Effect of aging on the sensitivity of growth hormone secretion to insulin-like growth factor-I negative feedback

To determine the effect of aging on the suppression of GH secretion by insulin-like growth factor (IGF)-I, we studied 11 healthy young adults (6 men, 5 women, mean +/- SD: 25.2 +/- 4.6 yr old; body mass index 23.7 +/- 1.8 kg/m2) and 11 older adults (6 men, 5 women, 69.5 +/- 5.8 yr old; body mass index 24.2 +/- 2.5 kg/m2). Saline (control) or recombinant human IGF-I (rhIGF-I) (2 h baseline then, in sequence, 2.5 h each of 1, 3, and 10 micrograms/kg.h) was infused iv during the last 9.5 h of a 40.5-h fast; serum glucose was clamped within 15% of baseline. Baseline serum GH concentrations (mean +/- SE: 3.3 +/- 0.7 vs. 1.9 +/- 0.5 micrograms/L, P = 0.02) and total IGF-I concentrations (219 +/- 15 vs. 103 +/- 19 micrograms/L, P < 0.01) were higher in the younger subjects. In both age groups, GH concentrations were significantly decreased by 3 and 10 micrograms/kg.h, but not by 1 microgram/kg.h rhIGF-I. The absolute decrease in GH concentrations was greater in young than in older subjects during the 3 and 10 micrograms/kg.h rhIGF-I infusion periods, but both young and older subjects suppressed to a similar GH level during the last hour of the rhIGF-I infusion (0.78 +/- 0.24 microgram/L and 0.61 +/- 0.16 microgram/L, respectively). The older subjects had a greater increase above baseline in serum concentrations of both total (306 +/- 24 vs. 244 +/- 14 micrograms/L, P = 0.04) and free IGF-I (8.5 +/- 1.4 vs. 4.2 +/- 0.6 micrograms/L, P = 0.01) than the young subjects during rhIGF-I infusion, and their GH suppression expressed in relation to increases in both total and free serum IGF-I concentrations was significantly less than in the young subjects. We conclude that the ability of exogenous rhIGF-I to suppress serum GH concentrations declines with increasing age. This suggests that increased sensitivity to endogenous IGF-I negative feedback is not a cause of the decline in GH secretion that occurs with aging.     

A low dose euglycemic infusion of recombinant human insulin-like growth factor I rapidly suppresses fasting-enhanced pulsatile growth hormone secretion in humans

To determine if insulin-like growth factor I (IGF-I) inhibits pulsatile growth hormone (GH) secretion in man, recombinant human IGF-I (rhIGF-I) was infused for 6 h at 10 micrograms.kg-1.h-1 during a euglycemic clamp in 10 normal men who were fasted for 32 h to enhance GH secretion. Saline alone was infused during an otherwise identical second admission as a control. As a result of rhIGF-I infusion, total and free IGF-I concentrations increased three- and fourfold, respectively. Mean GH concentrations fell from 6.3 +/- 1.6 to 0.59 +/- 0.07 micrograms/liter after 120 min. GH secretion rates, calculated by a deconvolution algorithm, decreased with a t 1/2 of 16.6 min and remained suppressed thereafter. Suppression of GH secretion rates occurred within 60 min when total and free IGF-I concentrations were 1.6-fold and 2-fold above baseline levels, respectively, and while glucose infusion rates were < 1 mumol.kg-1.min-1. During saline infusion, GH secretion rates remained elevated. Infusion of rhIGF-I decreased the mass of GH secreted per pulse by 84% (P < 0.01) and the number of detectable GH secretory pulses by 32% (P < 0.05). Plasma insulin and glucagon decreased to nearly undetectable levels after 60 min of rhIGF-I. Serum free fatty acids, beta-hydroxybutyrate, and acetoacetate were unaffected during the first 3 h of rhIGF-I but decreased thereafter to 52, 32, and 50% of levels observed during saline. We conclude that fasting-enhanced GH secretion is rapidly suppressed by a low-dose euglycemic infusion of rhIGF-I. This effect of rhIGF-I is likely mediated through IGF-I receptors independently of its insulin-like metabolic actions.     

Effects of low-dose recombinant human insulin-like growth factor-I on insulin sensitivity, growth hormone and glucagon levels in young adults with insulin-dependent diabetes mellitus

Despite recent interest in the therapeutic potential of recombinant human insulin-like growth factor-I (rhIGF-I) in the treatment of diabetes mellitus, its mechanism of action is still not defined. We have studied the effects of low-dose bolus subcutaneous rhIGF-I (40 microg/kg and 20 microg/kg) on insulin sensitivity, growth hormone (GH) and glucagon levels in seven young adults with insulin-dependent diabetes mellitus (IDDM) using a randomized double-blind placebo-controlled crossover study design. Each was subjected to a euglycemic clamp (5 mmol/L) protocol consisting of a variable-rate insulin infusion clamp (6:00 PM to 8:00 AM) followed by a two-dose hyperinsulinemic clamp (insulin infusion of 0.75 mU x kg(-1) x min(-1) from 8 to 10 AM and 1.5 mU x kg(-1) x min(-1) from 10 AM to 12 noon) incorporating [6,6 2H2]glucose tracer for determination of glucose production/utilization rates. Following rhIGF-I administration, the serum IGF-I level (mean +/- SEM) increased (40 microg/kg, 655 +/- 90 ng/mL, P < .001; 20 microg/kg, 472 +/- 67 ng/mL, P < .001; placebo, 258 +/- 51 ng/mL). Dose-related reductions in insulin were observed during the period of steady-state euglycemia (1 AM to 8 AM) (40 microg/kg, 48 +/- 5 pmol/L, P = .01; 20 microg/kg, 58 +/- 8 pmol/L, P = .03; placebo, 72 +/- 8 pmol/L). The mean overnight GH level (40 microg/kg, 9.1 +/- 1.4 mU/L, P = .04; 20 microg/kg, 9.6 +/- 2.0 mU/L, P = .12; placebo, 11.3 +/- 1.7 mU/L) and GH pulse amplitude (40 microg/kg, 18.8 +/- 2.9 mU/L, P = .04; 20 microg/kg, 17.0 +/- 3.4 mU/L, P > .05; placebo, 23.0 +/- 3.7 mU/L) were also reduced. No differences in glucagon, IGF binding protein-1 (IGFBP-1), acetoacetate, or beta-hydroxybutyrate levels were found. During the hyperinsulinemic clamp conditions, no differences in glucose utilization were noted, whereas hepatic glucose production was reduced by rhIGF-I 40 microg/kg (P = .05). Our data demonstrate that in subjects with IDDM, low-dose subcutaneous rhIGF-I leads to a dose-dependent reduction in the insulin level for euglycemia overnight that parallels the decrease in overnight GH levels, but glucagon and IGFBP-1 levels remain unchanged. The decreases in hepatic glucose production during the hyperinsulinemic clamp study observed the following day are likely related to GH suppression, although a direct effect by rhIGF-I cannot be entirely discounted.     

Effects of androgen administration on the growth hormone-insulin-like growth factor I axis in men with acquired immunodeficiency syndrome wasting

It is unknown whether hypogonadism contributes to decreased insulin-like growth factor I (IGF-I) production and/or how testosterone administration may effect the GH-IGF-I axis in human immunodeficiency virus (HIV)-infected men with the acquired immunodeficiency syndrome (AIDS) wasting syndrome (AWS). In this study, we investigate the GH-IGF-I axis in men with the AWS and determine the effects of testosterone on GH secretory dynamics, pulse characteristics determined from overnight frequent sampling, arginine stimulation, and total and free IGF-I levels. Baseline GH-IGF-I parameters in hypogonadal men with AWS (n=51) were compared before testosterone administration (300 mg, im, every 3 weeks vs. placebo for 6 months) with cross-sectional data obtained in two age-matched control groups: eugonadal men with AIDS wasting (n=10) and healthy age-matched normal men (n=15). The changes in GH-IGF-I parameters were then compared prospectively in testosterone- and placebo-treated patients. Mean overnight GH levels [1.8+/-0.3 and 2.4+/-0.3 vs. 0.90+/-0.1 microg/L (P=0.04 and P=0.003 vs. healthy controls)] and pulse frequency [0.35+/-0.06 and 0.37+/-0.02 vs. 0.22+/-0.03 pulses/h (P=0.06 and P=0.002 vs. healthy controls)] were comparably elevated in the eugonadal and hypogonadal HIV-positive groups, respectively, compared to those in the healthy control group. No significant differences in pulse amplitude, interpulse interval, or maximal GH stimulation to arginine administration (0.5 g/kg, i.v.) were seen between either the eugonadal and hypogonadal HIV-positive or healthy control patients. In contrast, IGF-I levels were comparably decreased in both HIV-positive groups compared to the healthy control group [143+/-16 and 165+/-14 vs. 216+/-14 microg/L (P=0.004 and P=0.02 vs. healthy controls)]. At baseline, before treatment with testosterone, overnight GH levels were inversely correlated with IGF-I (r=-0.42; P=0.003), percent ideal body weight (r=-0.36; P=0.012), albumin (r=-0.37; P=0.012), and fat mass (r=-0.52; P=0.0002), whereas IGF-I levels correlated with free testosterone (r=0.35; P=0.011) and caloric intake (r=0.32; P= 0.023) in the hypogonadal HIV-positive men. In a stepwise regression model, albumin (P=0.003) and testosterone (P=0.011) were the only significant predictors of GH [mean GH (microg/L)=-1.82 x albumin (g/dL) + 0.003 x total testosterone (microg/L) + 6.5], accounting for 49% of the variation in GH. Mean overnight GH levels decreased significantly in the testosterone-treated patients compared to those in the placebo-treated hypogonadal patients (0.9+/-0.3 vs. 0.2+/-0.4 microg/L; P=0.020). In contrast, no differences in IGF-I or free IGF-I were observed in response to testosterone administration. The decrement in mean overnight GH in response to testosterone treatment was inversely associated with increased fat-free mass (r=-0.49; P= 0.024), which was the only significant variable in a stepwise regression model for change in GH [change in mean GH (microg/L)=-0.197 x kg fat-free mass - 0.53] and accounted for 27% of the variation in the change in GH. In this study, we demonstrate increased basal GH secretion and pulse frequency in association with reduced IGF-I concentrations, consistent with GH resistance, among both hypogonadal and eugonadal men with AIDS wasting. Testosterone administration decreases GH in hypogonadal men with AIDS wasting. The change in GH is best predicted by and is inversely related to the magnitude of the change in lean body mass in response to testosterone administration. These data demonstrate that among hypogonadal men with the AWS, testosterone administration has a significant effect on the GH axis.     

Increased pulsatile, but not basal, growth hormone secretion rates and plasma insulin-like growth factor I levels during the periovulatory interval in normal women

The secretion of GH changes during the menstrual cycle, exhibiting high levels during the periovulatory phase (PO). Previous studies have not investigated whether this difference in GH status is due to increased secretion or reduced clearance of pituitary GH and amplified pulsatile vs. basal GH secretion. It is also unclear whether the PO phase is accompanied by changes in circulating insulin-like growth factor I (IGF-I). In this study we investigated the 24-h GH release patterns in the early follicular (EF) vs. the periovulatory menstrual phase in the same individuals. Ten young (aged 24-34 yr) healthy women with regular menses were studied with deconvolution analysis of GH profiles obtained by blood sampling every 20 min for 24 h, followed by an arginine stimulation test. A high sensitivity immunofluorometric GH assay was used. All women were studied in both the EF and PO phases in random order. There were no differences in the basal GH secretion rate or GH half-life during the two phases. The number of GH secretory bursts identified during the 24-h sampling period was significantly increased during the PO (13.3 +/- 0.5) compared to the EF (10.3 +/- 0.6) phase (P = 0.002); conversely, the mean interburst interval was shorter in the PO (107 +/- 5 min) than in the EF (134 +/- 8 min) phase (P = 0.004). There was no difference in GH pulse mass (P = 0.13) or amplitude (P = 0.21) between the two phases. The pulsatile GH production rate (milligrams per L/24 h) was significantly elevated during the PO (61 +/- 6) compared to that during the EF (37 +/- 8; P = 0.004). Increased total GH pulse area was confirmed by Cluster analysis (P = 0.027). Furthermore, the 24-h mean serum GH concentration was significantly increased in the PO (1.4 +/- 0.1 mg/L) vs. that in the EF (0.9 +/- 0.1 mg/L; P = 0.002). There was a positive correlation between estradiol (E2) and GH secretory pulse amplitude, frequency, and mean 24-h serum GH concentration in the PO cycle phase, indicating E2 to be a major statistical determinant of GH secretion. Serum GH increased significantly after arginine infusion in both phases (P < 0.001), whereas there was no difference between the two cycle phases (P = 0.20). Serum IGF-I levels were increased during the PO phase (253 +/- 20 mg/L) compared to those during the EF phase (210 +/- 16 mg/L; P = 0.03), whereas serum IGF-binding protein-3, IGF-II, and GH-binding protein were similar during the two phases. This study unequivocally documents elevated GH levels during the PO phase of the menstrual cycle, mediated by increased GH production rate and burst frequency. The concomitant increase in serum IGF-I suggests a central stimulation of the GH-IGF-I axis, which may be mediated by endogenous E2 levels.     

Evaluation of disease status with sensitive measures of growth hormone secretion in 60 postoperative patients with acromegaly

Traditionally, suppression of GH measured by polyclonal RIA to less than 2.0 microg/L after oral glucose was accepted as evidence of remission after transsphenoidal surgery for acromegaly. Recently, with newer, more sensitive GH assays, a cut-off of less than 1.0 microg/L has been suggested. With the development of accurate insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) assays, additional tools are now available for assessing postoperative GH secretion. There has, however, never been a systematic comparison of sensitive GH, IGF-I, and IGFBP-3 assays in defining disease status in a large cohort of postoperative patients with acromegaly. Therefore, we evaluated how the use of modern assays impacts on our assessment of disease activity in these patients. Sixty postoperative subjects with acromegaly and 25 age-matched healthy subjects were evaluated with nadir GH levels after 100 g oral glucose as well as baseline IGF-I and IGFBP-3 levels. GH was assayed by polyclonal RIA, sensitive immunoradiometric assay (IRMA), and highly sensitive enzyme-linked immunosorbent assay. The mean nadir GH determined by IRMA was 0.09 +/- 0.004 microg/L in the healthy subjects, with the upper limit of the normal nadir being 0.14 microg/L (mean + 2 SD). Subjects with acromegaly were divided into those with active disease (n = 22), defined by elevated IGF-I levels, and those in remission (n = 38), defined by normal IGF-I levels. GH determined by IRMA failed to suppress into the normal range defined by our healthy subjects in all patients with active disease; nadir GH determined by IRMA ranged from 0.33-5.0 microg/L in this group. In 50% of the active group, nadir GH levels determined by IRMA were less than 1.0 microg/L, a GH nadir previously considered normal by strict criteria. When nadir GH levels in the subjects with active disease were measured by polyclonal RIA, there was overlap with the range of RIA values in the healthy subjects. Thus, the IRMA was superior to the RIA in that the overlap between these two groups was eliminated. Subjects with acromegaly in remission included those with normal GH suppression (n = 23; mean nadir GH by IRMA, 0.10 +/- 0.006 microg/L) and others with abnormal GH suppression by IRMA (n = 15; mean nadir GH by IRMA, 0.35 +/- 0.07 microg/L). The latter group may have persistent GH dysregulation detected by the sensitive IRMA. GH levels measured by enzyme-linked immunosorbent assay confirmed the IRMA results. IGFBP-3 levels were significantly higher in subjects with active acromegaly (4940 +/- 301 microg/L) vs. those in healthy subjects (2887 +/- 153 microg/L; P < 0.0001) and those in the subjects in remission (2966 microg/L; P < 0.0001). IGFBP-3 levels correlated overall with IGF-I levels (r = 0.765; P < 0.0001), but IGFBP-3 levels were not predictive of disease status because 32% of the subjects with active acromegaly had normal IGFBP-3 levels. In addition, failure of GH to suppress adequately was not associated with a higher IGFBP-3 level among the subjects in remission. These data indicate that the IRMA is superior to the RIA in distinguishing between patients with active disease (defined by elevated IGF-I levels) and healthy subjects. We also show that GH levels after oral glucose measured with highly sensitive GH assays can be much lower in subjects with active disease than previously believed; values less than 1.0 microg/L may be found in up to 50% of patients. In addition, in 39% of patients in apparent remission with normal IGF-I levels, GH determined by highly sensitive assays fails to suppress normally; it remains to be determined whether these patients are at higher risk for recurrence of active disease.     

Influence of chronic Naltrexone treatment on growth hormone and insulin secretion in obese subjects

OBJECTIVE: Recent studies have demonstrated the restoration of a normal 24 h GH profile induced by a reduction of insulinaemia after weight loss, suggesting a reciprocal relationship between plasma insulin and GH concentrations. We aimed to clarify if an opiate-induced reduction in plasma insulin could affect GH secretion in obesity. DESIGN: We have studied the insulin response to an oral glucose tolerance test (OGTT) and the GH response to GHRH before and after prolonged treatment with Naltrexone (NTX). C-peptide, IGF-I, IGFBP-3 plasma levels and the IGF-I/IGFBP-3 molar ratio were also determined. SUBJECTS: Twelve obese women (aged 25-41 y; Body mass index (BMI): 31-39 kg/m2) and six lean normal women (aged 25-38; BMI: 19.8-23.1 kg/m2). MEASUREMENT: GH was determined by the IRMA method; insulin, C-peptide, IGF-I and IGFBP-3 were assayed by the RIA method. For molar comparison between IGF-I and IGFBP-3 we have considered 30.5 kDa the molar weight of IGFBP-3. Results are expressed as mean +/- s.e.m. RESULTS: We observed a significant decrease in basal concentration of both insulin (230.1 +/- 34.9 vs 133.2 +/- 16.9 pmol/L; P < 0.005) and C-peptide (3.7 +/- 0.3 vs 2.4 +/- 0.1 micrograms/L; P < 0.02). No modifications in the insulin secretory response to the OGTT were observed. A significant increase of the GHRH-induced GH peak response (7.7 +/- 1.4 vs 19.7 +/- 3.1 micrograms/L; P < 0.01) and GH-AUC (533 +/- 151 vs 1415 +/- 339 micrograms/L/120 min; P < 0.01) was found after NTX treatment. A negative correlation was found between basal insulin and GH peak values, both before (r = -0.641, P = 0.027) and after NTX (r = -0.714, P = 0.013). No modifications were found in IGF-I, IGFBP-3 and IGF-I/IGFBP-3 molar ratio. Moreover, NTX affected neither the insulin response to OGTT or IGF-I, IGFBP-3 and IGF-I/IGFBP-3 molar ratio in a group of six lean controls. Conversely, NTX significantly reduced the GH response to GHRH, when expressed as both peak and AUC values. CONCLUSIONS: The opiate antagonist significantly reduced basal insulin concentrations and augmented the GH response to GHRH in obese subjects. In the absence of modifications in IGF-I and IGFBP-3 plasma levels and their molar ratio, we propose that insulin may exert a negative feedback on GH secretion.     

Comparison of the metabolic effects of recombinant human insulin-like growth factor-I and insulin. Dose-response relationships in healthy young and middle-aged adults

The actions of recombinant human insulin-like growth factor-I (rhIGF-I) and insulin were compared in 21 healthy young (24 +/- 1 yr) and 14 healthy middle-aged (48 +/- 2 yr) subjects during 3-h paired euglycemic clamp studies using one of three doses (rhIGF-I 0.2, 0.4, and 0.8 micrograms/kg.min and insulin 0.2, 0.4, and 0.8 mU/kg.min, doses chosen to produce equivalent increases in glucose uptake). In younger subjects, rhIGF-I infusions suppressed insulin by 19-33%, C-peptide by 47-59% and glucagon by 33-47% (all, P < 0.02). The suppression of C-peptide was less pronounced with insulin than with rhIGF-I (P < 0.007). The metabolic responses to rhIGF-I and insulin were remarkably similar: not only did both hormones increase glucose uptake and oxidation in a nearly identical fashion, but they also produced similar suppression of glucose production, free fatty acid levels, and fat oxidation rates. In contrast, rhIGF-I had a more pronounced amino acid-lowering effect than did insulin (P < 0.004). In middle-aged subjects, basal IGF-I levels were 44% lower (P < 0.0001) whereas basal insulin and C-peptide were 20-25% higher than in younger subjects. Age did not alter the response to rhIGF-I. However, insulin-induced stimulation of glucose uptake was blunted in older subjects (P = 0.05). Our data suggest that absolute IGF-I and relative insulin deficiency contribute to adverse metabolic changes seen in middle age.     

Promotion of tyrosinase folding in COS 7 cells by calnexin

To evaluate the role of serum free or unbound insulin-like growth factor I (IGF-I) on bone growth, we measured serum free IGF-I levels in 354 healthy children and adults (193 males and 161 females, aged 0-40 yr) and in 21 prepubertal GH-deficient (GHD) children (complete GHD, n = 5; partial GHD, n = 16) using a recently developed immunoradiometric assay. We obtained the following results. 1) In the normal children, the serum free IGF-I levels were low in infancy (<1 yr of age; males, 0.71 +/- 0.26 microg/L, mean +/- SD; females, 1.05 +/- 0.49 microg/L), increased during puberty (males, 5.84 +/- 2.18 microg/L; females, 5.80 +/- 1.49 microg/L), and declined thereafter. 2) Free IGF-I in the serum occupied about 0.95-2.02% of the total IGF-I values, with the highest ratio occurring in infancy (males, 1.77 +/- 0.60%; females, 2.02 +/- 0.87%). 3) The SD scores of serum free IGF-I in the 21 GHD children ranged from -3.30 to 0.30, and the 5 complete GHD children had free IGF-I values more than -2 SD below those of age-matched normal subjects. 4) There was a significant correlation between the SD scores of free IGF-I and those of total IGF-I (r = 0.715; P < 0.0005) in the GHD children. 5) In the 16 partial GHD children receiving GH treatment, the serum free IGF-I levels were elevated to 209% of pretreatment levels after 1 month of GH treatment and remained high during GH therapy. The GH-induced increase in the serum free IGF-I levels was significantly higher than those of the total IGF-I and IGF binding protein-3 levels. 6) The percent increase in the serum free IGF-I level after 1 month of GH treatment showed a significant positive correlation with that of the GH-induced improvement in the percent increase in the height velocity during 1 yr of GH therapy (r = 0.526; P < 0.05). These results show that free IGF-I in the serum has an essential role in bone formation because the higher free IGF-I levels were observed when the growth rate accelerated. The measurement of serum free IGF-I may become a useful tool for both diagnosing GH deficiency and predicting growth responses to long term GH therapy.     

Contribution of growth hormone and IGF-I to early diabetic nephropathy in type 1 diabetes

In children and adolescents with type 1 diabetes, we have reported an association between duration of puberty and the prevalence of nephromegaly and microalbuminuria (MA), which are early markers of diabetic nephropathy. Growth hormone (GH), IGF-I, testosterone, and prorenin are potential mediators of this effect. This study examined the relationship of these hormonal factors to kidney volume (KV) and MA in 155 subjects (78 males, age 13.2 +/- 3.5 years [mean +/- SD]) with similar diabetes duration (6.83 +/- 1.6 years) but varying pubertal experience (0-10 years). KV (by ultrasound), plasma IGF-I, testosterone, prorenin, and NaLi countertransport, and urinary albumin, urinary GH, and urinary IGF-I from three 24-h collections were measured. Multiple regression analysis showed that BSA (P < 0.0001) and urinary IGF-I (P = 0.001) were significantly associated with KV. MA subjects (albumin excretion rate 15-200 microg/min) had higher urinary IGF-I (P = 0.005) and urinary GH (P = 0.05) compared with normoalbuminuric subjects. Only 9% of the variance in urinary IGF-I could be attributed to plasma IGF-I (r = 0.30, P < 0.0001). Testosterone and prorenin were not associated with MA, but they were associated with KV in univariate analyses. The strong association of urinary IGF-I with KV, a marker for glomerular hypertrophy, and of both urinary IGF-I and urinary GH with MA suggests a role for these growth factors in the development of human diabetic nephropathy. Together, these data support animal studies that have shown that renal GH and IGF-I may contribute significantly to the pathogenesis of early diabetic nephropathy.     

Responses of IGF-I to endogenous increases in growth hormone after heavy-resistance exercise

The purpose of this study was to examine the effects of a heavy-resistance exercise protocol known to dramatically elevate immunoreactive growth hormone (GH) on circulating insulin-like growth factor I (IGF-I) after the exercise stimulus. Seven men (23.1 +/- 2.4 yr) volunteered to participate in this study. Each subject was asked to perform an eight-station heavy-resistance exercise protocol consisting of 3 sets of 10 repetition maximum resistances with 1-min rest between sets and exercises followed by a recovery day. In addition, a control day followed a nonexercise day to provide baseline data. Pre- and postexercise (0, 15, and 30 min) blood samples were obtained and analyzed for lactate, creatinine kinase, GH, and IGF-I. Postexercise values for lactate and GH were significantly (P < 0.05) elevated above preexercise and resting baseline values. The highest mean GH concentration after the heavy-resistance exercise protocol was 23.8 +/- 11.8 micrograms/l, observed at the immediate postexercise time point. Significant increases in creatine kinase were observed after the exercise protocol and during the recovery day. No significant relationships were observed between creatine kinase and IGF-I concentrations. No significant changes in serum IGF-I concentrations were observed with acute exercise or between the recovery and control days. Thus, these data demonstrate that a high-intensity bout of heavy-resistance exercise that increases circulating GH did not appear to affect IGF-I concentrations over a 24-h recovery period in recreationally strength-trained and healthy young men.     

Insulin-like growth factor-I (IGF-I) plasma concentrations are increased in depressed patients

There is some evidence that the somatotrophic system in depression, as assessed by basal growth hormone (GH) concentrations and by GH releasing hormone (GHRH) challenge, might be dysfunctional. However, the rather limited data have been inconclusive so far and plasma concentrations of both insulin-like growth factor-1 (IGF-I) and binding proteins (IGFBP 1 to IGFBP-6) have not been measured simultaneously in depressed patients. We studied 24 severely depressed patients and 33 healthy controls and estimated 24-hour mean plasma cortisol, six-hour evening mean plasma growth hormone (GH), morning plasma IGF-I, IGFBP 2 and 3 and GH-binding protein (GH-BP). Twenty-four-hour mean cortisol (306 +/- 69 vs. 196 +/- 30 nmol/l, p < .001) and IGF-I (157 +/- 40 vs. 120 +/- 33 micrograms/l, p < .01) plasma concentrations were found to be significantly increased in depressed patients, while there was no difference in GH or binding proteins between both groups. MANOVA analysis revealed age and diagnosis to have main effects upon plasma IGF-I. Especially young age and a diagnosis of major depression are associated with higher plasma IGF-I. After treatment only patients in remission had attenuated IGF-I plasma concentrations. We conclude that plasma IGF-I is increased in acutely depressed patients similar to other states of hypercortisolemia.     

Pretreatment with somatostatin analog SMS 201-995 potentiates growth hormone (GH) responsiveness to GH-releasing factor in short children

Previous studies in children have shown inconsistent, poorly reproducible GH responses to exogenous GH-releasing factor (GRF), with wide individual variability. In the present study, we tested the hypothesis that prior administration of the long-acting somatostatin analog, SMS 201-995 (SMS), will enhance GH responsiveness to a subsequent GRF challenge. Two study protocols were employed in 37 children with short stature [M = 31, F = 6, ages 11.8 +/- 1.6 yr (mean +/- SEM), height -2.25 +/- 0.55 SDS (SD scores)]. In both studies, each subject served as his/her own control. In the first study, which was designed to determine optimal SMS dose and regimen, SMS, in doses ranging from 0.8-2.2 micrograms/kg sc, was randomly administered or omitted at 0800 h after an overnight fast, and a GRF bolus (50 micrograms, iv) was given 4 h later. In the second study, we employed a protocol identical to study 1 except for the use of standard doses of SMS (1 microgram/kg, sc) and GRF (1 microgram/kg, iv) and an additional 1-h delay of the GRF injection. Plasma GH levels were measured every 20 min from 0800 h until 2 h after the GRF injection in both studies. In study 1 (n = 12; M = 10, F = 2), SMS significantly suppressed spontaneous GH secretion (expressed as the mean +/- SEM GH AUC during the 4-h SMS-GRF interval, AUC 1:2.2 +/- 0.4 vs. 6.2 +/- 0.9 micrograms/L.h; P < 0.001), GH responsiveness to GRF (GH AUC during the 2 h after the GRF injection, AUC 2: 41.5 +/- 7.8 vs. 85.0 +/- 13.5 micrograms/L.h; P < 0.001), and the GH peak response (17.4 +/- 3.1 vs. 36.0 +/- 6.2 micrograms/L; P < 0.001), compared to control tests. In contrast, in study 2 (n = 25; M = 21, F = 4), whereas spontaneous GH secretion was still suppressed during the 5-h SMS-GRF interval (AUC 1:3.8 +/- 0.4 vs. 7.4 +/- 1.1 micrograms/L.h; P < 0.001), both the GH peak response (56.7 +/- 5.5 vs. 30.5 +/- 3.0 micrograms/L; P < 0.0001) and the GH AUC (AUC 2: 103.7 +/- 10.3 vs. 77.5 +/- 6.8 micrograms/L.h; P < 0.05) after GRF administration were significantly augmented by pretreatment with SMS, compared to control tests. Taken together, these results indicate that a priming SMS dose of 1 microgram/kg has a significant permissive effect on GH responsiveness to exogenous GRF administered 5 h later.(ABSTRACT TRUNCATED AT 400 WORDS)     

Insulin-like growth factor binding protein-1 induces insulin release in the rat

Injections of human insulin-like growth factor binding protein (hIGFBP-1) are reported to induce hyperglycemia in the rat, suggesting that IGFBP-1 acutely regulates glucose homeostasis. We now report the effects on glucose and insulin levels of administering recombinant (r) hIGFBP-1. In a series of studies, normal and streptozotocin (STZ) diabetic male Wistar rats (180-210 g), fasted for 6 or 16 h, were injected with rhIGFBP-1 (i.v., 80-500 microg/rat). rhIGFBP-1 did not affect blood glucose acutely but did stimulate insulin release in normal rats (5 min post injection; PBS, 103.5 +/- 8.5; rhIGFBP-1 (500 microg), 166.8 +/- 15.7; rhIGFBP-1 (100 microg); 151.4 +/- 14.1% initial). rhIGFBP-1 pretreatment, in normal and diabetic rats, reduced the hypoglycemic response to rhIGF-I (diabetic rats after 20 min: PBS, 103.4 +/- 11.4; BP-1 (500 microg) +/- rhIGF-I (50 microg), 97.6 +/- 3.6; rhIGF-I, 48.2 +/- 4.3% initial) but did not affect the hypoglycemic response to des(1-3)IGF-I or insulin (0.5 U/kg). These studies show that rhIGFBP-1 causes insulin release, has a minimal effect on blood glucose, and inhibits the hypoglycemic effect of rhIGF-I. These data suggest that endogenous IGF-I tonically suppresses insulin secretion and imply that aberrant IGFBP levels or reduced IGF-I bioactivity may lead to chronic hyperinsulinemia.     

Free and total insulin-like growth factors and insulin-like growth factor binding proteins during 14 days of growth hormone administration in healthy adults

The objective was to investigate the effect of growth hormone (GH) administration on circulating levels of free insulin-like growth factors (IGFs) in healthy adults. Eight healthy male subjects were given placebo and two doses of GH (3 and 6 IU/m2 per day) for 14 days in a double-blind crossover study. Fasting blood samples were obtained every second day. Free IGF-I and IGF-II were determined by ultrafiltration of serum. Total IGF-I and IGF-II were measured after acid-ethanol extraction. In addition, GH, insulin, IGF binding protein 1 (IGFBP-1) and IGFBP-3 were measured. Serum-free and total IGF-I increased in a dose-dependent manner during the 14 days of GH administration. After 14 days, serum-free IGF-I values were 610 +/- 100 ng/l (mean +/- SEM) (placebo), 2760 +/- 190 ng/l (3 IU/ m2) and 3720 +/- 240 ng/l (6 IU/m2) (p = 0.0001 for 3 and 6 IU/m2 vs placebo; p = 0.004 for 3 IU/m2 vs 6 IU/m2). Total IGF-I values were 190 +/- 10 micrograms/l (placebo), 525 +/- 10 (3 IU/m2), and 655 +/- 40 micrograms/l (6 IU/m2) (p < 0.0001 for 3 and 6 IU/m2 vs placebo; p = 0.04 for 3 IU/m2). There were no differences in the levels of free or total IGF-II during the three study periods. Insulin-like growth factor binding protein 1 was decreased during GH administration (p = 0.04 for placebo vs 3 IU/m2; p = 0.006 for placebo vs 6 IU/m2). In conclusion, fasting serum free IGF-I increased dose dependently during GH administration and free IGF-I increased relatively more than total IGF-I. This may partly be due to the decrease in IGFBP-1.     

Effects of insulin-like growth factor I combined with growth hormone on glucocorticoid-induced whole-body protein catabolism in man

Treatment with insulin-like growth factor I (IGF-I) alone failed to affect glucocorticoid-induced protein catabolism in a previous study from our laboratory. To assess the effects of the combination of IGF-I and GH in a similar protocol, 24 normal subjects received (in a double-blind, randomized, placebo-controlled manner) s.c. injections of either GH alone (0.3 IU/kg.day), the combination of IGF-I (80 micrograms/kg.day) and GH (0.3 IU/kg.day), or placebo for a period of 6 days during which they were treated with methylprednisolone (0.5 mg/kg.day). Whole-body protein kinetics measured, using the [1-13C]-leucine infusion technique, demonstrated that leucine flux (a parameter of protein breakdown) increased during administration of glucocorticoids alone (placebo group) and during GH-treatment, whereas the glucocorticoid-induced increase was abolished during IGF-I plus GH (P < 0.03 vs. GH). Leucine oxidation (a parameter of irreversible protein catabolism) increased in the placebo group (+60 +/- 14.5%, P < 0.005, day 7 vs. day 1), remained unchanged in the GH group (+2.5 +/- 10%), and decreased in the combination group (-17.7 +/- 3.3%, P < 0.002, day 7 vs. day 1). Glucose MCR decreased in the group receiving placebo (P < 0.05) and remained unchanged during combined treatment with IGF-I plus GH. It is concluded that glucocorticoid-induced protein, catabolism (leucine oxidation) is abolished during coadministration of GH (anticatabolic effect), whereas treatment with IGF-I and GH results in a net anabolic effect without adverse effects on peripheral glucose clearance.     

Insulin-like growth factor I is an independent coregulatory modulator of natural killer (NK) cell activity

We aimed to investigate the natural killer (NK) cell activity in hGH-deficient adults and to analyze the effect of insulin-like growth factor (IGF)-I in vivo and in vitro on NK cell activity. NK cell activity was measured in a 4-h nonisotopic assay with europium-labeled and cryopreserved K-562 cells. NK-cell numbers were measured after incubation with murine monoclonal CD3 and CD16 antibodies by flow cytometry analysis. In a cross-sectional study, the basal and interferon-beta (IFN-beta) stimulated (1000 IU/ml) NK cell activity of 15 hGH-deficient patients and 15 age- and sex-matched controls was measured. The percentages and absolute numbers of CD3-/16+ NK-cells were not significantly different in the patient vs. control group. The basal and IFN-beta stimulated NK cell activity however was significantly decreased in the patient vs. control group at all effector/target (E/T) cell ratios from 12.5-100 (e.g. 17 +/- 3 vs. 28 +/- 3% lysis without IFN-beta, P < 0.05, and 42 +/- 4 vs. 57 +/- 4% lysis with IFN-beta, P < 0.05; both at E/T 50). IGF-I levels of patients and controls showed a significant positive correlation with NK cell activity (r = 0.37; P < 0.05). In an IGF-I in vitro study (IGF-I in vitro 250-1250 microg/L), the basal and IFN-beta stimulated NK cell activity of 13 hGH-deficient patients and of 18 normal subjects was significantly enhanced by IGF-I in vitro (e.g. GH-deficient patients: 9 +/- 2 vs. 10 +/- 2% lysis without IFN-beta, P < 0.05 and 25 +/- 4 vs. 30 +/- 4% lysis with IFN-beta, P < 0.005; and normal subjects: 15 +/- 3 vs. 23 +/- 3% lysis without IFN-beta, P < 0.001 and 35 +/- 4 vs. 44 +/- 5% lysis with IFN-beta, P < 0.001; both at IGF-I 500 microg/L). In summary, in our cross-sectional study, adult GH-deficient patients showed a significantly lower basal and IFN-beta stimulated NK cell activity than matched controls, despite equal NK cell numbers. IGF-I levels of patients and controls showed a weak positive correlation with NK cell activity. In an in vitro study, IGF-I significantly enhanced basal and IFN-beta stimulated NK cell activity of hGH-deficient patients and also of normal subjects. The decreased NK cell activity in GH-deficient patients may be caused at least in part by low serum IGF-I levels. IGF-I appears to be an independent coregulatory modulator of NK cell activity.     

Unchanged testosterone production rates in growth hormone-treated healthy men

The effect of biosynthetic human GH on the production rates of testosterone was determined in healthy men (n = 7) using the stable isotope dilution technique and mass spectrometry. 1Alpha,2alpha-d-testosterone (20 microg/h) was infused for 10 h (0800-1800 h). Blood samples obtained at 20-min intervals from 1400-1800 h were pooled during two 2-h periods. Subsequently, each volunteer received a daily dose of biosynthetic human GH (4 IU/day sc) for 7 days. This resulted in a rise in plasma concentrations of somatomedin-C from, basal, 0.67+/-0.13 U/mL to 1.20+/-0.2 U/mL on day 7 (P < 0.0001). Testosterone production rates (basal: 209.9+/-31.0 microg/h) were unchanged by treatment with GH (day 7: 192.2+/-30.1 microg/h). In healthy men, short-term treatment with sc GH does not influence endogenous testosterone production rates.     

The role of the growth hormone/insulin-like growth factor I axis in stimulation of protein synthesis in skeletal muscles following oral refeeding

The mechanisms behind stimulation of protein synthesis in skeletal muscles following oral feeding are not well understood. Previous research has not confirmed that insulin is a major factor behind this stimulation. In the present study we have used genetically altered mice, with either a lack of GH secretion due to a mutational gene inactivation [GH (-/-) dwarf, DW/JOrlBom-dw] or mice with a homozygous site-specific insertion mutation in the insulin-like growth factor-1 gene [IGF-I (m/m)], leading to a deficient IGF-I production. These gene knock-outs were used in comparison to their normal wild types for evaluation of the role that the GH/IGF-I axis may have in activation of nutritionally induced stimulation of protein synthesis in skeletal muscles during oral refeeding. Weight stable adult C57B16 mice served as an additional normal control group. Protein synthesis was measured by a modified flooding dose technique with radioactive L-[14C-U]phenylalanine incorporation into acid precipitated muscle proteins. Fractional protein synthesis in skeletal muscles after an overnight fast was comparable among C57B16 (0.076 +/- 0.009%/h), wild-type IGF-I(+/+) (0.061 +/- 0.008) and IGF-I(m/m) deficient mice (0.068 +/- 0.006%/h), whereas GH(-/-) incompetent mice had a lower fractional synthesis rate compared with GH(+/+) competent mice (0.045 +/- 0.006 vs. 0.068 +/- 0.007, P < 0.05). Refeeding with standard chow diet stimulated protein synthesis in muscles by more than 60% in all animal groups. This response was independent of circulating GH, total IGF-I concentrations in blood, as well as up-regulation of locally produced IGF-I messenger RNA (mRNA) in skeletal muscles.