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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-0501
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 2 1061-1067
Copyright © 2005 by The Endocrine Society

Insulin-Like Growth Factor-I Response to a Single Bolus of Growth Hormone Is Increased in Obesity

Helena K. Gleeson, Catherine A. Lissett and Stephen M. Shalet

Department of Endocrinology, Christie Hospital, Manchester M20 4BX, United Kingdom

Address all correspondence and requests for reprints to: Professor S. M. Shalet, Department of Endocrinology, Christie Hospital, Wilmslow Road, Withington, Manchester M20 4BX, United Kingdom. E-mail: helena.gleeson{at}christie-tr.nwest.nhs.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Reduced GH levels are found in obesity; despite which IGF-I levels are reported as low normal or normal. Previously peripheral responsiveness to GH has been investigated and reported to be increased in obese men and premenopausal women; however, the use of weight-based GH doses in these studies made data interpretation difficult. GH binding protein (GHBP) measurement constitutes an indirect estimate of GH receptor number. GHBP has been reported to be elevated in obesity; however, results from a recent study implied that this was only in men and premenopausal but not postmenopausal women. Therefore, we pursued this question further by challenging a cohort of healthy normal-weight and obese subjects with a non-weight-based dose of GH and examined the relationship of GHBP with the IGF-I response in the context of their body composition.

Ninety-eight (40 male) healthy subjects with a wide range of ages and body mass index (BMI) were studied. Ninety-one (34 male) of these subjects were divided into groups of similar age: men and women with a BMI less than 30 [normal-weight men (NM), BMI 26 (22–29) kg/m2 (n = 19) and women (NW), BMI 24 (19–29) kg/m2 (n = 23) and with a BMI > 30 (obese men (OM), 41 (30–72) kg/m2 (n = 15) and women (OW), 43 (30–68) kg/m2 (n = 34)]. Fat mass and percentage fat were measured by a bioelectrical impedance analyzer. An IGF-I generation test, which involved a sc injection of 21 IU (7 mg) GH, was performed. At baseline serum samples were assayed for GHBP; serum IGF-I and IGFBP3 levels were measured both at baseline and 24 h after GH administration.

There was a higher increment IGF-I in obese men and women, compared with the equivalent normal-weight subjects [NM vs. OM: 245 (33–342) vs. 291 (192–427) ng/ml (P < 0.05); NW vs. OW: 220 (103–435) vs. 315 (144–450) ng/ml (P < 0.0005)]. Increment IGF-I was negatively correlated with baseline IGF-I (F = 12.1) and positively correlated with GHBP (F = 18.2) (R2 = 0.29). GHBP levels were significantly higher in OM and OW (pre- and postmenopausal) than in the equivalent normal-weight groups [NM vs. OM: 2175 (995–4190) vs. 3030 (1540–5470) pmol/liter (P < 0.05); NW vs. OW: 2131 (1010–5040) vs. 3585 (1540–5740) pmol/liter (P < 0.0005)]. GHBP levels correlated highly with BMI, percentage fat, and fat mass (R > 0.6, P < 0.0001). Baseline IGF-I was not affected by body composition.

In conclusion, in obese compared with normal-weight healthy subjects, there is a larger increment IGF-I to a single bolus of GH in men, and irrespective of menopausal status, women. Increment IGF-I is associated positively with GHBP level, which in turn is associated with markers of increasing obesity in men and women. GH responsiveness is increased in obesity.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
OBESITY IS ASSOCIATED with decreased GH secretion (1, 2, 3, 4) and increased GH clearance (1, 5), resulting in low 24-h spontaneous GH levels, despite which IGF-I levels, a measure of GH bioactivity (6, 7), are reported as low normal or normal (8, 9, 10, 11). To explain the discordancy between GH and IGF-I status in obese subjects, an increase in peripheral (hepatic) responsiveness to GH activity has been hypothesized (12).

Recently the IGF-I generation test has been employed in adults to determine whether peripheral (hepatic) responsiveness varies with age and estrogen status in the female (13, 14, 15, 16). Previous studies employing this test in obese subjects demonstrated increased peripheral responsiveness to GH in men and premenopausal women (17, 18) but not in postmenopausal women (19); however, the use of weight-based GH doses in these studies, thereby making the GH dose a confounding factor, made data interpretation difficult.

One hypothesis for the mismatch in GH and IGF-I status is that the number of GH receptors is up-regulated to compensate for decreased GH levels. GH binding protein (GHBP) corresponds to the extracellular domain of the GH receptor (20) and has been used as an indirect measure of GH receptor number. A positive correlation between the circulating GHBP level and estimates of body fat have been described (21). A recent study in women observed this finding in pre- but not postmenopausal women (22). No association has been found between IGF-I response to GH and GHBP levels (13, 17).

Therefore, we pursued this question further by challenging a cohort of healthy normal-weight and obese subjects with a non-weight-based dose of GH. The relationship between GHBP and the IGF-I response to GH in the context of body composition has also been studied.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Ninety-eight (40 male) healthy subjects were studied. Ethical approval was obtained from the local ethical committee, and all subjects gave informed written consent. No subject had either a condition (e.g. diabetes, liver disease, or pituitary disease) or was taking any medication (e.g. estrogen replacement or opioids) known to affect the GH-IGF-I axis. All screening baseline blood tests (e.g. liver function tests, random glucose, hemoglobin A1c, and thyroid function tests) were normal.

Ninety-one of the 98 subjects were divided into groups: men and women with a body mass index (BMI) less than 30 [normal-weight men (NM) (n = 19) and women (NW) (n = 23)] and those with a BMI of greater than 30 [obese men (OM) (n = 15) and women (OW) (n = 34)]. The women were further subdivided by menopausal status: premenopausal and postmenopausal women with a BMI of less than 30 [normal-weight premenopausal women (NPr) (n = 11) and postmenopausal women (NPo) (n = 12)] and those with a BMI of greater than 30 [obese premenopausal women (OPr) (n = 20) and postmenopausal women (OPo) (n = 14)]. The seven youngest subjects (six male) were excluded from the division into groups so that the groups were of equivalent median ages.

Seventy-eight (29 male) of the 98 subjects had a more prolonged IGF-I generation test and were divided into groups similar in age for the assessment of the IGF-I and IGF binding protein (IGFBP)3 response to GH; NM (n = 14) and NW (n = 15) with a BMI less than 30 and those with a BMI greater than 30 [OM (n = 15) and OW (n = 34)].

Characteristics of the groups are presented in Tables 1–3GoGoGo.


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  		TABLE 1. Characteristics of normal weight and obese male and female groups

 

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  		TABLE 2. Characteristics of normal weight and obese females by menopausal status

 

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  		TABLE 3. Subjects who underwent prolonged IGF-I generation tests: characteristics, baseline IGFBP3, and response to GH in normal-weight and obese male and female groups

 
Body composition

Height and weight were measured and BMI was calculated. Bioimpedance analyzer (BIA) (Tanita, Tokyo, Japan) was used to estimate body composition, percentage fat (F%), and fat mass (FM). BIA has been used in a previous study performed in this unit and has demonstrated a high degree of correlation with dual-energy x-ray absorptiometry-derived fat measurements (R = 0.9; P < 0.0001) (23).

IGF-I generation test

An IGF-I generation test was performed in each subject. Seven milligrams of recombinant GH (Pfizer, Genotropin 1 mg = 3 IU) was given sc. This dose of GH was chosen to study near maximal IGF-I production. It is also the largest dose of GH to have been used in previous studies without side effects (13, 14).

All subjects had blood samples taken before and 24 h after the injection of GH; serum GHBP levels were estimated at baseline only, whereas serum IGF-I and IGFBP3 levels were measured at baseline and at 24 h. This timing for blood sampling was chosen because it is established that IGF-I levels peak 18–24 h after a sc injection of GH (14). This was confirmed in 78 of the 98 subjects who also had blood samples taken at 18, 48, and 72 h. Peak IGF-I occurred at a median time of 24 h after sc injection irrespective of BMI. This prolonged IGF-I generation test also enabled assessment of area under the curve (AUC) IGF-I response and evaluation of maximal IGFBP3 peak after a GH injection that occurs at a median time of 48 h (14).

Assays

Serum IGF-I. Serum IGF-I was measured by an immunoradiometric assay (Diagnostic Systems Laboratories, Webster, TX) with acid/ethanol extraction. The sensitivity of the assay was 0.8 ng/ml. The intraassay coefficients of variation for mean IGF-I concentrations of 9.3, 55, and 263 ng/ml were 3.4, 3.0, and 1.5%, respectively. The interassay coefficients of variation for mean IGF-I concentrations of 10.4, 53, and 256 ng/ml were 8.2, 1.5, and 3.7%, respectively. The value is multiplied by 0.13 to convert nanograms per milliliter into nanomoles per liter for calculating molar ratios.

Serum IGFBP3. Serum IGFBP3 was measured by an immunoradiometric assay (Diagnostic Systems Laboratories). The sensitivity of the assay was 0.5 µg/liter. The intraassay coefficients of variation for mean IGFBP3 concentrations of 1.0, 2.2, and 9.8 mg/liter were 6.1, 4.1, and 4.4%, respectively. The interassay coefficients of variation for mean IGFBP3 concentrations of 0.9, 3.5, and 11.0 mg/liter were 9.0, 4.6, and 3.8%, respectively.

Serum GHBP. Serum GHBP was measured by an ELISA (Diagnostic Systems Laboratories). The sensitivity of the assay was 1.6 pmol/liter. The intraassay coefficients of variation for mean GHBP concentrations of 20.2, 93.4, and 198.2 pmol/liter were 5.5, 3.1, and 4.7%, respectively. The interassay coefficients of variation for mean GHBP concentrations of 19.9, 93.8, and 195.7 pmol/liter were 8.3, 6.2, and 5.1%, respectively.

Analysis and statistics

Data are presented as median (range). The rank sum test was used to compare the different groups. Forward stepwise regression analysis was used to identify dependent variables (e.g. gender, age, height, and F% as well as baseline IGF-I or IGFBP3 and GHBP in some analyses) in the whole cohort (98 subjects). Because the three indices of obesity, BMI, F%, and FM were closely correlated, F%, a more accurate marker of obesity, was selected for use in regression analyses. F% and GHBP were also closely correlated; consequently, the strongest dependent variable was included in the regression analyses. Statistical significance was assumed for P < 0.05.

Increment IGF-I or IGFBP3 was calculated by subtracting baseline from peak levels. AUC IGF-I was calculated using the trapezoidal method; AUC IGF-I minus baseline IGF-I was calculated accordingly.

GHBP corresponds to the extracellular domain of the GH receptor (20) and provides an indirect measure of GH receptor number. Therefore, as a marker of GH responsiveness in the context of estimated GH receptor number, the molar ratio of IGF-I to GHBP was calculated for baseline, peak, and increment. For forward stepwise regression analysis, it was necessary to convert the molar ratio of IGF-I to GHBP into natural logs because the values were not normally distributed.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
GHBP

GHBP levels were significantly greater in the groups of OM, OPr, and OPo than in the equivalent normal-weight groups (Tables 4Go and 5Go). GHBP levels correlated with BMI, F%, and FM (R > 0.6, P < 0.0001); F% correlated the most strongly and was therefore included in the forward stepwise regression analysis. GHBP was dependent on F% (F = 47.12) and gender (F = 4.97), i.e. GHBP increased with increasing F% but also for equivalent F%, GHBP was slightly lower in females (R2 = 0.38) (Fig. 1Go); serum IGFBP3 at baseline (F = 9.29) was also a dependent variable when included in the regression analysis (R2 = 0.44).


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  		TABLE 4. Baseline GHBP, IGF-I, IGF-I/GHBP, and IGFBP3 and response to GH in healthy weight and obese male and female groups

 

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  		TABLE 5. Baseline GHBP, IGF-I, IGF-I/GHBP, and IGFBP3 and response to GH in healthy weight and obese females by menopausal status

 


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  		FIG. 1. Correlation of GHBP and F% stratified by gender; regression lines for males (R = 0.5; P < 0.005) (upper line) and females (R = 0.7; P < 0.005) (lower line).

 
There was no difference in GHBP levels between males and females or pre- and postmenopausal women of equivalent BMI.

IGF-I

There was a greater increment IGF-I in OM, OPr, and OPo (Tables 3–5GoGoGo), compared with the equivalent normal-weight subjects (Fig. 2Go). Increment IGF-I was negatively correlated with baseline IGF-I (F = 12.1) and positively correlated with GHBP (F = 18.2) (R2 = 0.29). If GHBP was excluded from the analysis, baseline IGF-I and F% were dependent variables (R2 = 0.22). If baseline IGF-I was excluded from the analysis, age and GHBP were dependent variables (R2 = 0.23). Therefore, the lower the baseline, the greater the increment IGF-I, and in addition increasing levels of GHBP or increasing obesity was associated with a larger increment IGF-I.



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  		FIG. 2. Increment of IGF-I in NM vs. OM, NPr vs. OPr, and NPo vs. OPo (column represents median, whisker 95th centile).

 
Baseline IGF-I level was not significantly affected by body composition in males or females (pre- or postmenopausal). However, in females but not in the males, the median baseline IGF-I level was lower in the obese compared with the normal-weight group; this difference almost reached significance in the premenopausal (P = 0.06) but not in the postmenopausal (P = 0.4) women. There was an age (F = 42.8)-related decline in baseline IGF-I as well as an additional effect of height (F = 12.4), with taller subjects having a higher baseline IGF-I (R2 = 0.43).

In both males and females, the peak IGF-I level was nonsignificantly (P = 0.6) higher in the obese compared with the normal-weight groups. However, AUC IGF-I and the calculation, AUC IGF-I minus baseline IGF-I (ng/ml x h), was increased in OM and OW, compared with the equivalent normal-weight subjects (P < 0.02) (Fig. 3Go, A and B).



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  		FIG. 3. A and B, IGF-I levels before and after a sc injection of GH in male (A) and female (B) normal-weight ({blacksquare}) and obese subjects (•). Symbolrepresents median, whiskers fifth (below) and 95th (above) centile.

 
There was no gender difference in baseline, increment, or AUC IGF-I.

IGF-I/GHBP ratio

Baseline IGF-I/GHBP was higher in NM, NPr, and NPo groups than in the equivalent obese groups (Tables 4Go and 5Go). Baseline IGF-I/GHBP levels were significantly higher in NPr, compared with NPo, and almost reached significance between the same subdivisions within the obese groups. Baseline IGF-I/GHBP was dependent on the variable F% (F = 32.3) and age (F = 16.1), i.e. older and more obese subjects produced less IGF-I per nanomole per liter of GHBP (R2 = 0.44) (Fig. 4Go).



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  		FIG. 4. Relationship between molar ratio or IGF-1 to GHBP and F%.

 
Peak IGF-I/GHBP was higher in NM, NPr, and NPo groups than in the equivalent obese groups. Consequently, F% was also a dependent variable for peak IGF-I/GHBP (F = 38.3) (R2 = 0.32).

Only in postmenopausal women was the increment IGF-I/GHBP greater in the normal-weight group, compared with the obese group. The increment IGF-I to GHBP ratio was negatively correlated with F% (F = 9.59) in females (R2 = 0.13) but not males.

There was no gender difference in basal, peak, or increment IGF-I/GHBP levels.

IGFBP3

No differences in IGFBP3 were seen between NM and OM (Tables 3–5GoGoGo).

Baseline IGFBP3 was significantly greater in OW than NW (postmenopausal only). The expected age-related decline in baseline IGFBP3 was seen only in NW but not OW. Baseline IGFBP3 was dependent on GHBP (F = 20.2) and age (F = 9.2) (R2 = 0.26). If GHBP was excluded from the analysis, the dependent variables were age and F% (R2 = 0.25). Therefore, like baseline IGF-I, baseline IGFBP3 declines with age, but unlike IGF-I it rises with increasing obesity.

The peak IGFBP3 occurred at a median of 48 h after the acute GH bolus in those subjects who underwent a prolonged IGF-I generation test. The increment IGFBP3, whether it is calculated from the 24-h level in all subjects or at the actual peak in those who had the prolonged IGF-I generation test, showed similar results. The increment IGFBP3 was greater in NW than OW (effect seen in postmenopausal only). NPo also had a significantly greater increment IGFBP3 than NPr. Increment IGFBP3 negatively correlated with baseline IGFBP3 and, also but less strongly, GHBP and F%.

There was no gender difference for baseline or increment IGFBP3.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Decreased GH secretion (1, 2, 3, 4) and increased GH clearance (1, 5) contribute to low GH levels found in obesity, despite which IGF-I levels, a measure of GH bioactivity (6, 7), are reported as low-normal or normal (8, 9, 10, 11). To explain the discordancy between GH and IGF-I status in obese subjects, an increase in peripheral (hepatic) responsiveness to GH activity has been hypothesized (12). Previously peripheral responsiveness to GH in obesity has been investigated and reported to be increased in men and premenopausal women (17, 18) and unchanged in postmenopausal women (19); however, the use of weight-based GH doses (17, 18, 19) and also the suboptimal timing of blood sampling (17, 18, 19) makes interpretation of the results from these studies difficult. Our study using a non-weight-based fixed dose of GH in a larger number of subjects confirms that obese subjects, men, and pre- or postmenopausal women, have a greater IGF-I response to a single bolus of GH and therefore show increased peripheral GH responsiveness. Increment IGF-I was also associated with the GHBP level. GHBP levels were found to be elevated in obesity, as has been previously reported (11, 24, 25). GHBP was elevated not only in obese men and premenopausal women but also in postmenopausal women, demonstrating, contrary to the findings of a recent study (22), that estrogen status is not the sole factor responsible for the increase in GHBP levels found in obesity.

In the past, the justification for using a weight-based dose of GH for the assessment of IGF-I response was presumably based on the knowledge that there is increased metabolic clearance of GH in obesity (1, 5). There is, however, no evidence that this affects the extent of the IGF-I response after a single bolus of GH. The use of weight-based doses in previous studies (17, 18) has resulted in the obese individuals receiving a dose of GH close to double that of the normal-weight individuals; therefore, the conclusion that the results demonstrate an increased sensitivity to GH in obese individuals are unfounded.

Previous studies that examined the effect of obesity on IGF-I generation in men and premenopausal women used only BMI and waist to hip ratio measurements; the latter are indirect measures of body composition (17, 18). In the current study, BIA has been employed to provide a better estimate of fatness of an individual. A previous study at this unit showed a high correlation between fat mass estimates obtained using dual-energy x-ray absorptiometry and BIA (23).

There are several possible explanations for increased peripheral responsiveness to GH in obesity. The low levels of GH observed in obesity may result in up-regulation of the GH receptors and/or sensitivity as tends to occur in physiological systems to compensate for diminished ligand availability. GHBP corresponds to the extracellular domain of the GH receptor (12, 20). It has been proposed that serum GHBP activity may provide an indirect measure of GH receptor status (26) and an index of tissue responsivity to GH (12). Although the exact biological role of GHBP has not yet been determined, it has been shown to protect GH from degradation and elimination and increase the half-life of GH in the circulation. This suggests that GHBP may potentiate GH action by prolonging the availability of GH to target tissues.

The liver is the primary source of GHBP (27), but the observation of a strong correlation between GHBP levels and visceral adipose tissue mass (11, 24, 25) indirectly suggests that adipose tissue also plays a significant role in the generation of GHBP. Plasma GHBP concentrations are reported to increase in obese subjects and return to normal after diet-induced weight loss (11). In this study, as noted by others (11, 12, 24), an elevated GHBP level was observed in all the obese groups. In contrast with the findings of a recent study, which found an effect of body composition on GHBP in premenopausal but not postmenopausal women, a phenomenon hypothesized to be related to estrogen status (22), our results indicate that the effect of FM on GHBP levels persists into the postmenopausal years. The previous study did, however, include women with a narrower range of BMI (22). Although within-group comparisons revealed no gender difference in GHBP levels, gender was an additional dependent variable to F% for GHBP. For a similar F%, GHBP was lower in females; the results in previous studies reporting that GHBP was higher in females (28, 29) may simply reflect the greater F% in females, compared with males. GHBP did not alter with age, consistent with the findings of some (12, 22) but not all studies (30, 31).

In agreement with the belief that levels of GHBP provide an indirect measure of GH receptor status (26) and an index of tissue responsivity to GH (12), increasing GHBP levels were associated with an increasing peak and increment IGF-I. GHBP has not previously been shown to be associated with IGF-I response to both high- and low-dose GH in adults of normal weight and with obesity (13, 17). There was, however, no association between GHBP and baseline IGF-I, whereas previous studies have reported this association in younger (32) but not older subjects (29).

Despite increased levels of GHBP, the peak IGF-I was not as elevated as might have been predicted, and this is reflected in the reduced peak IGF-I to GHBP molar ratio seen in the obese groups. The interpretation was that GHBP does not accurately reflect GH receptor status of the liver and the increase in GHBP may relate to the GH receptor status of adipose tissue (33, 34); that the dose of 7 mg GH was not large enough to saturate the GH receptors; or that there is reduced responsiveness of the GH receptor due to other factors.

As previously stated, GHBP is closely associated with markers of obesity and therefore has also been shown to be closely associated both with insulin secretion and sensitivity and leptin (35, 36). It is therefore not possible to determine whether the increased IGF-I response is due to elevated GHBP and/or other factors associated with increasing obesity (29, 35, 36, 37, 38, 39). For instance, insulin acutely increases the availability of GH receptors in liver cells (40). Insulin also by itself stimulates IGF-I synthesis in hepatocytes, but a synergistic effect is seen when insulin is administered in combination with GH (41). Therefore, high levels of insulin could increase hepatic GH responsiveness.

Although serum IGFBP3 is partly regulated by GH, it does not reflect the 24-h GH secretion as accurately as IGF-I. In this study IGFBP3 at baseline and after an acute bolus of GH was only minimally affected by body composition in postmenopausal women. The IGFBP3 data differed from the IGF-I data because IGFBP3 levels were higher at baseline in obese subjects, in keeping with a previous study (37), but at variance from another, which found no difference in IGFBP3 levels at baseline or after GH administration (18).

In summary, the apparent GH deficiency with IGF-I sufficiency seen in obesity can at least in part be explained by an increase in responsiveness to GH. This effect is seen independent of gender, age, or menopausal state.


   Footnotes
 
First Published Online November 2, 2004

Abbreviations: AUC, Area under the curve; BIA, bioimpedance analyzer; BMI, body mass index; F%, percentage fat; FM, fat mass; GHBP, GH binding protein; IGFBP, IGF binding protein; NM, normal-weight men; NPo, normal-weight postmenopausal women; NPr, normal-weight premenopausal women; NW, normal-weight women; OM, obese men; OPo, obese postmenopausal women; OPr, obese premenopausal women; OW, obese women.

Received March 15, 2004.

Accepted October 27, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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