Long-term effects of insulin-like growth factor (IGF)-I treatment on serum IGFs and IGF binding proteins in adolescent patients with growth hormone receptor deficiency

OBJECTIVE The aim of this investigation was to study the effect of relatively high dose IGF-I therapy given for several months, on serum levels of IGF-I, IGF-II and IGFBP-3, and on IGF-I pharmacokinetics In patients with growth hormone insensitivity due to GH receptor dysfunction. DESIGN AND PATIENTS Two adolescent subjects from Ecuador were treated with recombinant IGF-I at a dosage of 120μg/kg s.c. twice dally, in combination with a GnRH analogue for 8 months. MEASUREMENTS Serum was sampled at baseline and at 3–8 months, for determination of IGF-I, IGF-II and IGFBP-3 by radioimmunoassay, and for evaluation of IGFBPs and IGFBP-3 protease activity by Western ligand blot and protease assay, respectively. RESULTS Peak serum IGF-I levels ranged from 272 to 492μg/l. Mean serum IGF-II levels were decreased concurrently with the increase in IGF-I. Serum IGFBP-3 levels failed to rise with prolonged IGF-I treatment. There was no apparent change In the half-life of IGF-I during the treatment period. CONCLUSIONS IGF-I administration does not increase serum levels of IGFBP-3 or significantly alter IGF-I pharmacokinetics.     

Is further evaluation for growth hormone (GH) deficiency necessary in fibromyalgia patients with low serum insulin-like growth factor (IGF)-I levels?

OBJECTIVE: Fibromyalgia (FM) is characterized by diffuse pain, fatigue, and sleep disturbances; symptoms that resemble the adult growth hormone (GH) deficiency syndrome. Many FM patients have low serum GH levels, with a hypothesized aetiology of dysregulated GH/insulin-like growth factor (IGF)-I axis. The aim of this study was to assess the GH reserve in FM patients with low serum IGF-I levels using the GH-releasing hormone (GHRH)-arginine test. DESIGN: We retrospectively reviewed the GHRH-arginine data of 77 FM patients with low serum IGF-I levels referred to our tertiary unit over a 4-year period. RESULTS: Of the 77 FM patients, 13 patients (17%) failed the GHRH-arginine test. Further evaluation with pituitary imaging revealed normal pituitary glands (n=7), coincident microadenomas (n=4), empty sella (n=1) and pituitary cyst (n=1), and relevant medical histories such as previous head injury (n=4), Sheehan's syndrome (n=1), and whiplash injury (n=1). In contrast, the remaining 64 patients (83%) that responded to the GHRH-arginine test demonstrated higher peak GH levels compared to age and BMI-matched controls (n=24). CONCLUSION: Our data shows that a subpopulation of FM patients with low serum IGF-I levels will fail the GHRH-arginine test. We, thus, recommend that the GH reserve of these patients should be evaluated further, as GH replacement may potentially improve the symptomatology of those with true GH deficiency. Additionally, the increased GH response rates to GHRH-arginine stimulation in the majority of FM patients with low serum IGF-I levels further supports the hypothesis of a dysregulated GH/IGF-I axis in the pathophysiology of FM.     

Diurnal variation in serum insulin-like growth factor (IGF)-I and IGF binding protein-3 concentrations during daily subcutaneous injections of recombinant human growth hormone in GH-deficient adults

OBJECTIVE  Whereas there seems to be little, if any, circadian variation in circulating concentrations of IGF-I and IGFBP-3 in healthy subjects, there are conflicting reports on this issue in GH-deficient patients treated with GH as a daily subcutaneous injection. We have therefore investigated the 24-hour serum profiles of IGF-I and IGFBP-3 concentrations after one week and more than one year of GH treatment.
PATIENTS  Eleven subjects, with adult onset GH deficiency mainly caused by pituitary adenomas were included in the study.
DESIGN AND MEASUREMENTS  In an open study, six subjects (three women and three men; age (±SEM) 41.2±3.9 years) were investigated after one week of GH therapy and five subjects (three women and two men; age (±SEM) 61.4±3.3 years) were investigated after 13–40 months of GH therapy. The GH injections were given at 2000 h. The subjects were hospitalized for 24-hour blood sampling at 1-hour intervals and serum concentrations of GH, IGF-I and IGFBP-3 were determined.
RESULTS  There was a significant diurnal variation in serum IGF-I and IGFBP-3 concentrations both in the subjects who had received GH for one week and in those who had received GH treatment for more than one year. The serum concentrations of IGF-I and IGFBP-3 were highest in the morning and lowest during night-time and early morning. The molar IGF-I/IGFBP-3 ratio varied significantly with time in both groups of patients in a similar way as IGF-I and IGFBP-3 indicating a more pronounced variation in IGF-I compared with IGFBP-3 in response to the GH therapy.
CONCLUSION  Significant diurnal variations in serum IGF-I and IGFBP-3 concentrations occur after one week and more than one year of GH treatment with daily subcutaneous injections. The results indicate that the free fraction of IGF-I may exhibit a diurnal variation.     

Characterization of specific insulin-like growth factor (IGF)-I and IGF-II receptors on cultured rabbit articular chondrocyte membranes

The interaction of insulin-like growth factor (IGF)-I and IGF-II with specific type-I and -II receptor sites on rabbit articular chondrocyte membranes was studied. With labelled IGF-I as tracer, half-maximal displacement of the label was obtained with 1.4 ng IGF-I/ml and 22 ng IGF-II/ml. Using IGF-II as labelled peptide. 16 ng unlabelled IGF-II/ml and 200 ng IGF-I/ml were needed to inhibit the binding by 50%. Covalent cross-linking experiments revealed the presence of typical type-I (Mr 130,000 under reducing conditions) and type-II (Mr 260,000) receptor sites. In addition, with 125I-labelled IGF-II a very intense labelled band appeared at Mr greater than 300,000. This band was not found in mouse liver membranes and human placental membranes.     

Long-term treatment with recombinant insulin-like growth factor (IGF)-I in children with severe IGF-I deficiency due to growth hormone insensitivity

CONTEXT: Children with severe IGF-I deficiency due to congenital or acquired defects in GH action have short stature that cannot be remedied by GH treatment. OBJECTIVES: The objective of the study was to examine the long-term efficacy and safety of recombinant human IGF-I (rhIGF-I) therapy for short children with severe IGF-I deficiency. DESIGN: Seventy-six children with IGF-I deficiency due to GH insensitivity were treated with rhIGF-I for up to 12 yr under a predominantly open-label design. SETTING: The study was conducted at general clinical research centers and with collaborating endocrinologists. SUBJECTS: Entry criteria included: age older than 2 yr, sd scores for height and circulating IGF-I concentration less than -2 for age and sex, and evidence of resistance to GH. INTERVENTION: rhIGF-I was administered sc in doses between 60 and 120 microg/kg twice daily. MAIN OUTCOME MEASURES: Height velocity, skeletal maturation, and adverse events were measured. RESULTS: Height velocity increased from 2.8 cm/yr on average at baseline to 8.0 cm/yr during the first year of treatment (P < 0.0001) and was dependent on the dose administered. Height velocities were lower during subsequent years but remained above baseline for up to 8 yr. The most common adverse event was hypoglycemia, which was observed both before and during therapy. It was reported by 49% of treated subjects. The next most common adverse events were injection site lipohypertrophy (32%) and tonsillar/adenoidal hypertrophy (22%). CONCLUSIONS: Treatment with rhIGF-I stimulates linear growth in children with severe IGF-I deficiency due to GH insensitivity. Adverse events are common but are rarely of sufficient severity to interrupt or modify treatment.     

Treatment of iodine deficiency in school-age children increases insulin-like growth factor (IGF)-I and IGF binding protein-3 concentrations and improves somatic growth

CONTEXT: Iodine deficiency in utero impairs fetal growth, but the relationship between iodine deficiency and postnatal growth is less clear. OBJECTIVE: The objective of the study was to determine whether iodine repletion improves somatic growth in iodine-deficient children and investigate the role of IGF-I and IGF binding protein (IGFBP)-3 in this effect. DESIGN, PARTICIPANTS, AND INTERVENTIONS: Three prospective, double-blind intervention studies were done: 1) in a 10-month study, severely iodine-deficient, 7- to 10-yr-old Moroccan children (n = 71) were provided iodized salt and compared with children not using iodized salt; 2) in a 6-month study, moderately iodine-deficient, 10- to 12-yr-old Albanian children (n = 310) were given 400 mg iodine as oral iodized oil or placebo; 3) in a 6-month study, mildly iodine-deficient 5- to 14-yr-old South African children (n = 188) were given two doses of 200 mg iodine as oral iodized oil or placebo. At baseline and follow-up, height, weight, urinary iodine (UI), total T4 (TT4), TSH, and IGF-I were measured; in Albania and South Africa, IGFBP-3 was also measured. RESULTS: In all three studies, iodine treatment increased median UI to more than 100 microg/liter, whereas median UI in the controls remained unchanged. In South Africa, iodine repletion modestly increased IGF-I but did not have a significant effect on IGFBP-3, TT4, or growth. In Albania and Morocco, iodine repletion significantly increased TT4, IGF-I, IGFBP-3, weight-for-age z scores, and height-for-age z scores. CONCLUSION: This is the first controlled study to clearly demonstrate that iodine repletion in school-age children increases IGF-I and IGFBP-3 concentrations and improves somatic growth.     

Fetal insulin-like growth factor (IGF)-I, IGF-II, and ghrelin in association with birth weight and postnatal growth in monozygotic twins with discordant growth

OBJECTIVE: To investigate the relative contribution of genetic (fetal) vs. environmental (maternal/placental) factors on growth, we studied monozygotic twins with intertwin birth weight difference. PATIENTS AND METHODS: Twenty-seven twins (15 with discordant growth) who have been treated for severe twin-to-twin transfusion syndrome by laser coagulation were studied. Cord blood samples were analyzed for IGF-I, IGF-II, IGF-binding protein-2, and ghrelin. Intertwin difference (Delta) of birth weight was correlated to Delta of the parameters analyzed. The Delta weight after 1 yr was correlated with Delta birth weight and all hormones. RESULTS: The Delta birth weight was positively correlated with Delta IGF-I (r = 0.66; P < 0.0002) and negatively correlated with Delta IGF-binding protein-2 levels (r = -0.68; P < 0.001) but with neither Delta IGF-II nor Delta ghrelin. There was a strong intertwin correlation for all hormones. By comparing the growth in the first year, we found an overall reduction of the relative weight difference between the twins of 57%. ANOVA was used to calculate factors for prediction of postnatal catch-up growth. Besides the birth weight difference (R2= 0.84; P < 0.0001), only ghrelin was of prognostic value for postnatal catch-up growth (R2= 0.94; P = 0.0035). CONCLUSION: These data confirm the importance of IGF-I in contrast to IGF-II for fetal weight. Additionally, ghrelin seems to be involved in fetal and probably postnatal growth.     

Investigation of insulin-like growth factor (IGF)-I and insulin receptor binding and expression in jejunum of parenterally fed rats treated with IGF-I or growth hormone.

To investigate the ability of insulin-like growth factor-I (IGF-I), but not GH, to stimulate jejunal growth, we compared indices of IGF-I and insulin receptor expression in jejunal membranes from rats maintained with total parenteral nutrition (TPN) and treated with rhIGF-I and/or rhGH. TPN without growth factor treatment (TPN control) induced jejunal atrophy, reduced serum IGF-I, increased serum insulin concentrations, and increased IGF-I receptor number, IGF-I receptor messenger RNA, and insulin-specific binding to 133% to 170% of the orally fed reference values, P < 0.01. Compared with TPN control, IGF-I or IGF-I + GH stimulated jejunal mucosal hyperplasia; IGF-I treatment increased serum IGF-I by 2- to 3-fold and decreased serum insulin concentrations by 60%, decreased IGF-I receptor number by 50% (P < 0.001), and increased insulin receptor affinity and insulin receptor protein content. Treatment with GH alone increased serum IGF-I concentration, did not alter TPN-induced jejunal atrophy, and decreased insulin-specific binding and insulin receptor protein content (39% and 59%, respectively, of the TPN control values, P < 0.01). We conclude that: 1) jejunal IGF-I receptor content reflects circulating concentration of ligand and is not limiting for jejunal growth; and 2) increased circulating concentration of IGF-I may promote jejunal growth via interaction with jejunal insulin or IGF-I receptors.     

Characterization of serum growth hormone (GH) and insulin-like growth factor I in active acromegaly with minimal elevation of serum GH

In most patients with acromegaly basal serum GH concentrations are elevated and remain above 5 micrograms/L after oral glucose administration. In some patients, however, serum insulin-like growth factor I (IGF-I) concentrations are elevated with only minimal elevations of serum GH. We studied the serum GH and IGF-I of two such patients to determine whether these peptide hormones are normal in this clinical situation. The serum GH of these patients was found to bind normally to receptors of the IM-9 lymphocyte. The elution pattern of IGF-I extracted from the patients' serum was similar to that of (Thr59) human IGF-I after passage through a Bio-Rad P-60 column in 0.5 M acetic acid. The IGF-I was further characterized by isoelectric focusing and C18 reverse phase high pressure liquid chromatography (HPLC). The isoelectric points of the IGF-I components were similar to those of IGF-I in normal serum. The IGF-I in one patient had two components by HPLC, while that of the other patient had only one major component. The IGF-I components isolated by HPLC were normally active in stimulating [3H] alpha-aminoisobutyric acid uptake by normal human fibroblasts. The elevated serum IGF-I concentrations of these two patients were GH dependent. Transsphenoidal adenomectomy in one patient resulted in a decline in serum IGF-I to a high normal concentration. Lowering the serum GH to subnormal concentrations by the administration of the somatostatin analog SMS 201-995 (Sandoz) restored normal IGF-I concentrations in the second patient. We conclude that the GH and IGF-I of these two patients cannot account for their apparent enhanced GH responsiveness.     

Serum levels of free insulin-like growth factor (IGF)-I and IGF-binding protein-1 in prepubertal children with idiopathic short stature

The study was performed to evaluate the relationships among serum free and total insulin-like growth factor (IGF)-I, IGF-binding protein-1 (IGFBP-1), IGFBP-3, and insulin concentrations in prepubertal children with idiopathic short stature (ISS). Eighteen children with ISS and 15 age-matched controls were included in the study. All short children had a height standard deviation score of more than 2 below the mean, and maximum stimulated GH levels greater than 10 microg/l after two standard provocation tests. The serum levels of free IGF-I were significantly lower in short children (1.6 +/- 0.3 microg/l) than in the controls (2.8 +/- 0.6 microg/l, P<0.05), while total IGF-I levels were slightly, but not significantly, lower in short children than in controls. The serum levels of IGFBP-1 were significantly higher in the ISS group (124.6 +/- 5.6 microg/l) than in controls (80.0 +/- 8.7 microg/l, P < 0.0001). The fasting insulin and IGFBP-3 levels were similar in both groups. A stepwise regression analysis for all subjects revealed that IGFBP-1 is the only independent predictor of log free IGF-I (R2 = 0.23, P<0.01). The present study shows that the serum levels of free IGF-1 are significantly lower and insulin-like growth factor-binding protein-1 levels are higher in prepubertal children with idiopathic short stature, as compared with age-matched controls. The high IGFBP-1 may contribute to growth retardation in a subgroup of idiopathic short stature through a decrease in free IGF-1.     

Acid-labile subunit in growth hormone excess and deficiency in adults: evaluation of its diagnostic value in comparison with insulin-like growth factor (IGF)-I and IGF-binding protein-3

In serum, insulin-like growth factors (IGFs) are primarily present as a approximately 150 kDa ternary protein complex, which consists of IGFs, IGF binding protein-3 (IGFBP-3), and acid-labile subunit (ALS). Like IGF-I and IGFBP-3, serum levels of ALS depend on growth hormone (GH). To date, the diagnostic relevance of ALS in adult GH deficiency (GHD) has remained uncertain. To clarify the clinical utility of ALS measurement in adults, we measured serum ALS levels in patients with adult GHD or acromegaly. We also measured the levels of serum IGF-I and IGFBP-3 in these patients to compare the utility of ALS with IGF-I and IGFBP-3 as a marker of GH secretion. Serum ALS was measured by radioimmunoassay (RIA) kit, and serum IGF-I and IGFBP-3 were measured by immunoradiometric assay (IRMA) kits in 56 patients with adult GHD (adult-onset (AO)/child-onset (CO), 13/43) and 43 patients with acromegaly. Serum ALS levels were less than 5th percentile in 40 of 56 (71%) patients with adult GHD (32/43 (74%) for CO and 8/13 (62%) for AO), and more than 95th percentile in 38 of 43 (88%) patients with acromegaly, respectively. Serum IGF-I levels were less than -1.96 SD in 43 of 56 (77%) patients with adult GHD (35/43 (81%) for CO and 8/13 (62%) for AO) and more than +1.96 SD in 42 of 43 (98%) patients with acromegaly, respectively. Serum IGFBP-3 levels were less than -1.96 SD in 51 of 56 (91%) patients with adult GHD (42/43 (98%) for CO and 9/13 (69%) for AO) and more than +1.96 SD in 31 of 43 (72%) patients with acromegaly, respectively. These data suggested that measurement of ALS offers no advantage over measurements of serum IGF-I and IGFBP-3. Furthermore, our results indicate that serum IGFBP-3 is the most suitable marker of GH secretion for adult GHD, especially CO, while IGF-I may be the most useful in acromegaly.     

Effects of combined recombinant insulin-like growth factor (IGF)-I and IGF binding protein-3 in type 2 diabetic patients on glycemic control and distribution of IGF-I and IGF-II among serum binding protein complexes

CONTEXT: Administration of recombinant human IGF-I (rhIGF-I)/recombinant human IGF binding protein-3 (rhIGFBP-3) to patients with type 2 diabetes improves blood glucose and enhances insulin sensitivity. The changes in various components of the IGF system that occur in response to rhIGF-I/rhIGFBP-3 as well as the minimum effective dose have not been determined. OBJECTIVES: The aim was to determine the dose of rhIGF-I/rh-IGFBP-3 necessary to achieve a significant decrease in glucose and to determine the changes that occur in the IGF-II and acid labile subunit in response to treatment. DESIGN: A total of 39 insulin-requiring type 2 diabetics were randomized to placebo or one of six groups that received different dosages of rhIGF-I/rhIGFBP-3. After 3 d in which insulin doses were adjusted to improve glucose control, a variable insulin dosage regimen was continued, and either placebo or one of six dosages (0.125-2.0 mg/kg.d) of rhIGF-I/rhIGFBP-3 was administered for 7 d. All subjects were hospitalized, and dietary intake as well as insulin dosage were controlled with instructions to treat to normal range targets. RESULTS: Fasting glucose was reduced in the groups that received either 1 (32 +/- 5% reduction) or 2 mg/kg.d (40 +/- 6% reduction) of the complex. Mean daily glucose (four determinations) was reduced by 26 +/- 4% in the 1 mg/kg group and by 33 +/- 5% in the 2 mg/kg group compared with 18 +/- 4% in the placebo group. Total serum IGF-I increased between 2.0 +/- 0.3- and 5.7 +/- 1.3-fold by d 8. IGFBP-3 concentrations increased significantly only in the 2 mg/kg group. IGF-II concentrations declined to values that were between 27 +/- 4% and 64 +/- 7% below baseline. Acid labile subunit concentrations declined significantly in the three highest dose groups. The sum of the IGF-I + IGF-II concentrations was significantly increased at the two highest dosages. There were very few drug-associated adverse events reported in this study with the exception of hypoglycemia, which occurred in 15 subjects who had received rhIGF-I/rhIGFBP-3 treatment. CONCLUSIONS: Administration of rhIGF-I/rhIGFBP-3 resulted in a redistribution of the amount of IGF-I and IGF-II that bound to IGFBP-3. Fasting and mean daily blood glucose were reduced significantly in the two highest dosage groups. The results suggest that both the total concentration of IGF-I as well as its distribution in blood may determine the extent to which insulin sensitivity is enhanced.     

Free and total insulin-like growth factor (IGF)-I levels decline during fasting: relationships with insulin and IGF-binding protein-1

We have previously demonstrated that IGF-binding protein-1 (IGFBP-1) levels rise steadily during fasting, following an inverse relationship with insulin. The function of the IGFBP-1 rise is unknown, but it has been hypothesized that IGFBP-1 serves as a glucose counterregulatory hormone during fasting and hypoglycemia by binding free IGFs, thus inhibiting IGF interactions with IGF receptors. Our objective in this study was to determine levels of free and total IGFs during fasting together with their interrelationships with simultaneous IGFBP-1, insulin, and glucose levels. Our patient population consisted of 22 children, aged 6 months to 15 yr, who underwent diagnostic fasting studies in the General Clinical Research Center. Blood was sampled at baseline and at 6-h intervals for glucose, IGFBP-1, free and total IGF-I, and insulin. The fasting studies lasted 14-40 h and were terminated at a glucose concentration of less than 50 mg/dl (n = 11) or for the completion of the allotted fasting duration (n = 11). Of the children studied, 11 had ketotic hypoglycemia, 8 had no disorder, 2 had steroid-induced adrenal suppression, and 1 had recovered transient hyperinsulinism. During fasting, IGFBP-1 levels rose above mean initial levels of 27.1 +/- 13.4 ng/ml to a mean of 318.4 +/- 29.9 ng/ml at the end point (P < 0.001). Insulin levels declined from a mean initial level of 7.4 +/- 1.3 mU/ml to a mean level of 1.4 +/- 0.4 mU/ml at the end point (P < 0.001). Concomitantly, free and total IGF-I levels declined from initial levels of 0.48 +/- 0.08 and 180.3+/- 27 ng/ml, respectively, to mean levels of 0.10 +/- 0.02 ng/ml (P < 0.001) and 119.3 +/- 22 ng/ml (P = 0.001), respectively, at the end point. Levels of free IGF-I were inversely associated with IGFBP-1 over the course of fasting (P = 0.002). Similarly, total IGF-I was negatively associated with IGFBP-1 (P = 0.01). We conclude that free and total IGF-I levels decline steadily over the course of fasting. This decline in free IGF-I appears to be the result of the steady rise in IGFBP-1 that occurs as insulin declines. We speculate that the decline in IGF levels, controlled by the rise in IGFBP-1, serves to protect against possible insulin-like activity of the IGFs during fasting.     

Circadian patterns of serum insulin-like growth factor (IGF) II and IGF binding protein 3 in growth hormone-deficient patients and age- and sex-matched normal subjects.

Knowledge of the circadian patterns of serum IGF-II and the large molecular weight IGF binding protein, IGFBP-3 might, apart from its physiological relevance, be of clinical interest, inasmuch as measurements of these parameters are being introduced into the evaluation of GH deficiency. We therefore evaluated the 24-h (08.00-08.00 h) patterns of serum IGF-II and IGFBP-3 in 8 GH-deficient patients who were studied during three periods when receiving 1. GH (2 IU) at 20.00 h; 2. GH (2 1U) at 08.00 h and 3. no GH. For comparison, 10 age- and sex-matched untreated healthy subjects were studied once under similar conditions. The serum IGF-II levels of the patients were relatively stable over the 24-h periods, yielding mean levels which were significantly lower during no GH: 553 +/- 78 (evening GH), 554 +/- 54 (morning GH), and 429 +/- 65 micrograms/l (no GH). The mean IGF-II level in the normal subjects was 635 +/- 29 micrograms/l, which was significantly higher than in either patient study. Similarly, stable 24-h levels of IGFBP-3 were recorded in all studies. The mean IGFBP-3 level of the patients was significantly lower when they received no GH, and the mean level in the healthy subjects was higher than in any of the patient studies: 1853 +/- 301 (no GH), 2755 +/- 317 (evening GH), 2904 +/- 269 (morning GH), and 3856 +/- 186 micrograms/l (healthy subjects). However, minute but significant changes over time, characterised by slight decrements at night, were observed for both parameters in several of the studies.(ABSTRACT TRUNCATED AT 250 WORDS)     

Free/dissociable insulin-like growth factor (IGF)-I, not total IGF-I, correlates with growth response during growth hormone treatment in children born small for gestational age

CONTEXT: IGF-I plays an important role in pre- and postnatal growth. Its serum levels are regulated by metabolic and genetic factors. Mean total IGF-I in short, small for gestational age (SGA) children is reduced, but within the normal range. Free/dissociable IGF-I is the bioactive form of IGF-I. Objectives: The aim of the study was to investigate changes in free IGF-I during GH treatment in short SGA children and to evaluate whether free IGF-I levels contribute to predicting first-year growth response and/or adult height. DESIGN, SETTING, AND INTERVENTION: We conducted a randomized, double-blind GH dose-response study with a GH dose of either 1 mg/m(2).d (group A) or 2 mg/m(2).d (group B). Free IGF-I, total IGF-I, and IGF binding protein (IGFBP)-3 were determined at baseline, after 1 and 5 yr, at stop, and 6 months after GH discontinuation. PATIENTS: We studied 73 (46 male) short SGA children (36 group A) with a baseline mean age of 7.7 (2.2) yr and a mean GH duration of 8.2 (2.1) yr. MAIN OUTCOME MEASURES: Untreated SGA children had a mean free IGF-I sd score (SDS) of -0.2 (1.2), not related to total IGF-I. During GH therapy, free IGF-I significantly increased to 1.6 (0.7) SDS, as did total IGF-I and IGFBP-3 [2.0 (0.8) and 1.3 (0.9), respectively]. Multiple regression analysis showed that baseline free IGF-I and IGFBP-3 were negatively correlated with adult height SDS, whereas baseline bone age delay, target height SDS, baseline height SDS, and GH dose were positively correlated. Free IGF-I was also negatively correlated with first-year growth response. CONCLUSIONS: Circulating baseline free IGF-I and IGFBP-3 were better predictors for adult height in GH-treated SGA children than total IGF-I, or total IGF-I to IGFBP-3 ratio. This suggests a possible role for free IGF-I measurement in predicting the effect of GH therapy in short SGA children.     

Effect of intraperitoneal insulin delivery on growth hormone binding protein,insulin-like growth factor (IGF)-I,and IGF-binding protein-3 in IDDM

Summary Low plasma insulin-like growth factor (IGF)-I despite high circulating growth hormone (GH) in insulin-dependent diabetes mellitus (IDDM) indicate a hepatic GH resistance. This state may be reflected by the reduction of the circulating GH binding protein (GHBP), corresponding to the extracellular domain of the GH receptor, and the reduction of insulin-like growth factor binding protein (IGFBP)-3, major IGF-I binding protein, upregulated by GH. We carried out two studies. In the first, plasma GHBP activity was compared in patients with IDDM on continuous subcutaneous insulin infusion (CSII) or on conventional therapy and in healthy subjects. In the second study, the 18 patients on CSII at baseline were then treated by continuous intraperitoneal insulin infusion with an implantable pump (CPII) and prospectively studied for GH-IGF-I axis. Although HbA_{1 c} was lower in patients on CSII than in those on conventional therapy, GHBP was similarly reduced in both when compared to control subjects (10.2 ± 0.8 and 11.6 ± 0.9 % vs 21.0 ± 1.3, p < 0.01). CPII for 12 months resulted in: a slight and transient improvement in HbA_{1 c} (Time (T)0: 7.6 ± 0.2 %, T3:7.1 ± 0.2 %, T12: 7.5 ± 0.2 %, p < 0.02), improvement in GHBP (T0: 10.2 ± 0.8 %, T12: 15.5 ± 1.5, p < 0.0001), near-normalization of IGF-I (T0: 89.4 ± 8.8 ng/ml, T12: 146.9 ± 15.6, p < 0.002) and normalization of IGFBP-3 (T0: 1974 ± 121 ng/ml, T12: 3534 ± 305, p < 0.0001). The hepatic GH resistance profile in IDDM does not seem to be related to glycaemic control, but partly to insufficient portal insulinization. Intraperitoneal insulin delivery, allowing primary portal venous absorption, may influence GH sensitivity, and improve hepatic IGF-I and IGFBP-3 generation. [Diabetologia (1996) 39: 1498–1504] Received: 23 March 1996 and in revised form: 22 July 1996     

Contribution of insulin-like growth factor (IGF)-I and IGF-binding protein-3 to mitogenic activity in bovine mammary extracts and serum.

Peripubertal development of the mammary gland is probably mediated by locally produced growth factors acting in concert with circulating mitogens. Our objective was to investigate the effect of recombinant human insulin-like growth factor-binding protein-3 (rhIGFBP-3) or insulin-like growth factor-I (IGF-I) antibodies on the IGF-I-related mitogenic activity of bovine serum and of mammary tissue extracts in primary mammary epithelial cell cultures. Cells were obtained from prepubertal female calf mammary tissue and cultured in three-dimensional collagen gels. An aqueous mammary parenchymal tissue extract (pooled from 20 prepubertal heifers) or serum (pooled from 3 heifers) at a concentration of 5% was added to the medium containing either rhIGFBP-3 or monoclonal or polyclonal antibodies to human IGF-I. Cell proliferation was evaluated using [methyl-3H]thymidine incorporation as a measure of DNA synthesis. Addition of mammary extracts stimulated DNA synthesis 545% compared with basal medium. Addition of serum stimulated DNA synthesis by 28%. Mitogenic activity of serum and added IGF-I was abolished by addition of rhIGFBP-3 in equimolar concentrations with IGF-I. For mammary extracts, mitogenic activity was inhibited by 35%, 50%, and 82% by the addition of rhIGFBP-3 at, respectively, 1, 2 and 4 times the molar IGF-I concentration in the extract. Addition of rhIGFBP-3 to basal medium reduced DNA synthesis by 26%, whereas IGF-I antibodies had no consistent effect. These results indicate that circulating and mammary-synthesized IGF-I and IGFBPs probably play a critical role in prepubertal development of the bovine mammary gland.     

Dose-dependent effects of recombinant human insulin-like growth factor (IGF)-I/IGF binding protein-3 complex on overnight growth hormone secretion and insulin sensitivity in type 1 diabetes

GH hypersecretion in type 1 diabetes has been implicated in the pathogenesis of insulin resistance, and microangiopathic complications, and may result from reduced circulating IGF levels. We examined the effects of recombinant human (rh)IGF-I [complexed in equimolar ratio with rhIGF binding protein (BP)-3 (rhIGF-I/IGFBP-3)] replacement on overnight GH levels and insulin sensitivity in type 1 diabetes. Fifteen subjects, 13-24 yr old (10 male), were given rhIGF-I/IGFBP-3 or placebo as a daily sc injection for 2 d. After the second injection overnight, insulin requirements for euglycemia were determined (0400-0800 h), followed by a 4-h, two-step (insulin, 0.6 and 1.5 mU/kg.min) hyperinsulinemic euglycemic [90 mg/dl (5 mmol/liter)] clamp. In each subject, the protocol was repeated on three occasions in random order. Seven subjects received placebo and rhIGF-I/IGFBP-3 (0.1 mg/kg.d and 0.4 mg/kg.d), and eight subjects received placebo and rhIGF-I/IGFBP-3 (0.2 mg/kg.d and 0.8 mg/kg.d). We found dose-dependent increases in circulating IGF-I and IGFBP-3 concentrations after rhIGF-I/IGFBP-3. These were paralleled by significant reductions in mean overnight GH levels and GH pulse amplitude. We also observed dose-dependent effects of rhIGF-I/IGFBP-3 on overnight insulin requirements for euglycemia, with reductions of up to 41%. Insulin sensitivity, defined by M-values, was improved with rhIGF-I/IGFBP-3 (0.4 and 0.8 mg/kg.d). Thus, restoration of circulating IGF-I and IGFBP-3 levels with rhIGF-I/IGFBP-3 suppresses GH secretion in adolescents with type 1 diabetes, leading to reduced insulin requirements and improvements in insulin sensitivity.     

An acid-stable insulin-like growth factor (IGF)-binding protein from pig serum inhibits binding of IGF-I and IGF-II to vascular endothelial cells

The effects of a porcine insulin-like growth factor (IGF)-binding protein on binding of IGF-I and IGF-II to porcine aortic endothelial cells (PAEC) were determined. Binding of 125I-labelled IGF-I and -II to IGF receptors was inhibited by IGF-binding protein. IGF-binding protein inhibited binding of IGF-I and -II in a dose-dependent manner with half-maximal inhibition occurring at 5.43 and 108 micrograms/l respectively. A 125I-labelled IGF-I--IGF-binding protein complex, formed by incubating 125I-labelled IGF-I with IGF-binding protein overnight at 4 degrees C, did not effectively bind to endothelial IGF receptors. Addition of IGF-binding protein to PAEC previously incubated with IGF-I caused a marked dissociation of bound IGF-I (47% dissociation within 12h). These results indicate that the acid-stable IGF-binding protein which appears to be a part of the 150 kDa GH-dependent binding protein, blocks binding of IGF-I and -II by the IGF receptors and appears to exhibit a higher affinity for IGF-I than the endothelial type-I IGF receptor. The ramifications of this latter point with respect to transfer of circulating IGFs (bound to their IGF-binding proteins) across the vascular endothelium are not clear.