Total IGF-I Concentrations Research Articles

Growth factors of premature infants in relation to parenteral nutrition during the first month of life

The changes in the circulating levels of growth factors were followed during the first month of life in order to determine any effects of parenteral nutrition on insulin-like growth factors in preterm infants. Thirty-five preterm infants were assigned into two groups. Group one (n = 21, gestational age (GA) 32.1 ± 1.8 wks, birth weight (BW) 1676 ± 112 g) was receiving total parenteral nutrition (TPN) for the first 2–11 days and the other group (n = 14, GA 31.7 ± 1.9 wks, BW 1700 ± 96 g) was milk fed from the 2nd day of life. Serum total and free IGF-I and IGFBP-3 concentrations were determined and auxologic measurements were carried out. One month after birth total and free IGF-I and IGFBP-3 circulating levels had increased similarly in both study groups. However on day 15 the TPN group neonates while they were on lower calorie and protein intakes demonstrated smaller changes in the total IGF-I and IGFBP-3 peptides (IGF-I: 36.3 ± 3.9 vs 58.6 ± 10.6 ng/mL in the milk fed group, p < 0.05; IGFBP-3: 0.50 ± 0.04 vs 0.60 ± 0.07 μg/mL, p < 0.05). Their body weight gain was also lower for the same period (1681 ± 112 vs 1805 ± 92 g in the milk fed group). No significant differences could be seen in the free IGF-I levels and the free to total IGF-I ratio. However the weight gain was better correlated with free IGF-I and the intake of calories and protein in the TPN group (r = 0.7, p < 0.001, r = 0.5, p < 0.01 and r = 0.5, p < 0.001 respectively) than in the milk fed group (r = 0.6, p < 0.05, r = 0.2 and r = 0.1, NS). Whether increasing the energy intake with TPN will enhance the growth peptides and weight gain which would be of great clinical importance, needs to be verified.

The insulin-like growth factor-I system and hormone replacement therapy

Objective: To determine the effects of hormone replacement therapy on plasma concentrations of free and total insulin-like growth factor (IGF)-I, IGF binding protein (BP)-1, and IGFBP-3. Design: Clinical study. Setting: Gynecologic clinic at a university hospital. Patient(s): Seventy-one postmenopausal women. Intervention(s): Six cycles of four different hormonal replacement therapy regimens: oral conjugated estrogens, transdermal estradiol, oral conjugated estrogens and norethisterone, and transdermal estradiol and norethisterone acetate. Main Outcome Measure(s): Blood samples were collected before and after treatment for measurement of free and total IGF-I, IGFBP-1, and IGFBP-3. Result(s): Conjugated estrogen replacement therapy is associated with a decrease in plasma concentration of total IGF-I and increase in concentrations of free IGF-I and IGFBP-1. Transdermal estrogens have no effect on total and free IGF-I and IGFBP-1 concentrations. Oral norethisterone plus conjugated estrogens increased free IGF-I and IGFBP-1 concentrations but did not change IGF-I concentrations. Transdermal conjugated estrogens plus norethisterone acetate increased free IGF-I concentrations but not total IGF-I or IGFBP-1 concentrations. The plasma concentration of IGFBP-3 did not change in any group. Conclusion(s): Alterations in total IGF-I concentration can occur depending on the route of hormone replacement therapy administration. Free IGF-I concentrations were elevated in all study groups except that treated with transdermal estrogens.

Regulation of insulin-like growth factor-binding protein-3 ternary complex in feline diabetes mellitus.

The 140 kDa ternary complex of insulin-like growth factor-binding protein-3 (IGFBP-3), IGFs and an acid-labile subunit (ALS) has previously been shown to be decreased in diabetes mellitus in humans and rats. We have studied IGF-I levels and ternary complex formation in normal and diabetic cats. Total IGF-I concentrations, measured by RIA using des(1-3)-IGF-I as tracer were (+/-s.e.m.) 54+/-13 nmol/l in eight normal and 227+/-57 nmol/l in eight diabetic cats (P<0.01). The size-distribution of IGFBPs in the cat circulation was determined by incubation with (125)I-IGF-II and Superose 12 chromatography. In normal animals 26+/-2% of the (125)I-IGF-II were in a 140 kDa form compared with 48+/-5% in diabetic cats (P<0.01). When samples from normal and diabetic animals were co-incubated 52+/-3% were at 140 kDa. A similar shift was seen when normal cat and normal human serum were co-incubated. A 2-fold increase in the 140 kDa form in diabetic cats was confirmed first by size-fractionating samples and then performing a ligand-binding assay with (125)I-IGF-I or -II and charcoal separation. SDS-PAGE and Western ligand blotting demonstrated a 45 kDa doublet (presumably IGFBP-3) and 30-35 kDa forms. There were no apparent differences between normal and diabetic profiles on SDS-PAGE, suggesting that a proportion of IGFBP-3 which circulates 'free' in normal cats forms a ternary complex in the diabetic circulation. We conclude that (i) in contrast to humans and rats, ALS is the limiting factor for ternary complex formation in normal cats, (ii) ALS concentrations increase in feline diabetes mellitus and, by promoting ternary complex formation, this leads to an increase in total IGF-I concentrations, and (iii) total IGF-I concentrations may not be reliable in the diagnosis of acromegaly in diabetic cats.

Serum concentrations of insulin, insulin-like growth factor-I and insulin-like growth factor binding proteins are different between white and African American girls

Objectives: To determine whether serum insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP) concentrations are different between African American and white girls. Study design: Serum glucose and hormone concentrations were measured in blood samples collected after a 12-hour fast from 79 white and 57 African American healthy girls between 9 and 17 years of age. Tanner stages of pubic hair development were evaluated by physical examination, and body composition by dual energy x-ray absorptiometry. Results: The African American girls were older and sexually more mature and had higher fat mass, higher serum insulin and free IGF-I concentrations, higher serum free IGF-I to total IGF-I ratio, but lower serum IGFBP-1 concentrations than the white girls. After controlling for sexual maturation and fat mass, the serum concentrations of total IGF-I, bound IGF-I, and IGFBP-3 in the white girls became significantly higher than those in the African American girls. The higher concentrations of total IGF-I in the white girls were due to a proportional increase in the concentrations of bound IGF-I that coincided with a similar increase in serum IGFBP-3 concentrations. Conclusions: Higher serum insulin concentrations in the African American girls are associated with lower serum IGFBP-1 concentrations and increased bioavailability of free IGF-I, which may contribute to their accelerated growth compared with their white counterparts. (J Pediatr 1999;135:296-300)

Evaluation of free insulin-like growth factor-I measurement on the diagnosis and follow-up treatment of growth hormone-deficient adult patients.

Insulin-like growth factor (IGF-I) and IGF binding protein-3 (IGFBP-3) are GH-dependent and their concentrations have been used in the diagnosis of GH deficiency. Recently, the free fraction of IGF-I has received more attention. The aim of the study was to assess the role of free IGF-I in the diagnosis of GH deficiency in adults, and in follow-up during treatment with recombinant human GH (rhGH). We studied 24 adult patients with pituitary disease and GH deficiency and 25 matched controls. Nine patients were re-evaluated after 6 months of treatment with rhGH (0.25 U/kg/week). Serum levels of IGF-I, free IGF-I, IGFBP-3 and IGFBP-1 were measured by immunoradiometric assay. Serum free IGF-I levels were significantly lower in the GH deficient group than in the normal group (mean: 0.84 and 1.32 micrograms/l respectively, P = 0.0009). Furthermore, serum IGF-I levels were also lower (mean: 92.24 and 230.47 micrograms/l respectively, P < 0.0001). 63% of patients had serum IGF-I concentration below the normal range. For free IGF-I, 52% of the GH deficient patients showed levels below the lowest value obtained for the normal group. Seventy-five percent of the patients showed at least one of the two determinations below the normal range. The free-total IGF-I ratio was significantly higher (P = 0.025) in GH deficient group (range: 0.19-21.29, mean: 2.53) than in normal controls (range: 0.2-2.15, mean: 0.6). Regarding IGFBP-3 and IGFBP-1 no differences were observed between the two groups. During rhGH treatment the increase in serum total and free IGF-I and IGFBP-3 paralleled the beneficial effects on body composition. Free IGF-I may be another useful method for the diagnosis of GH deficiency, particularly if related to total IGF-I concentration.

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.

Endurance training and its effect upon the activity of the GH-IGFs system in the elderly.

There is an age-associated decline in the activity of the GH-IGFs system. However, so far, it has not been studied, whether this decline in somatotrophic activity might be preventable by intensive exercising. We studied 11 elderly male (50-78 years) marathon runners and 10 age-matched male (52-73 years) sedentary controls to evaluate plasma concentrations of GH, total and free IGF-I and IGF-II and of IGF-binding protein-1 (IGFBP-1), IGFBP-2, IGFBP-3 and insulin. When comparing the two groups (runners vs controls) no differences were found in GH (1.0 +/- 1.2 vs 1.3 +/- 1.3 microg/l [mean +/- SD]), IGF-1 (115 +/- 23 vs 113 +/- 21 microg/l), IGF-II (961 +/- 192 vs 864 +/- 125 microg/l), free IGF-1 (227 +/- 80 vs 318 +/- 146 ng/l), free IGF-II (563 +/- 249 vs 492 +/- 108 ng/l), IGFBP-3 (2403 +/- 515 vs 2307 +/- 326 microg/l) or insulin (26 +/- 13 vs 27 +/- 18 mU/l). However, IGFBP-1 (4.44 +/- 2.61 vs 2.28 +/- 0.93 microg/l) and IGFBP-2 (493 +/- 143 vs 340 +/- 186 microg/l) were found to be significantly increased in marathon runners. In conclusion, our findings do not support the hypothesis that the age-associated decline in GH, IGF-1 and IGFBP-3 may be preventable by intensive endurance training. However, marathon running affects the regulation of the GH-IGFs system activity at the level of IGFBP-1 and -BP-2.

The metabolic syndrome and insulin-like growth factor I regulation in adolescent obesity.

Although low GH levels are commonly seen in obese adults and children, the effects of obesity on the insulin-like growth factor (IGF)/IGF-binding protein (IGFBP) system have not been established. As GH and IGF-I normally increase during adolescence, we investigated the effects of obesity on circulating total and free IGF-I levels and IGFBP-1, -2, and -3 in 19 obese adolescents [14 +/- 1 yr old; body mass index (BMI), 34 +/- 3], 20 lean adolescents (14 +/- 1 yr old; BMI, 23 +/- 0.5), and 10 lean adults (22 +/- 0.7 yr; BMI, 22 +/- 0.7). Fasting plasma insulin levels were significantly greater in obese adolescents than in either lean group, whereas circulating IGFBP-1 levels were suppressed in an inverse relationship to basal insulin (r = -0.49; P < 0.01). Low IGFBP-1 levels were associated with normal to increased free IGF-I levels in obese adolescents, even though total IGF-I values were lower than those in lean adolescents. Basal GH and IGFBP-3 levels were also lower in obese vs. lean adolescents. Basal IGFBP-1 levels were markedly reduced in obese adolescents (14 +/- 3 ng/mL) vs. those in adolescents and adults. No further suppression of IGFBP-1 levels was observed in the obese group during a two-step 8 and 40 mU/m2 insulin clamp. In contrast, IGFBP-1 levels were promptly lowered in lean adults. Basal IGFBP-2 levels were significantly lower in both groups of adolescents vs. lean adults (P < 0.05), and IGFBP-2 levels did not change during euglycemic hyperinsulinemia. These data suggest that the compensatory hyperinsulinemia that characterizes adolescent obesity chronically suppresses levels of IGFBP-1, and low IGFBP-1 concentrations may serve to increase the bioavailability of free IGF-I, which may, in turn, contribute to lower circulating GH, total IGF-I, and IGFBP-3 concentrations.

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.

Acute alterations in growth hormone-insulin-like growth factor axis in humans injected with endotoxin.

The purpose of the present study was to characterize the acute changes in the insulin-like growth factor (IGF) system in humans after administration of endotoxin (lipopolysaccharide; LPS). Escherichia coli LPS (4 ng/kg) was injected intravenously into healthy adults, and serial blood samples were collected for the next 5 h; subjects injected with saline served as time-matched controls. LPS administration resulted in a gradual decrease in the total extractable IGF-I concentration, which was reduced by approximately 20% over the final 2 h of the experiment; levels of free IGF-I were not significantly altered. LPS also produced a marked but transient elevation in growth hormone (GH) concentration. IGF-binding protein (BP)-1 levels were elevated more than fivefold 2 h after LPS injection, and thereafter levels gradually returned toward baseline. IGFBP-2 concentration also increased after LPS injection, but the maximal increase (approximately 50% above basal) was observed during the final 2 h of the protocol. In contrast, IGFBP-3 levels did not vary over the period examined in response to LPS, and there was no apparent increase in number of BP-3 proteolytic fragments. Cortisol levels were increased early and remained two- to threefold above baseline throughout the protocol. No significant alterations in serum concentration of glucose or insulin were noted. LPS also produced an early elevation in tumor necrosis factor and a later increase in interleukin-6. These data indicate that the acute changes in the GH-IGF axis in humans in response to LPS are comparable with those observed in humans in other traumatic conditions and in animal models of endotoxemia and infection.

Insulin treatment normalizes reduced free insulin-like growth factor-I concentrations in diabetic children.

We have recently demonstrated multiple aberrations in the GH-IGF axis in the sera of children with untreated insulin-dependent diabetes mellitus (IDDM) which were restored after insulin replacement. However, the net result of these alterations in the IGF system on the concentrations of free/biologically available IGF-I in the serum have not been examined directly in diabetic children. In the present study, the effect of diabetes and subsequent insulin replacement on the circulating free IGF-I concentrations are assessed. Fasting venous serum samples were obtained longitudinally, before and at various times after the initiation of insulin treatment in untreated diabetic subjects. Ten prepubertal, aged (mean +/- SEM) 6.3 +/- 1.0 years, and six adolescent, aged 12.7 +/- 1.1 years, subjects with newly diagnosed and untreated IDDM, and age and pubertal status-matched control children and adolescents were recruited. The serum samples were collected before initiating insulin treatment and 12-24 h, 1 week, and 1 month thereafter in subjects with IDDM. Insulin doses ranged from 0.5 to 1.2 U/kg/day. Free IGF-I concentration was assayed by a recently developed two-site immunoradiometric assay. Total IGF-I was measured by radioimmunoassay after acid-ethanol extraction of binding proteins. Differences in free and total IGF-I concentrations in IDDM subjects before and during insulin treatment were analysed by repeated measures analysis of variance followed by pairwise multiple comparisons test. In seven subjects with IDDM, where serum IGFBP-1 and IGFBP-3 concentrations, and IGFBP-3 protease activity had also been measured in a previous study, the relationship between these variables and circulating free IGF-I concentrations were examined by linear regression analysis. Free IGF-I concentrations in prepubertal subjects with IDDM were 0.9 +/- 0.2, 1.5 +/- 0.3, 1.6 +/- 0.3 and 2.5 +/- 0.4 micrograms/l before, 1 day, 1 week and 1 month after insulin treatment, respectively. Free IGF-I concentrations of control prepubertal children were 2.6 +/- 0.5 micrograms/l. Pubertal subjects had higher free IGF-I concentrations than prepubertal subjects but demonstrated a similar type of pattern; before insulin 2.3 +/- 1.1, 1 day 3.8 +/- 1.3, 1 week 3.7 +/- 0.6, 1 month 6.5 +/- 1.5 vs pubertal controls 7.7 +/- 2.0 micrograms/l. Total IGF-I concentrations were also reduced in untreated diabetic subjects and showed a slower pattern of normalization than free IGF-I concentrations. Free IGF-I concentrations correlated positively with total IGF-I and negatively with IGFBP-1 concentrations. There was no significant correlation between free IGF-I and either serum IGFBP-3 concentrations or IGFBP-3 protease activity. Alterations in the IGF system during untreated IDDM lead to a reduction in circulating free IGF-I concentrations which is restored progressively during insulin treatment. An increase in free IGF-I precedes that of total IGF-I suggesting that the former is a more sensitive indicator of the metabolic status. An inverse correlation between free IGF-I and IGFBP-1 supports the hypothesis that IGFBP-1 plays an important role in the acute modulation of free IGF-I levels.

Endocrine and metabolic responses to realimentation in feed-restricted prepubertal gilts: associations among gonadotropins, metabolic hormones, glucose, and uteroovarian development.

Temporal relationships among plasma LH, FSH, metabolic hormones, and glucose concentrations were studied in nutritionally manipulated prepubertal gilts. Twenty-four growth-matched littermate gilts (73.6 +/- 1.2 kg) were fed at maintenance for 7 d (d 1 to 7). From d 8 to 14, littermates were divided between two treatments and were either fed twice daily to appetite or continued on feed restriction. Feeding to appetite increased episodic LH secretion during the first 6 h of sampling on d 8 (P < .05). Plasma FSH concentrations were not affected by treatment between d 8 and 14. Nocturnal increases in plasma LH (P < .01) and FSH (P < .002) concentrations were detected in feed-restricted gilts but not realimented gilts. Mean total plasma IGF-I concentrations gradually increased in gilts fed to appetite (d 12, P < .02; d 13 to 14, P < .001). Mean postprandial insulin concentrations were also greater in gilts fed to appetite (P < .01). Treatment differences in mean postprandial glucose concentrations on d 9 and 10 indicate that normoglycemia was established by d 9 in gilts fed to appetite. At slaughter on d 15, numbers of ovarian follicles (P < .01), follicular volume (P < .001), and uterine weight (P < .05) were greater in gilts fed to appetite. In conclusion, uteroovarian responses to realimentation after short-term feed restriction in prepubertal gilts are mediated by enhanced LH secretion. This rapid enhancement of LH secretion in response to dietary repletion might have been mediated by changes in glucose and insulin status. Ovarian responses to gonadotropins may also be potentiated by observed increases in plasma glucose, insulin, and IGF-I. During feed restriction, a distinct diurnal rhythm in gonadotropin secretion was evident.

Hypophysectomy or Adrenalectomy of Rats with Insulin-Dependent Diabetes Mellitus Partially Restores Their Responsiveness to Growth Hormone

The studies reported herein were conducted to confirm that the pituitary gland is involved in maintaining growth hormone (GH) resistance in rats with insulin-dependent diabetes mellitus (IDDM) and to determine whether the adrenocorticotropic hormone (ACTH)-adrenal cortical axis is responsible. The rats were made diabetic by injecting streptozotocin (85 mg/kg body wt) IP once daily on two consecutive days. They were then injected with 15 IU insulin SC twice daily on two consecutive days to enable them to survive hypophysectomy or adrenalectomy. Intact nondiabetic (NonDb), diabetic (Db), hypophysectomized diabetic (HxDb), and adrenalectomized diabetic (AxDb) rats were injected twice daily with 50 micrograms porcine (p) GH or with 0.9% saline for 2 weeks following the surgeries. Serum glucose levels of the saline-injected Db, HxDb, and AxDb rats were significantly greater than those of the NonDb rats by 106%, 65% and 49%, respectively. However, the levels in the HxDb and AxDb animals were significantly lower than those of the Db group by 20% and 28%, respectively. Injections of pGH into NonDb rats increased serum glucose concentrations by 38%, over their saline-treated controls, and by 29% in AxDb rats. This diabetogenic effect of GH was not seen in any other group. Administration of pGH to Db rats failed to increase body weight gain, tall growth, tibial epiphysial plate width, or serum IGF-I concentration over saline-injected controls. By contrast, HxDb and AxDb rats injected with pGH showed significant increases in all four growth parameters. Total serum IGF-I concentrations in AxDb rats injected with pGH equaled those in NonDb controls. To determine whether the lack of corticosterone (B) in the AxDb rats was responsible for the reduced hyperglycemia and restored responsiveness to pGH, AxDb rats were given B in their drinking water at 5 or 25 micrograms/ml. Administration of B reduced the beneficial effects of adrenalectomy by restoring hyperglycemia and growth impairment, and partially restored resistance to the pGH injections. These studies confirm that the pituitary contributes to diabetic growth impairment and show that the ACTH-adrenal cortical axis is primarily responsible for the GH-resistant state that develops in rats with IDDM.

THE EFFECTS OF rhIGF-1 ON GH,IEF-BP3 BND IGF-BP1 CONCENTRHTIONS BND INSULIN SENSITIVITY IN ADOLESCENTS UITH INSULIN DEPENDENT DIABETES MELLITUS (IDDW)

Insulin resistance and poor growth during adolescene in IDDM have been linked with reduced IGF bioactivity and elevated GH levels. In a double blind placebo controlled study we have examined the effects of a single sc injection of rhIGF-1 (40ug/kg) on total IGF-I, IGF-BP1, IGF-BP3 and GH concentrations in 9 adolescents with IDDM (aged 14-18y, Tanner Stage 4 or 5, HbA1 range 7.1-17X). RhIGF-I or placebo were given at 18.00h, blood glucose was clasped around 5mmol/L between 02.00-008.00h to assess insulin sensitivity, and sampling was continued for a total of 22 h. Peak IGF-I levels were achieved at 5.5h and declined with a T/2 of 17.3h. Mean levels were 350±26 ng/ml after rhIGF-I vs 204±21 ng/nl on control night (p<.001). Both IGF-BP1 and IGF-BP3 tended to be higher after rhIGF-I.IGF bioactivity was increased by 56X. Overall mean GH concentrations were reduced after rhIGF-I (16.9±3.2 vs 27.7±4.6 mU/l, p<0.001) and there was no evidence of rebound GH secretion over 22h. During the stable clamp period, insulin requirements following rhIGF-I were reduced (0.25±0.12 vs 0.31±0,07 mU/kg/min, p<0.03) as were levels of free insulin (31.9 ± 2.7 vs 67.9 ± .16 mU/L, p<0.001). BOHbutyrate and acetoacetate tended to be lower during rhIGF-I administration whereas lactate levels were unchanged. RhIGF-I adninistration in adolescents with IDDM results in a significant result of increased free IGF-I or reduced GH concentrations.

Effects of recombinant human insulin-like growth factor-I (rhIGF-I) on total and free IGF-I concentrations, IGF-binding proteins, and glycemic response in humans.

To examine the effects of repeated administration of recombinant human insulin-like growth factor-I (rhIGF-I) on IGF-I levels, free IGF-I pharmacokinetics, glycemic response, and IGF-binding proteins (IGFBP), we administered rhIGF-I (0.03 mg/kg iv bolus) to 12 healthy males each morning for 5 consecutive days. Serum was collected over 24 h on days 1 and 5 for measurement of total and free IGF-I, glucose, insulin, and IGFBP. Total IGF-I was measured by RIA after acid/ethanol extraction. Free IGF-I was separated from binding protein-complexed IGF-I using size exclusion high performance liquid chromatography before measurement by RIA. IGFBP were quantitated by optical densitometry of Western ligand blots. Total IGF-I increased significantly from 0-24 h after administration on day 1 (mean +/- SD, micrograms/L: 120 +/- 44 to 166 +/- 51, P = 0.0002) but did not increase significantly from 24 h on day 1 to 0 h on day 5 (166 +/- 51 to 178 +/- 62) or from 0-24 h on day 5 (178 +/- 62 to 209 +/- 89). The area under the total IGF-I concentration curve was greater on day 5 than day 1 (311 +/- 99 min.g/L vs. 249 +/- 77, P = 0.0001). There were no significant differences in free IGF-I concentration or pharmacokinetic parameters or in the degree or timing of hypoglycemia between days 1 and 5. Plasma insulin levels decreased significantly following rhIGF-I administration (day 1 baseline: 53 +/- 11 pmol/L, nadir: 18 +/- 6 pmol/L at 30 min, P = 0.003); day 5 baseline: 47 +/- 15 pmol/L, nadir: 16 +/- 8 pmol/L at 30 min, P = 0.0003. Western ligand blotting revealed the transient appearance of a 30-kilodalton band which migrates in a manner similar to IGFBP-1. This band was undetectable at baseline, peaked between 150 and 210 min after rhIGF-I administration, and diminished by 480-600 min. The response was similar on days 1 and 5. There were no substantial changes in the serum levels of any other IGFBP. In summary, repeated iv bolus administration of rhIGF-I increased the level of total circulating IGF-I without changing free IGF-I disposition or glycemic response. A 30-kilodalton IGFBP band, most likely IGFBP-1, appeared transiently following rhIGF-I administration, probably as a result of suppression of insulin levels. IGFBP-2, -3, and -4 were unaffected.

Effects of recombinant human insulin-like growth factor-I (rhIGF-I) on total and free IGF-I concentrations, IGF-binding proteins, and glycemic response in humans

Effects of recombinant human insulin-like growth factor-I (rhIGF-I) on total and free IGF-I concentrations, IGF-binding proteins, and glycemic response in humans

Increase in milk secretion and mammary blood flow by intra-arterial infusion of insulin-like growth factor-I into the mammary gland of the goat

The close-arterial infusion of free insulin-like growth factor-I (IGF-I; 1.1 nmol/min) for 6 h into the pudic artery supplying one mammary gland of lactating goats caused a 25 +/- 6% (mean +/- S.E.M., n = 6) increase in the rate of milk secretion of that gland. The increase in the rate of milk secretion in the adjacent noninfused gland (14 +/- 4%) was not significantly different from that observed during saline infusion (4 +/- 5%). Blood flow to the infused gland was increased from 378 +/- 26 ml/min 1 h before to 487 +/- 56 ml/min approximately 5 h after the start of the infusion of IGF-I, declining to 420 +/- 44 ml/min approximately 2 h after the end of the infusion. The total concentration of IGF-I (free and bound) in milk of the infused gland was significantly higher than that of the non-infused gland. The concentrations of IGF-I in carotid arterial plasma samples increased during IGF-I infusion from a mean value of 32 +/- 2 nmol/l before to a maximum of 49 +/- 3 nmol/l 5 h after the infusion commenced. Circulating concentrations of total IGF-I declined slowly after the infusion with an estimated half-life of 5 h. Infusion of saline alone did not alter mammary blood flow or the concentration of total IGF-I in milk or plasma. The results indicate that the infusion of free IGF-I into the mammary arterial supply enhances milk secretion and mammary blood flow in intact, conscious goats.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of GH status on IGF-I and IGF-II concentrations and serum IGF binding profiles in pigs.

The present study was conducted to determine 1) whether porcine growth hormone (pGH) affected insulin-like growth factor (IGF)-II concentrations in growing pigs and 2) the distribution of [125I]IGF-I and [125I]IGF-II binding activity and immunoreactive IGF-I and IGF-II in serum from control, pGH-treated and hypophysectomized (hypox) pigs. Seven weeks of pGH treatment had no effect on serum IGF-II concentrations, but after 11 wk serum IGF-II had increased by up to 50%. In normal pig serum, [125I]IGF-I bound to specific insulin-like growth factor binding proteins (IGF-BP) of 40 kDa (87.5%) and 150 kDa (12.5%). Treatment with pGH increased the proportion of IGF-I bound to the large IGF-BP (approximately 48%). In contrast, [125I]IGF-II partitioned to specific IGF-BP of 450 kDa (30%), 150 kDa (46%) and 40 kDa (23%). After treatment with pGH, binding of IGF-II to the 150-kDa IGF-BP increased to 57% of total specific binding. Binding of IGF-I and IGF-II to the 150-kDa IGF-BP was virtually abolished in hypox pig serum. IGF-I immunoreactivity was predominantly associated with the 150-kDa IGF-BP (67 to 83%), with the remainder bound to the small IGF-BP. There was no detectable free IGF-I in pig serum. Treatment with pGH did not affect the distribution of immunoreactive IGF-I between the two IGF-BP complexes, although there was a marked elevation in total serum IGF-I concentration. Immunoreactive IGF-II was detected in all three IGF-BP complexes. In control serum, the largest quantity (46%) of immunoreactive IGF-II was associated with the 40-kDa IGF-BP. Thirty-four percent was bound to the 150-kDa IGF-BP complex. Administration of pGH led to an increased association with the 150-kDa complex (50%) and a concomitant decrease in IGF-II associated with the 40-kDa species (35%). In summary, IGF-II concentrations in the pig are elevated by prolonged pGH treatment. Furthermore, there is a unique large IGF-BP in postnatal pig serum that specifically binds IGF-II but not IGF-I.

Insulin-like growth factor I binding proteins in dairy cows, calves and bulls

Our objective was to measure relative amounts and distributions of serum IGF-I binding proteins and concentrations of hormones and metabolites in dairy cows during the dry period and during lactation, as well as in calves and in growing bulls. Concentrations of IGF-I were lower in cows during lactation than during the dry period. Concentrations of IGF-I, growth hormone, insulin, T3, T1 and glucose were higher in calves and bulls as compared with cows, whereas concentrations of non-esterified fatty acids, urea, protein and albumin were lower. Three different IGF-I binding protein fractions were found with apparent molecular weights of greater than 200, 140-160 and 45-65 kD. Relative amounts of IGF-I binding proteins were similar, although great differences in hormones and metabolites were found in cows, bulls and calves. accessible binding sites were higher in dairy cows than in calves and bulls, mainly owing to the fact that dairy cows had lower concentrations of IGF-I bound to these fractions. additionally, we found significant negative correlations between total accessible binding sites and total IGF-I concentrations. There were significant differences in the distribution of binding proteins. In particular, there was a shift of binding ability from the 140-160 to the 45-65 kD binding sites from the end of pregnancy to early lactation. Amounts of IGF-I bound to proteins increased from lactating to dry cows and calves and were highest in bulls. IGF-I levels in the greater than 200 kD fraction were lower in lactating than in dry cows, and lower in cows than in calves and bulls. IGF-I measured in the 140-160 kD fraction was lowest in lactating cows and comparable in dry cows, calves and bulls. Concentrations of IGF-I in the 45-65 kD fraction were lowest in cows and highest in bulls. In conclusion, there were marked differences in growing, pregnant and lactating cattle, particularly as concerns accessible protein binding and amounts of IGF-I bound to proteins.

Effects of human growth hormone administration on serum somatomedins, somatomedin carrier proteins, and growth rates in children with growth hormone deficiency.

We have determined the growth rates and serum somatomedin (Sm) and Sm carrier protein (CP) levels in 30 children with GH deficiency and short stature before and up to 3 yr of GH therapy. Initially, the mean (±SEM) bone age (BA) of this group (6.9 ± 0.5 yr) was significantly (P<0.001) less than the chronological age (CA; 10.4 ± 0.7 yr), and their growth rate (3.45 ± 0.33 cm/yr) was markedly less than those of normal control groups matched either for CA (5.45 ± 0.22 cm/yr) or BA (6.46 ± 0.33 cm/yr). Compared to serum levels in a group of 40 age-matched controls, we found diminished concentrations of total Sm insulin-like growth factor (IGF) activity (0.31 ± 0.03 vs. 1.61 ± 0.12 μg/ml), IGF-I (0.09 ± 0.02 vs. 0.44 ± 0.04/ig/ml), and CP (123 ± 18.8 vs. 366 ± 28.2 μg/ml). Both total IGF and IGF-I were inversely related to the degree of growth retardation, expressed as the ratio of BA to CA. Serum Sm increased in 19 of 21 subjects after short term (up to 18 h) GH administration (0.1 U/kg), but the magnitude of ...