rhIGF-I Infusion Research Articles

Peripheral Infusion of Insulin-Like Growth Factor-I Increases the Number of Newborn Oligodendrocytes in the Cerebral Cortex of Adult Hypophysectomized Rats

We have previously shown that recombinant human (rh) IGF-I induces cell proliferation and neurogenesis in the hippocampus of hypophysectomized rats. In the current investigation, we determined the effects of rhIGF-I on proliferation and differentiation in the cerebral cortex. Adult hypophysectomized rats were injected with bromodeoxyuridine (BrdU) to label newborn cells (once a day for the first 5 d), and rhIGF-I was administered peripherally for 6 or 20 d. In the cerebral cortex, the number of BrdU-labeled cells increased after 20 d but not after 6 d of rhIGF-I infusion. This suggests that rhIGF-I enhances the survival of newborn cells in the cerebral cortex. Using BrdU labeling combined with the oligodendrocyte-specific markers myelin basic protein and 2',3'-cyclic nucleotide 3'-phosphodiesterase, we demonstrated an increase in oligodendrogenesis in the cerebral cortex. The total amount of myelin basic protein and 2',3'-cyclic nucleotide 3'-phosphodiesterase was also increased on Western blots of homogenates of the cerebral cortex, confirming the immunohistochemical findings. Also, we observed an increase in the number of capillary-associated BrdU-positive cells, although total capillary area was not increased. rhIGF-I treatment did not affect cortical astrogliogenesis and neurogenesis was not observed. The ability of rhIGF-I to induce cortical oligodendrogenesis may have implications for the regenerative potential of the cortex.

Anabolic effects of insulin and IGF-I in the ovine fetus are reduced by prolonged maternal fasting

Fetal nutritional stress may result in intrauterine growth restriction and postnatal insulin resistance. To determine whether insulin resistance can begin in utero, we subjected late-gestation (130-135 days) ewes to 120 h of complete fasting and compared the results with our previous work in fed ewes (38). We determined the effect of insulin and/or recombinant human (rh)IGF-I infusion on ovine fetal phenylalanine kinetics, protein synthesis, and phenylalanine accretion. Experimental infusates were 1) saline, 2) rhIGF-I plus a replacement dose of insulin (40 nmol IGF-I/h + 16 mIU insulin/h), 3) insulin (890 mIU/h), and 4) IGF-I plus insulin (40 nmol IGF-I/h + 890 mIU insulin/h). During hormone infusion, both glucose and amino acid concentrations were clamped at basal concentrations. Amino acid infusion was required during infusion of either hormone to maintain plasma concentrations constant. However, the amount required during insulin infusion was less than during IGF-I infusion and 40% less than the amount required during identical studies in nonfasted animals. Phenylalanine used for protein synthesis and accretion was increased compared with control animals but again less so than in the nonfasted animals. In contrast to nonfasted animals, neither hormone increased the fractional synthetic rate of skeletal muscle protein nor that of plasma albumin. These results indicate that a short but severe nutritional stress can significantly alter the fetal anabolic response to insulin even when both glucose and amino acid substrate supplies are restored. Therefore, adaptive responses characterized by insulin resistance begin in utero when the fetus is subjected to sufficient nutritional stress.

Regulation of the splenic somatotropic axis by dietary protein and insulin-like growth factor-I in the rat.

Protein intake is a critical regulatory factor of the GH/IGF-I axis. Recently, it has been shown that splenic GH/IGF-I may respond to nutritional stress by preserving tissue homeostasis. To study the effects of exogenous administration of rhIGF-I on the splenic GH/IGF-I axis in protein malnourished rats, six-week-old male rats were assigned to one of four isocaloric diets differing in the protein content (0%, 4%, 12% and 20%) for a period of 12 days. Animals in the same dietary group on day 5 were randomly divided into two groups and during 7 days received a continuous subcutaneous infusion of either vehicle or rhIGF-I (300 microg/day). A low protein intake decreased the circulating levels of IGF-I, IGFBP-3, GH and insulin whereas the serum levels of IGFBP-1 were increased. Splenic IGFBP-3, -4 and -6 mRNA expression were up-regulated by protein malnutrition. Similarly, IGF-IR and GHR mRNA expression were significantly increased by the lack of dietary protein, whereas the levels of IGF-I mRNA remained unchanged. Exogenous rhIGF-I administration increased the circulating levels of IGFBP-1 and -3 in protein malnourished rats and reduced significantly the GH and insulin levels in well-fed rats. Similarly, rhIGF-I increased significantly the expression of the GHR in the spleen and splenic weight in all dietary groups, whereas nitrogen balance was enhanced only in the high-protein diet group. Among the cell subpopulations, B lymphocytes showed the highest GHR expression. These results suggest that in catabolic stress, induced by protein malnutrition the splenic GH/IGF-I axis is an important modulator and contributes to the maintenance of the homeostasis of the immune system.

Insulin-like growth factor I prevents corticosteroid-induced diaphragm muscle atrophy in emphysematous hamsters.

The aim of this study was to evaluate whether recombinant human insulin-like growth factor I (rhIGF-I) could attenuate or prevent diaphragm (DIA) fiber atrophy with corticosteroid (CS) administration to emphysematous (EMP) hamsters. DIA muscle IGF-I responses to CS administration with and without exogenous rhIGF-I administration were evaluated. Three groups were studied: 1) EMP; 2) EMP + triamcinolone (T; 0.4 mg.kg-1.day-1 im); and 3) EMP + T + IGF-I (600 microg/day by constant infusion). After 4 wk, the DIA was analyzed histochemically and biochemically (IGF-I mRNA levels by RT-PCR and endogenous and exogenous IGF-I peptide levels immunochemically). Body weights of EMP-T progressively decreased, while those of EMP and EMP-T-IGF-I remained stable despite similarly reduced food intake in both T groups. DIA weight was reduced with T but preserved with rhIGF-I infusion. DIA fiber proportions were similar among the groups. The cross-sectional areas of types I, IIa, and IIx fibers were reduced (17 to 31%) with T administration but unchanged with rhIGF-I infusion. DIA IGF-I mRNA levels were similar across all groups. By contrast, the endogenous DIA IGF-I levels were reduced (41%) in the EMP-T-IGF-I animals. Total DIA IGF-I levels (endogenous + exogenous) were still significantly reduced. IGF-I immunoreactivity confirmed this reduction in all DIA fibers. We conclude that DIA fiber atrophy with T was completely prevented by exogenous rhIGF-I administration. This effect was likely mediated by the pharmacological influences of exogenously administered rhIGF-I. We speculate that this results from increased bioavailability of free IGF-I to react with muscle receptors. Reduced endogenous IGF-I levels in the DIA likely reflect a negative-feedback influence. These results may have important clinical implications for treatment options to offset the adverse effects of CS on the respiratory muscles in patients with chronic lung disorders.

Protein anabolic effects of insulin and IGF-I in the ovine fetus.

We determined the effect of insulin and/or recombinant human (rh)IGF-I infusion on ovine fetal phenylalanine kinetics, protein synthesis, and phenylalanine accretion. The chronically catheterized fetal lamb model was used at 130 days gestation. All studies were performed while fetal glucose and amino acid concentrations were held constant. Experimental infusates were 1). saline, 2). rhIGF-I plus a replacement dose of insulin (40 nmol), 3). insulin (890 mIU/h), and 4). IGF-I plus insulin (40 nmol IGF-I/h and 890 mIU insulin/h). Both hormones increased glucose and amino acid utilization, with insulin having a greater effect. The major effect on phenylalanine kinetics was a pronounced fall in phenylalanine hydroxylation, again with insulin having the greatest effect. Whole body protein breakdown was not significantly altered by either hormone; whole body protein synthesis was significantly increased during the combined infusion. Protein accretion was increased by both hormones, with the greatest increase during combined infusion. The fractional synthetic rate (FSR) of circulating albumin was increased by IGF-I but not by insulin. Both hormones significantly increased skeletal muscle FSR without a synergistic effect. The anabolic effects of insulin and IGF-I were more pronounced in these studies than in previous studies where amino acid concentrations were not maintained. The present data also suggest that insulin and IGF-I promote fetal growth through distinct, organ-specific mechanisms.

Growth Hormone Increases Connexin-43 Expression in the Cerebral Cortex and Hypothalamus

Several studies indicate that systemic GH influences various brain functions. Connexin-43 forms gap junctions that mediate intercellular communication and establish the astroglial syncytium. We investigated the effects of peripheral administration of bovine GH (bGH) and recombinant human insulin-like growth factor I (rhIGF-I) on the expression of connexin-43 in the rat brain. Hypophysectomized female Sprague Dawley rats were substituted with cortisol (400 μg/kg·day) and l-T4 (10 μg/kg·day) and treated with either bGH (1 mg/kg·day) or rhIGF-I (0.85 mg/kg·day) for 19 days. The abundance of connexin-43 messenger RNA (mRNA) and protein in the brainstem, cerebral cortex, hippocampus, and hypothalamus was quantified by means of ribonuclease protection assays and Western blots. Treatment with bGH increased the amounts of connexin-43 mRNA and protein in the cerebral cortex and hypothalamus. No changes were found in the brainstem or hippocampus. Infusion of rhIGF-I did not affect connexin-43 mRNA or protein levels in any of the brain regions studied. These results show that administration of bGH increases the abundance of cx43 in specific brain regions, suggesting that GH may influence gap junction formation and thereby intercellular communication in the brain.

Growth hormone increases connexin-43 expression in the cerebral cortex and hypothalamus.

Several studies indicate that systemic GH influences various brain functions. Connexin-43 forms gap junctions that mediate intercellular communication and establish the astroglial syncytium. We investigated the effects of peripheral administration of bovine GH (bGH) and recombinant human insulin-like growth factor I (rhIGF-I) on the expression of connexin-43 in the rat brain. Hypophysectomized female Sprague Dawley rats were substituted with cortisol (400 microg/kg x day) and L-T4 (10 microg/kg x day) and treated with either bGH (1 mg/kg x day) or rhIGF-I (0.85 mg/kg x day) for 19 days. The abundance of connexin-43 messenger RNA (mRNA) and protein in the brainstem, cerebral cortex, hippocampus, and hypothalamus was quantified by means of ribonuclease protection assays and Western blots. Treatment with bGH increased the amounts of connexin-43 mRNA and protein in the cerebral cortex and hypothalamus. No changes were found in the brainstem or hippocampus. Infusion of rhIGF-I did not affect connexin-43 mRNA or protein levels in any of the brain regions studied. These results show that administration of bGH increases the abundance of cx43 in specific brain regions, suggesting that GH may influence gap junction formation and thereby intercellular communication in the brain.

Glucose and amino acid kinetic response to graded infusion of rhIGF-I in the late gestation ovine fetus.

Insulin-like growth factor I (IGF-I) has anabolic effects and is thought to be important in fetal development. The present study was designed to determine the dose response of recombinant human (rh) IGF-I on ovine fetal glucose and amino acid kinetics. Chronically catheterized fetal lambs were studied at 122-127 days gestation. The kinetics of leucine, phenylalanine, and glucose were measured before and during the infusion of rhIGF-I. rhIGF-I was infused into the fetal inferior vena cava at low, medium, or high rates (9.9, 20.1, or 40.2 nmol/h, respectively). A stepwise increase in serum IGF-I was achieved (164 +/- 3, 222 +/- 7, and 275 +/- 5 ng/ml). Insulin concentrations were decreased at the medium and high rhIGF doses. The rate of appearance (Ra) of leucine and phenylalanine and leucine oxidation decreased. Phenylalanine appearance from protein breakdown was decreased, with a maximal suppression of 30% observed at the highest rate of infusion. Glucose Ra was increased at the medium and high doses; other aspects of glucose metabolism were unchanged. The change in both glucose Ra and suppression of proteolysis was significantly correlated to the rhIGF-I infusion rate. It is concluded that rhIGF-I exerts dose-related effects in the ovine fetus, increasing fetoplacental glucose turnover and causing significant suppression of both proteolysis and amino acid oxidation.

Parenteral amino acid intake alters the anabolic actions of insulin-like growth factor I in rats.

The anabolic properties of insulin-like growth factor (IGF) I are attenuated by oral diets that are low in protein. However, it is not known whether parenteral nutrition (PN) providing a low amino acid (AA) input will influence IGF-I action. With the use of a rat model, this study examined the interaction between AA input (1.27 and 0.62 g N. kg body wt(-1). 24 h(-1), AA and 1/2AA groups, respectively) and recombinant human IGF-I (rhIGF-I, 2.5 mg. kg body wt(-1). 24 h(-1)) infusion on the composition of the carcass and organs and on plasma insulin, IGF-I, IGF-binding protein 1 (IGFBP-1), and acid-labile subunit (ALS) concentrations. Carcass protein deposition only occurred in the AA groups (P < 0.003) and was not influenced by administration of rhIGF-I. However, visceral protein loss persisted in the AA group but was prevented by rhIGF-I infusion. The changes in water content of the carcass and the organs were generally in the expected proportion of normal lean tissue. The accumulation of lipid that follows the infusion of the AA-deficient PN was prevented by rhIGF-I infusion, which may indicate an improved energy utilization. Neither serum insulin nor ALS concentrations were influenced by the level of AA infusion but were reduced by rhIGF-I administration. However, plasma IGF-I levels were elevated by higher AA infusion and by IGF-I administration. Also, IGFBP-1 concentrations were reduced by the higher AA infusion and increased with rhIGF-I administration. Interestingly, there was a significant interaction effect between both of these influences. It is concluded that free IGF-I concentration, which may be regulated by IGFBP-1 through a direct effect of AAs on the liver, may have an important role in regulating anabolism in visceral and possibly skeletal tissue during PN.

Regulatory mechanisms of growth hormone secretion are sexually dimorphic.

Sexually dimorphic growth hormone (GH) secretory pattern is important in the determination of gender-specific patterns of growth and metabolism in rats. Whether GH secretion in humans is also sexually dimorphic and the neuroendocrine mechanisms governing this potential difference are not fully established. We have compared pulsatile GH secretion profiles in young men and women in the baseline state and during a continuous intravenous infusion of recombinant human insulin-like growth factor I (rhIGF-I). During the baseline study, men had large nocturnal GH pulses and relatively small pulses during the rest of the day. In contrast, women had more continuous GH secretion and more frequent GH pulses that were of more uniform size. The infusion of rhIGF-I (10 microg/kg/h) potently suppressed both spontaneous and growth hormone-releasing hormone (GHRH)-induced GH secretion in men. In women, however, rhIGF-I had less effect on pulsatile GH secretion and did not suppress the GH response to GHRH. These data demonstrate the existence of sexual dimorphism in the regulatory mechanisms involved in GH secretion in humans. The persistence of GH responses to GHRH in women suggests that negative feedback by IGF-I might be expressed, in part, through suppression of hypothalamic GHRH.

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.

Effects of GH and IGF-I administration on GHRH and somatostatin mRNA levels: I. A study on ad libitum fed and starved adult male rats.

The individual role played by GH and IGF-I in the regulation of hypothalamic GHRH and SRIF gene expression is still object of debate. We have investigated the effect of exogenously administered recombinant hGH (rhGH) and recombinant hIGF-I (rhIGF-I) in ad libitum fed control and starved rats, the latter an animal model which is characterized by low circulating levels of endogenous GH and IGF-I. Adult male rats were fed ad libitum (C) or food-deprived (S) for 72 hours; rats in either C or S groups were treated with systemic administration of rhGH and rhIGF-I for 3 days. GHRH, SRIF and GH mRNA levels were evaluated by Northern and slot blot hybridization. Administration of rhGH (250 micrograms/kg/twice daily, sc) induced a significant inhibition of GHRH and a significant stimulation of SRIF mRNA levels in C rats; GH treatment was, however, ineffective on both neuropeptide mRNA levels in the S group. Continuous infusion of rhIGF-I (300 micrograms/kg/day, sc) induced a significant increase of SRIF levels in both C and S rats but did not modify GHRH mRNA levels in either group. In the pituitary, GH mRNA levels followed a pattern very similar to that of GHRH. These results provide evidence for a direct role of GH in the inhibition of GHRH mRNA levels; IGF-I appears more involved in the direct stimulation of SRIF mRNA levels.

Effects of constant infusion with insulin-like growth factor-I (IGF-I) to immature female rats on body weight gain, tissue growth, and sexual function : Evidence that such treatment does not affect sexual maturation or fertility.

Plasma levels for insulin-like growth factor-I (IGF-I) steadily increase in female rats between 20 and 40 d of life, and this increase is intimately related to the wellknown growth spurt occurring at this age. Since specific actions of IGF-I related to sexual function have been described at the ovarian and hypothalamic levels, an endocrine role of rising circulating IGF-I levels during sexual maturation cannot be excluded. Therefore, the impact of adult-type plasma IGF-I levels during the juvenile age, on body weight (BW) gain, growth of several organs, sexual development, and fertility has been evaluated. Female Sprague-Dawley rats were infused with rhIGF-I (2 and 4 μg/g BW/d, using Alzet minipumps), between 20 and 41 d of life. When infusing 2 μg/g BW/d, plasma levels for IGF-I were increased 1.5- to 2-fold over controls at all ages studied. They were further increased with the higher dosage, but only after 35 d of age. Plasma levels for insulin-like growth factor binding protein (IGFBP)-1 to-3 were clearly increased. BW gain was significantly increased, but only with the higher dosage. Tail length was never modified. In contrast, a growth acceleration for spleen, kidneys, adrenals, and ovaries was observed with both dosages. The ovarian weight of treated animals represented approx 140% of control animals with the 4 μg/g BW/d dosage. Histology of the enlarged ovaries did not reveal any abnormalities. No meaningful modification of the timing of vaginal opening was observed, and fertility was not compromised by previous rhIGF-I infusion during the 20-41 d age period. In summary, early exposure to increased (adult-like) plasma IGF-I levels did not modify BW gain or tail length, but affected the development of spleen, kidneys, adrenals, and ovaries. Exposure to supraphysiological plasma IGF-I levels (>1200 ng/mL), accelerated BW gain and increased the weight of all organs studied. No signs of precocious sexual maturation were seen and fertility was normal. In conclusion, prematurely increased plasma IGF-I levels affected somatotropic parameters, but not the onset of sexual function.

Effects of circulating IGF-I on glucose and amino acid kinetics in the ovine fetus.

To investigate the role of insulin-like growth factor I (IGF-I) in the regulation of fetal metabolism, the kinetics of leucine, phenylalanine, and glucose were assessed in the chronically catheterized ovine fetus (0.85 gestation) before and during infusion of recombinant human IGF-I (rhIGF-I). Substrate kinetics were determined by tracer dilution. rhIGF-I was infused at 6.7 nmol.kg fetus-1.h-1. Fetal insulin and growth hormone concentrations were significantly decreased by 50% during rhIGF-I infusion. Net umbilical glucose uptake was unchanged, and glucose rate of appearance increased in the fed state only. There were no changes in the net umbilical uptakes of leucine or phenylalanine, but the rates of appearance of both declined during rhIGF-I infusion, indicative of decreased fetal protein breakdown (Ra,Leu 45.4 +/- 1.40 to 40 +/- 1.4 mumol/min in the fed state, 43 +/- 1.5 to 37 +/- 1.5 mumol/min in the fasted state; Ra,Phe 10.7 +/- 0.3 to 10.4 +/- 0.3 mumol/min in the fed state and from 10.7 +/- 0.3 to 9.8 +/- 0.3 mumol/min in the fasted state). Leucine oxidation was also decreased (8.90 +/- 0.76 to 6.52 +/- 0.81 mumol/min, P = 0.025), more so in the fasted than the fed state. These results indicate a significant antiproteolytic endocrine effect for IGF-I in the late-gestation mammalian fetus.

Acute Effects of Insulin-like Growth Factor I on Interorgan Glucose and Lactate Flux in Protein-Catabolic Dogs

Insulin-like growth factor-I (IGF-I) is a potent protein-anabolic hormone with a glucose-lowering effect and is therefore a possible agent for treating catabolic patients. In this study we investigated the effect of recombinant human (rh) IGF-I on the interorgan flux of glucose under hypo- and normoglycemic conditions in catabolic, anaesthetized, and catheterized dogs. We administered a primed (40 μg/kg) continuous (1.5 μg · kg-1 · min-1) infusion of rhIGF-I (Kabi Biopharma, Stockholm, Sweden) for 180 min together with either a saline (0.9% NaCl) or an amino acid solution (2.2 mg AA · kg-1 · min-1 solution of Vamin, Kabi Nutrition, Stockholm, Sweden). RhIGF-I administration lowered plasma glucose levels for approximately 50% of the baseline (P < 0.001) and stimulated glucose uptake from skeletal muscle about twofold (P < 0.01), but did not modify glucose balances across the gut and liver. The same effects were found when infusing rhIGF-I together with AA. A co-infusion of rhIGF-I and glucose to maintain normoglycemic conditions stimulated glucose uptake from skeletal muscle by about fivefold (P < 0.001) and glucose uptake across the gut by about 50%, but reduced the hepatic glucose liberation (-65%; P < 0.01). The rhIGF-I infusion did not alter arterial lactate levels, but stimulated lactate release from skeletal muscle (P < 0.05) and lactate uptake across the liver (P < 0.05). We conclude that rhIGF-I reduces plasma glucose levels mainly by stimulating glucose uptake across skeletal muscle. Because muscular glucose uptake was higher than lactate release, rhIGF-I possibly stimulated glycogen synthesis or ATP formation in skeletal muscle and therefore may have positive effects on the peripheral energy deficit in catabolic state.

IGF feedback effects on growth hormone secretion in ewes: evidence for action at the pituitary but not the hypothalamic level

The putative negative feedback effects of IGF-I and IGF-II on GH secretion were tested by intracerebroventricular (icv) and intrapituitary administration to sheep. Over two consecutive days, serial jugular blood samples were taken at 10 min intervals for 6 h from ewes (n = 3/group) fitted with indwelling stainless steel cannulae into the lateral or third cerebral ventricles. The sheep were injected (icv) with either vehicle or purified ovine IGF-I (2, 4 or 8 micrograms). IGF-I injection had no effect on plasma GH secretion. Serial blood samples were taken from a second group of nine ewes in which ovine or recombinant human (rh) IGF-I was infused (2.5 micrograms/h for 2 h) into the third ventricle; once again, IGF-I failed to affect the episodic pattern of GH secretion. Three ewes fitted with indwelling stainless steel cannulae placed in the anterior pituitary gland were consecutively infused with either ovine or rhIGF-I (2.5 micrograms/h for 2 h) or vehicle. Plasma GH concentrations were suppressed in 3/3 sheep from 1-1.5 h after the commencement of infusion and GH levels remained low for the remainder of the sampling period. In another group of five ewes synergistic effects of IGF-I and IGF-II on GH secretion were tested by icv infusion of rhIGF-I, rhIGF-II, or rhIGF-I+rhIGF-II (5 micrograms/h for 2 h) or vehicle (sterile 10 mM HCl/saline). Each sheep received each treatment in a randomised design. Infusion (icv) of IGF-I and IGF-II alone or in combination failed to alter GH secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin-like growth factor I exerts growth hormone- and insulin-like actions on human muscle protein metabolism.

The effect of a 6-h intra-arterial infusion of recombinant human (rh) insulin-like growth factor I (IGF-I) on forearm muscle metabolism was studied in 19 postabsorptive subjects. Forearm glucose, lactate, and phenylalanine (Phe) balances, as well as estimates of protein degradation (Phe Ra) and synthesis (Phe Rd) were measured before and at 3 and 6 h into an infusion of rhIGF-I at a dose of 1.8 (n = 6), 6.0 (n = 8), or 10.0 (n = 5) micrograms.kg-1.h-1. In response to intra-arterial IGF-I, deep venous IGF-I rose by 55, 141, and 315%, respectively (all P < 0.01), and forearm blood flow accelerated by 75 (1.8 microgram), 213 (6.0 micrograms), and 159% (10.0 micrograms; all P < 0.02). No change in forearm glucose uptake was observed at the lowest dose, whereas four- to sixfold increases were observed at both the 6 and 10 micrograms.kg-1.h-1 doses (both P < 0.02). Forearm Phe balance shifted positively at all three doses by 27 +/- 6, 48 +/- 7, and 51 +/- 9 nmol.min-1 x 100 ml-1, respectively (all P < 0.01). At all three doses, Phe Rd increased comparably by 49-74% (all P < 0.05). At the 6.0 and 10.0 but not the 1.8 microgram.kg-1.h-1 dose, Phe Ra decreased by approximately 45% (P < 0.02). Forearm muscle metabolism was also studied in the contralateral non-IGF-infused arm at these three doses. Despite increases in deep venous IGF-I up to 517 ng/ml due to recirculating IGF-I (10.0 micrograms.kg-1.h-1 dose), contralateral forearm muscle glucose, lactate, or Phe handling did not change. In conclusion, intra-arterial IGF-I exhibits growth hormone-like effects at all doses tested, whereas the insulin-like effects are observed at higher doses; these effects appear dependent on the route of administration.

Negative feedback regulation of pulsatile growth hormone secretion by insulin-like growth factor I. Involvement of hypothalamic somatostatin.

To investigate the mechanisms of the negative feedback inhibition of growth hormone (GH) secretion by IGF-I, we studied parameters of GH pulsatility in six normal, fed men before and during a 48-h infusion of recombinant human IGF-I (rhIGF-I) (10-15 micrograms/kg per h). Plasma levels of IGF-I increased from the baseline value of 163.5 +/- 9.3 micrograms/liter (mean +/- SE) to a new steady state of 452.0 +/- 20.9 micrograms/liter during the infusion. Plasma GH concentrations were measured every 10 min for 24 h during both saline and rhIGF-I infusions using a sensitive chemiluminescent assay. Overall, GH concentrations were suppressed during the rhIGF-I infusion by 85 +/- 3%, mainly by attenuating spontaneous GH pulse amplitude (77 +/- 4% suppression). The apparent GH pulse frequency was attenuated from 7.8 +/- 0.9 to 4.7 +/- 0.6 pulses/24 h (P = 0.006). Administration of rhIGF suppressed GH responses to exogenous GH-releasing hormone by 82 +/- 3%, and thyroid-stimulating hormone responses to thyrotropin-releasing hormone were also suppressed by 44 +/- 9%. This constellation of hormonal effects is most compatible with the rhIGF-I-induced stimulation of hypothalamic somatostatin secretion.

Acute effects of insulin-like growth factor I on inter-organ amino acid flux in protein-catabolic dogs

The effects of acute administration of human recombinant insulin-like growth factor-I (rhIGF-I) on amino acid (AA) flux between hindlimbs, liver and gut were investigated in anaesthetized post-operative dogs. rhIGF-I produced about a 10-fold increase in plasma IGF-I concentrations above baseline values (P < 0.001), increased the plasma levels of glucagon and adrenaline (P < 0.05), and evoked a fall in plasma glucose (-55 +/- 8%; (P < 0.001) and plasma total AA levels (-23 +/- 8%; P < 0.05). AA flux in post-absorptive dogs under NaCl infusions was characterized by an efflux of AA from the hindlimbs (as a result of the protein-catabolic situation), an equal AA balance across the gut and an AA uptake by the liver. The administration of rhIGF-I increased hepatic AA uptake in the NaCl group from 3.51 +/- 0.8 to 7.5 +/- 0.4 mumol/min per kg (P < 0.01) and in the AA-infused group from 16.8 +/- 0.6 to 22.4 +/- 1.5 mumol/min per kg (P < 0.05), but did not influence the AA balance across hindlimbs and gut. Glucose infusions normalized the plasma concentrations of counter-regulatory hormones without influencing the inter-organ AA balances. We conclude that hypoaminoacidaemia caused by rhIGF-I infusions is the result of a stimulated AA uptake by the liver, but is unrelated to alterations of AA exchange across the hindlimbs.

Effects of recombinant human IGF-I on glucose and leucine kinetics in men.

To examine the effects of recombinant human (rh) insulin-like growth factor I (IGF-I), insulin, and saline on metabolic parameters, we studied 20 young nonobese healthy men. Euglycemic clamps with 240-min IGF-I infusions at two doses (49 and 33 pmol.kg-1 x min-1, n = 8 and 12 subjects) were performed and compared with hyperinsulinemic-euglycemic clamps (2.25 pmol.kg-1 x min-1, n = 9). Leucine and glucose kinetics were examined with L-[1-13C]leucine and [3-3H]glucose. Glucose rate of appearance (Ra) declined equivalently in the 49 pmol.kg-1.min-1 IGF-I and insulin clamps but remained at basal levels during the 33 pmol.kg-1 x min-1 IGF-I infusions. In contrast, Rd of glucose was increased by 176% in the 49 pmol.kg-1 x min-1 IGF-I and 78% in the 33 pmol.kg-1 x min-1 IGF-I infusions. Furthermore, to prevent hypoglycemia after the termination of both rhIGF-I infusions, it was necessary to infuse glucose for an additional 2-20 h. Ra of leucine was suppressed significantly by both IGF-I and insulin, whereas leucine oxidation was not affected by either hormone. Therefore, the rate of disappearance of leucine expressed as the difference between Ra and oxidation rates was significantly reduced in all clamps. In addition, IGF-I significantly suppressed beta-cell secretion without affecting the other glucoregulatory hormones. In contrast to insulin, IGF-I had no apparent effect on lipolysis, as measured by changes in nonesterified fatty acids.(ABSTRACT TRUNCATED AT 250 WORDS)