that T/E fat ratio decreases. In AN, however, high levels of GH and cortisol have contrasting associations with fat mass. High cortisol levels in AN predict a redistribution of lean body mass such that extremity lean mass decreases. Further studies are necessary to better understand the implications of these data.     

Cardiovascular fitness and exercise as determinants of insulin resistance in postpubertal adolescent females

In obese adolescents, body mass index (BMI) is a poor predictor of insulin resistance, and the potential role of diminished physical activity has not been quantitated. We measured possible determinants of sensitivity to insulin in 53 adolescent females with a BMI between the 10th and the 95th percentile. We hypothesized that across weight and fitness spectra, relative fat mass, rather than BMI, and cardiovascular fitness would be predictors of insulin resistance. We measured body composition by total-body dual x-ray absorptiometry. Self-reported weekly frequency of aerobic exercise for 1 h (RDE) was recorded, and maximal oxygen consumption (VO(2)max) was measured. Insulin sensitivity was estimated by homeostasis model assessment index (HOMA(IR)) derived from fasting glucose and insulin concentrations. BMI was not related to HOMA(IR) (P = 0.20), RDE showed a marginal relationship (P = 0.049), whereas percent body fat and VO(2)max were significantly related to HOMA(IR) (P = 0.01 and 0.0008, respectively). In a multiple regression model, VO(2)max was a more critical determinant of insulin resistance than percent body fat (P = 0.03 vs. P = 0.67) or RDE (P = 0.01 vs. 0.51). For prevention strategies in youth, physical inactivity may represent a greater metabolic risk than obesity alone.     

Evidence of increased visceral obesity and reduced physical fitness in healthy insulin-resistant first-degree relatives of type 2 diabetic patients

OBJECTIVE: First-degree relatives (FDR) of type 2 diabetic patients are often insulin resistant. Visceral obesity is closely linked to both insulin resistance and type 2 diabetes. We therefore hypothesized that the inheritance of an increased tendency to store fat in visceral fat depots may be a characteristic phenotypic feature in FDR contributing to their insulin resistance. DESIGN AND METHODS: We measured fat distribution in 20 FDR and 14 age-, gender- and body mass index (BMI)-matched controls employing dual energy X-ray absorbtiometry (DEXA)- and computed tomography (CT)-scanning. Insulin-stimulated glucose uptake (ISGU) was determined by a hyperinsulinemic clamp and maximal aerobic work capacity (VO2 max) by a bicycle ergometer test. Baseline lipolysis was measured using [3H]palmitate. The activity level of the hypothalamic-pituitary-adrenal axis was assessed as the 24 h urinary (u)-cortisol/creatinine ratio. RESULTS: All subjects had a normal oral glucose tolerance test (OGTT), but FDR were insulin resistant (ISGU: 6.64+/-0.48 vs 9.12+/-0.98 mg/kg ffm/min, P=0.01). Despite similar BMI (25.2+/-0.5 vs 24.8+/-0.7 kg/m2, P=0.61) and overall fat mass (26.4+/-1.6 vs 24.2+/-2.1%, P=0.41) in FDR vs controls, the amount of visceral adipose tissue was substantially increased (65.9+/-10.0 vs 40.1+/-11.3 cm2, P<0.05) and VO2 max was reduced (52.2+/-3.1 vs 63.3+/-3.9 ml/kg ffm/min, P<0.05) in FDR. Visceral adiposity was inversely correlated with ISGU (FDR: r=-0.52, P<0.05; controls: r=-0.65, P<0.01) and in multiple regression analysis visceral adiposity (P<0.01), VO2 max (P<0.001) and a family history of type 2 diabetes (P<0.05) (r2=0.64) all significantly and independently contributed to the level of ISGU. Baseline palmitate appearance (145+/-10 vs 139+/-15 micromol/min, P=0.74) and the 24 h u-cortisol/creatinine ratio ((24.9+/-1.3 vs 27.4+/-2.0).10(-6), P=0.28) were both comparable in the two groups. CONCLUSION: Healthy but insulin-resistant FDR have enhanced visceral obesity and reduced VO2 max compared with people without a family history of diabetes, despite similar BMI and overall fat mass. Both the visceral adiposity and reduced aerobic fitness are strongly associated with and may contribute to their insulin resistance.