Effects of growth hormone and pregnancy on expression of growth hormone receptor, insulin-like growth factor-I, and insulin-like growth factor binding protein-2 and -3 genes in bovine uterus, ovary, and oviduct

The effects of growth hormone (GH) and pregnancy on insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-2, and IGFBP-3 mRNA in reproductive tissues were studied in cattle. Lactating dairy cows were inseminated at estrus and treated with 25 mg/day GH (n = 8) or saline (n = 8) for 16 days. Corpus luteum (CL), ovary (CL removed), oviduct, endometrium, and myometrium were collected at the end of treatment. Messenger RNA for GH receptor, IGF-I, IGFBP-2, IGFBP-3, and actin were measured by nuclease protection assays. The CL contained more GH receptor mRNA than the other reproductive tissues examined. Expression of IGF-I mRNA was highest in myometrium, with lower amounts found in endometrium; the CL expressed the least amount of IGF-I mRNA. The IGFBP-2 mRNA was most abundant in endometrium and least abundant in CL. Expression of IGFBP-3 mRNA was detected in all reproductive tissues examined. However, endometrium, a tissue that expressed the most IGFBP-2 mRNA, had the lowest amount of IGFBP-3 mRNA. The GH receptor mRNA was decreased in cows treated with GH whereas the mRNA for IGF-I, IGFBP-2, or IGFBP-3 was not changed. In the reproductive tissues evaluated, cows that contained a conceptus at tissue collection (pregnant) had higher amounts of IGF-I mRNA than did nonpregnant cows. In summary, the level of mRNA encoding GH receptor, IGF-I, IGFBP-2, and IGFBP-3 varied within the tissues examined, suggesting that these genes may play a variety of roles in the bovine female reproductive tract. Supplemental GH failed to change the expression of IGF-I, IGFBP-2, and IGFBP-3 mRNA, possibly because of low GH receptor mRNA levels in tissues other than CL. A direct action of GH on IGF-I, IGFBP-2, or IGFBP-3 gene expression within cow reproductive tissues was not supported because the amount of IGF-I, IGFBP-2, or IGFBP-3 mRNA was not altered by GH.     

Elemental iron does repress transferrin, haemopexin and haemoglobin receptor expression in Haemophilus influenzae

The present study was undertaken to determine the effect of GH administration on GH and IGF-I receptors in skeletal muscle compared with liver in growing pigs. Plasma IGF-I and GH-binding protein (GHBP) levels were also determined. Twelve Large White pigs (castrated males) were treated daily with 100 micrograms pituitary porcine GH (pGH) per kg body weight or vehicle for 41 days intramuscularly. Relative to controls, pGH administration increased plasma IGF-I concentrations by 3.3-fold. Administration of pGH had no effect on plasma GHBP levels. In liver, 125I-labelled bovine GH (bGH)-specific binding (P < 0.05) and GH receptor (GHR) mRNA levels (P < 0.05) were higher in pGH-treated than in control pigs. In longissimus dorsi (LD), 125I-labelled bGH specific binding did not differ significantly between the two groups while GHR mRNA levels (P < 0.05) were lower in pGH-treated than in control pigs. Administration of pGH had no effect on 125I-labelled bGH-specific binding and GHR mRNA levels in trapezius (TR). 125I-Labelled IGF-I-specific binding in liver was unaffected by pGH administration. Similarly, in liver, LD and TR, IGF-I receptor mRNA levels were not different between pGH-treated and control animals. It can be concluded that (1) GH binding and IGF-I receptor mRNA are not affected by GH in skeletal muscle, (2) GH influences GHR in a tissue-specific manner and (3) hepatic GHR and GHBP levels are not co-regulated.     

Ontogeny of insulin-like growth factors (IGF), IGF binding proteins, IGF receptors, and growth hormone receptor mRNA levels in porcine pancreas

We examined the ontogeny of mRNA levels of IGF-I and -II, IGF type 1 (IGFI-R) and type II receptors (IGFII-R), IGF binding protein-1 and -3 (IGFBP-1 and -3), GH receptor (GHR), and tissue concentrations of IGF and IGFBP in the pancreas of pigs. Tissues were collected from fetuses at 90 and 110 d of gestation and from pigs at 1, 21, 90 and 180 d of age. Northern blots were performed using total RNA hybridized with 32P-labeled cDNA probes (human IGF-I and human IGFI-R) and cRNA probes (rat IGF-II, human IGFII-R, human IGFBP-1, pig IGFBP-3, and pig GHR). There were two accelerated growth stages of the pancreas: the first one at 90 d of fetal life, which is characterized by cell hyperplasia (high ratio of DNA to body weight), and the second one at postnatal 90 d, which is attributed to cell hypertrophy (high ratios of pancreatic weight, RNA, and protein to DNA). The level of IGF-II mRNA and its tissue concentration were predominant during fetal life and low thereafter. The IGF-I mRNA level was high during fetal and early postnatal life and decreased thereafter. Messenger RNA levels of IGFI-R, IGFBP-3, and GHR and concentrations of IGFBP-1 and -2 were abundant during fetal and early postnatal life. In conclusion, IGF may be involved in various physiological periods of pancreatic development in pigs.     

Stimulation of intestinal growth is associated with increased insulin-like growth factor-binding protein 5 mRNA in the jejunal mucosa of insulin-like growth factor-I-treated parenterally fed rats

Surgically stressed rats maintained with total parenteral nutrition (TPN) exhibit jejunal atrophy, which can be attenuated by insulin-like growth factor-I (IGF-I) but not by growth hormone (GH) treatment. In order to understand the basis for the selective action of IGF-I, the levels of mRNAs encoding IGF-I, IGF-binding proteins (IGFBPs), IGF-I receptor, and GH receptor/binding protein (GHR/GHBP) were determined in rats given TPN and treated with GH, IGF-I, or GH + IGF-I. GH treatment significantly stimulated hepatic IGF-I mRNA. IGF-I treatment did not alter liver IGF-I mRNA, nor was there any evidence for interaction between GH and IGF-I. Jejunal mucosa IGF-I mRNA was extremely low and was not altered by TPN or by any of the hormonal treatments. The inability of GH to stimulate jejunal growth was not associated with a deficiency in GHR/GHBP mRNA. In jejunal mucosa, IGF-I and GH treatment independently and synergistically stimulated IGFBP-3 mRNA. IGF-I stimulated jejunal IGFBP-5 mRNA, but GH had no effect on IGFBP-5 mRNA. The levels of IGF-I receptor and IGFBP-1, 2, 4, and 6 mRNAs were extremely low and/or were not altered by any of the treatments. These results suggest that the ability of exogenous IGF-I, but not GH, to induce IGFBP-5 mRNA in jejunal mucosa may lead to the selective growth-promoting effect of IGF-I. Jejunal mucosa IGFBP-3 mRNA levels were not correlated with altered growth. We postulate that IGFBP-5 positively modulates the anabolic effects induced by exogenous IGF-I in the jejunum.     

Insulin-like growth factor binding proteins-2 and -3 stimulate growth hormone receptor binding and mitogenesis in rat osteosarcoma cells

GH exerts its biological actions on osteoblasts through a specific high affinity receptor expressed on these cells. GH receptor binding is positively modulated by a number of factors, including retinoic acid and dexamethasone, whereas fetal calf serum strongly decreases the binding. To identify responsible factors in serum, components of serum, the insulin-like growth factors (IGFs)-I and -II, and IGF binding proteins (IGFBPs)-2 and -3 were tested for a possible negative modulatory role. IGF-I and -II decreased [125I]hGH binding at an optimal concentration of 30 ng/ml for IGF-I and 100 ng/ml IGF-II, reducing the binding to 51% and 55%, respectively, of control values. A stimulation of [125I]hGH binding was observed with IGFBP-2 as well as IGFBP-3, inducing an increase to 148% and 151% of control binding at an optimal concentration of 3000 ng/ml for both peptides. The effects of all peptides were dependent on the incubation time, being significantly increased after 8 h of incubation and reaching the full effect thereafter. The effects were declined at 24 h compared with 16 h for IGFBP-2 and -3 but not for IGF-I and -II. Coincubation of the cells with IGF-I and -II and IGFBP-2 and -3 neutralized the effects of the factors alone. In conclusion, these results show that IGF-I and -II on the one hand and IGFBP-2 and -3 on the other hand exert opposite actions on [125I]hGH binding, IGFBP-2 and -3 exerting probably an IGF-independent effect. Further, IGF-I and -II decreased GH receptor messenger RNA (mRNA) levels, as quantified by a solution hybridization ribonuclease protection assay, from 8.65 +/- 1.78 attomoles (amol)/microgram DNA (control) to 2.4 +/- 0.68 and 2.16 +/- 0.92 amol/microgram DNA, respectively. IGFBP-2 increased GH receptor mRNA levels from 5.26 +/- 1.17 (control) to 13.19 +/- 3.48. Incubation with IGFBP-3 did not result in stimulation of GH receptor mRNA levels (8.59 +/- 2.91 amol/microgram DNA). This shows that the mechanism of regulation of the GH receptor is, except for IGFBP-3, at least in part on the mRNA level. Lastly, IGFBP-2 and IGFBP-3 are mitogenic for UMR-106.01 rat osteosarcoma cells, inducing an increase in cell number to 125% and 142% of control cell counts after 48 h of incubation with 1000 ng/ml IGFBP-2 and -3, whereas IGF-I, IGF-II and Long R3 IGF-I did not stimulate proliferation. IGFBP-2 and -3 potentiate hGH induced mitogenesis at low hGH concentrations of both factors, whereas at higher concentrations no such effect is observed.(ABSTRACT TRUNCATED AT 400 WORDS)     

Growth advantage of human leiomyoma cells compared to normal smooth-muscle cells due to enhanced sensitivity toward insulin-like growth factor I

Human uterine leiomyomas exhibit increased IGF-I binding compared to myometrium, while both tissues show IGF-I gene expression. In this study we have examined the functional importance of these findings by testing the presence of IGF-I in 15 leiomyoma biopsies and in 18 myometrium biopsies and the capacity of smooth-muscle cells cultured from these tissues to react to IGF-I. The mean IGF-I peptide concentration in leiomyomas was 3 times higher than in myometrium. This resulted from increased IGF-I uptake in leiomyomas rather than from increased synthesis, as these tissues contain higher concentrations of type-I IGF receptors, as detected by immunohistochemistry, and equal levels of IGF-I mRNA. Blocking IGF-I transport with cytochalasin-B and with the type-I IGF receptor blocking antibody alpha IR3 in cultured cells induced decreased immunostaining intensity for IGF-I in most myometrium and leiomyoma cultures, indicating that the detected IGF-I is internalized. Depending on the culture conditions, IGF-I administration yielded increased survival or a higher proliferation rate in leiomyoma cultures than in myometrium cultures, indicating the increased importance of exogenous IGF-I for the growth of transformed smooth-muscle cells. We conclude that the increased concentrations of type-I IGF receptors in leiomyoma compared to myometrial smooth-muscle cells are functional with respect to the enhanced internalization of IGF-I and that they provide these tumor cells with a growth advantage compared to their normal counterparts.     

Binding of insulin-like growth factors (IGF-I and IGF-II) to the IGF-II/mannose 6-phosphate receptor in fetal rat myocardium

Previous studies indicate that fetal rat heart tissue contains large amounts of insulin-like growth factor (IGF)-II/mannose 6-phosphate (Man 6-P) receptor messenger RNA, with receptor messenger RNA levels falling by 20 days after birth. We examined the amount of IGF receptor protein in developing rat myocardium. To establish a model in which the role of neural, hormonal, and hemodynamic controls of IGF receptor binding could be studied, we compared binding of IGF-I and IGF-II in normally growing rat atria and ventricles with embryonic day 12 (E-12) atria and ventricles maturing in the anterior eye chamber of an adult host rat. In oculo, embryonic myocardium matures without hemodynamic load or exposure to the fetal hormonal milieu. In fetal rat hearts (E-12 to E-19), both IGF-I and IGF-II intensely bound to a protein with a molecular weight corresponding to the IGF-II/Man 6-P receptor. Receptors were identified using sodium dodecyl sulfate/polyacrylamide gel electrophoresis autoradiography and western blot analysis using Ab3637, a specific polyclonal antibody against rat IGF-II/Man 6-P receptor antigens. This antibody competed for binding of both IGF-I and IGF-II to the band with molecular radius corresponding to 260,000 (reduced). In normally growing rat atria, IGF-I binding to the IGF-II/Man 6-P receptor was similar to ventricular tissue; however, there was significantly greater binding of IGF-II than of IGF-I in both atrial and ventricular tissue. High levels of IGF-II binding to the IGF-II/Man 6-P receptor were observed in both fetal rat atrial and ventricular grafts until 6-8 weeks in oculo. As in normally growing heart tissue, there was similar IGF-I binding to the IGF-II/Man 6-P receptor in atrial grafts compared with ventricular grafts from 2-8 weeks after implantation. For the first 2 weeks after grafting, the ventricular grafts had relatively higher IGF-I binding to the IGF-II/Man 6-P receptor compared with later time points examined. The present data indicate that atrial and ventricular binding of IGFs to the IGF-II/Man 6-P receptor decreases with age, suggesting that decreased IGF binding may be independent of postnatal hemodynamic changes. The decrease is similar in in oculo embryonic rat cardiac grafts and normally growing heart tissue.(ABSTRACT TRUNCATED AT 400 WORDS)     

Tissue-specific effects of chronic dietary protein restriction and gastrostomy on the insulin-like growth factor-I pathway in the liver and colon of adult rats

Dietary protein restriction decreases plasma concentrations of insulin-like growth factor-I (IGF-I) and reduces IGF-I mRNA levels in the liver. In addition to the actions of systemic IGF-I, locally produced IGF-I is thought to mediate autocrine and paracrine growth effects in the colon. The objectives of the present study were to investigate the IGF-I pathway in the colon and liver of adult rats under conditions of dietary protein restriction, surgical stress, and dietary protein repletion. Two groups of rats were placed on either a 20% or 2% casein diet for 19 days. Two additional groups of rats underwent gastrostomy after a 2% casein diet for 2 weeks, and then were either kept on the 2% casein diet or changed to a 20% casein diet until day 19. Dietary protein restriction reduced plasma concentrations of IGF-I and IGF-binding proteins (IGFBPs) and hepatic IGF-I mRNA content, while increasing colonic IGF-I receptor mRNA. Gastrostomy in protein-depleted animals had no effect on hepatic IGF-I mRNA, but led to a marked increase in colonic IGF-I mRNA levels. Dietary protein repletion resulted in a decrease in colonic IGF-I receptor mRNA. The distinct effects of dietary protein depletion and operative stress on the IGF pathway in the colon as compared with the liver may serve to maintain the level of IGF-I signaling in the colon by autocrine or paracrine mechanisms under these conditions.     

Insulin-like growth factor-I expression in normal and diseased endometrium

While the role of steroid hormones in the regulation of endometrial proliferation and differentiation is well established, the effects of growth factors and their receptors in normal and neoplastic endometrium remain a matter of debate. Previous studies have documented the positive effects of insulin-like growth factor-I (IGF-I) on epithelial cell proliferation and the active production of this growth factor in endometrial tissues. In view of decreased expression of transforming growth factor-beta1 (TGF-beta1), an antagonist of IGF-I, in endometrial carcinoma, we investigated the expression of IGF-I, at both the mRNA and protein levels, and the immunoreactivity for type I IGF-I receptor in 30 formalin-fixed, paraffin-embedded tissue samples of normal and neoplastic endometrium, in order to possibly clarify the role of IGF-I in endometrial proliferation and differentiation. Our results demonstrate a reduced expression of IGF-I mRNA in endometrial carcinomas compared with non-neoplastic tissues, despite equivalent immunohistochemical expression of IGF-I and IGF-I receptor. Our data suggest that IGF-I and its corresponding receptor may not be directly involved in endometrial cancer cell proliferation and differentiation in vivo, though other components of the IGF-I system (e.g., IGF binding proteins) may affect endometrial malignant transformation and tumor progression.     

Role of the insulin-like growth factors and their binding proteins in lactation

Insulin-like growth factor (IGF)-I is thought to mediate a portion of the effects of bST on lactation in dairy cows. Serum concentrations of IGF-I are increased in lactating cows that were treated with bST, and IGF-I receptors are present in bovine mammary tissue. In addition, close arterial infusion of IGF-I into the mammary gland of goats increases milk yield. Little evidence exists to support a direct galactopoietic effect of IGF-I in ruminants. However, IGF-I is a potent mitogen for mammary epithelial cells and may also influence the inhibition of apoptosis of this cell type. The IGF are found in association with a family of individual binding proteins. The high affinity of the IGF for these proteins relative to the IGF receptor allows them to modulate IGF-I bioactivity in the mammary gland at the cellular level. Mammary epithelial cells synthesize multiple forms of IGF binding proteins, and one of these, IGF binding protein-3, is specifically regulated by the IGF. Stimulation of DNA synthesis by IGF-I is enhanced in bovine mammary epithelial cells that overexpress the IGF binding protein-3. These data indicate that IGF-I can stimulate the synthesis of an IGF binding protein, which enhances its own mitogenic activity. However, whether this mechanism is operative in the lactating mammary gland in vivo is unknown. Given the complexity of the interactions between the IGF and their binding proteins, more information is needed before the role of these growth factors in regulating growth, differentiation, and apoptosis of mammary epithelial cells is delineated.     

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

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

Bioethics in the medical subspecialty literature

The high affinity growth hormone-binding protein (GHBP) circulates in human blood and represents the extracellular domain of the growth hormone (GH) receptor. It is well known that repetitive bouts of endurance type exercise result in increased integrated GH secretion. As the effects of chronic exercise on plasma GHBP levels have never been studied systematically, we investigated the effect of 2 weeks of intense endurance training on plasma GHBP as well as on plasma insulin-like growth factor (IGF)-I levels in 10 healthy, young, non-obese men. IGF-I was measured as an indicator of the effects of GH release. We also studied 10 control subjects matched for sex, age and activity, who were instructed not to change their customary activities. GHBP was determined by FPLC size exclusion chromatography and subsequent Scatchard plot analysis of the binding data; IGF-I levels were measured by RIA. The results showed that plasma IGF-I and GHBP levels were increased in the subjects who followed the training program. IGF-I and GHBP changed from 252 +/- 56 ng/ml and 912 +/- 59 pmol/l before training, to 344 +/- 61 ng/ml (p < 0.01) and 1020 +/- 48 pmol/l (p < 0.01), respectively. Another effect of the training was that the aerobic capacity of these subjects was better utilized and endurance was improved. In contrast, plasma IGF-I, GHBP, utilization of aerobic capacity and endurance did not change significantly in the control subjects. We conclude that two weeks of strenuous endurance training lead to increased plasma IGF-I and high affinity GHBP levels.     

Immune responses to intestinal parasites: protection, pathology and prophylaxis

It has been suggested that adjunctive growth hormone (GH) therapy improves ovarian response and in vitro fertilization (IVF) outcome in specific groups of patients. The correlation between insulin-like growth factor (IGF) and GH is well established. The aim of this study was to determine whether changes in plasma GH correlate with IGF blood levels in patients during IVF treatment. Thirty-six women undergoing IVF and embryo transfer (ET) were examined. Ovarian stimulation was carried out by gonadotropin-releasing hormone agonists (GnRHa) and gonadotropins. Blood was drawn at the early and late follicular phase, on the day of human chorionic gonadotropin (hCG) injection and at the mid- and the late luteal phases. The samples were assayed for IGF-I, IGF-II, IGF-binding protein-3 (IGF BP-3), GH and estradiol. According to the IGF-I and GH plasma levels, patients were divided into three major groups: Group I consisted of patients in whom peak levels of GH reached more than 4 ng/ml and IGF-I decreased significantly. In this group, estradiol levels were 1863 +/- 149 pg/ml. Group II consisted of patients in whom peak blood GH levels did not exceed 2.5 ng/ml and the IGF-I level remained unchanged. In this group estradiol levels were 630 +/- 57 pg/ml. Group III consisted of patients in whom blood GH levels were low and remained unchanged while estradiol levels were 1600 +/- 420 pg/ml. In this group no significant increase in IGF-levels were observed. There was no significant change in the levels of either IGF-II or IGF BP-3 in any of the groups. We can conclude that (1) there is a negative correlation between GH and IGF-I plasma levels in patients undergoing controlled ovarian hyperstimulation (COH)-IVF, when levels of estradiol and GH are elevated; (2) plasma levels of IGF-I under ovarian hyperstimulation are probably regulated by a multifactorial system; and (3) no correlation was found between the plasma levels of IGF-I and those of IGF-II and IGF BP-3 in all patient groups.     

Effects of short- and long-term dexamethasone treatment on growth and growth hormone (GH)-releasing hormone (GRH)-GH-insulin-like growth factor-I axis in conscious rats

Although the inhibitory effects of a chronic excess of glucocorticoids (GC) on body growth and GH secretion are well established, the mechanisms involved remain unclear. In this study, we examined the chronic effects of a high dose of dexamethasone (DEX) on spontaneous GH secretion and insulin-like growth factor (IGF)-I in conscious rats. The animals were given daily i.p. injections of DEX (200 microg/day) for either one or four weeks. Body growth assessed by tibia length and serum IGF-I levels was significantly inhibited 1 week after treatment. By contrast, spontaneous GH secretion was not altered 1 week after the treatment. Neither hypothalamic GRH and somtatostain mRNA levels nor GH responses to GRH from single somatotropes were affected 1 week after the treatment. Four weeks after DEX treatment, body growth of the rats was noticeably suppressed. Interestingly, spontaneous GH secretion, hypothalamic GRH mRNA levels and GH responses to GRH were all inhibited 4 weeks after treatment. Pituitary GRH receptor mRNA levels were not altered 1 week after treatment, but increased after 4 weeks. These results indicate that a high dose of DEX initially impairs IGF-I production and subsequently inhibits spontaneous GH secretion in rats. Inhibition of spontaneous GH secretion resulting from chronic GC excess is due, at least in part, to the impairment of hypothalamic GRH synthesis and pituitary GH responsiveness. An increase in the pituitary GRH receptor may be caused by decreased GRH secretion.     

Feeding colostrum increases circulating insulin-like growth factor I in newborn pigs independent of endogenous growth hormone secretion

Our objective was to examine the influence of feeding and endogenous GH secretion on circulating IGF-I in colostrum-deprived newborn pigs fed colostrum (n = 4), formula (control, n = 4), or water (n = 4). In another four formula-fed pigs, GH was ablated (GRF-A) with two intravenous injections of a GH releasing-factor antagonist (N-Ac-Tyr1,D-Arg2)-GRF(1-29)-NH2. Blood was serially sampled in all pigs to measure plasma IGF-I and GH profiles. Feeding increased plasma IGF-I concentration two- to fourfold and decreased GH secretion. Despite a more than 80% decrease in the plasma GH in GRF-A pigs, the circulating IGF-I concentration was similar to that in control pigs. In colostrum-fed pigs, plasma IGF-I was higher than that in control pigs, despite equal nutrient intake and lower circulating GH. There were no differences in plasma IGF binding protein (IGFBP)-3 levels among the treatment groups. However, the relative abundance of plasma IGFBP-4 was lower, and that of IGFBP-1 higher, in unfed pigs than in any of the three fed groups. The plasma insulin concentration was not different among fed pigs, but it was lower in unfed pigs. Our results indicate that the circulating IGF-I concentration is more dependent on nutrient intake than on GH in newborn pigs, despite relatively high GH concentrations. However, because the nutrient content in the formula was designed to match that of colostrum, a factor other than nutrient intake and GH was responsible for the maximal increase in circulating IGF-I concentration observed in colostrum-fed pigs.     

Histamine-stimulated expression of insulin-like growth factors in human glioma cells

Glioma tumour growth is associated with the expression of insulin-like growth factors I and II (IGFs) and of both type I and type II IGF receptors. It has also been shown that IGFs can stimulate proliferation of cultured glioma cells. We previously reported that histamine too can stimulate the growth of glioma cells in vitro. In this report, we study whether the histamine-induced growth of G47 glioma cells is mediated by the IGFs. We found that histamine stimulates the expression of both IGF-I and IGF-II mRNAs, as determined by a semiquantitative in situ hybridization analysis. Furthermore, incubation of G47 cells with histamine also induced cellular immunostaining for IGF-II. It could be shown that IGF-I-stimulated proliferation is inhibited by IGFBP-3, which decreases the availability of IGFs for binding to the IGF receptors, and by beta-galactosidase, which may decrease IGF binding to the type II IGF receptor, but is not inhibited by the anti-type I IGF receptor monoclonal antibody alphaIR3. However, neither IGFBP-3 nor beta-galactosidase nor alphaIR3 inhibited the histamine-induced proliferation. These results show that the growth-stimulatory effect of histamine is accompanied by the induction of IGFs. This histamine-induced growth stimulation is not mediated by activation of cell surface IGF receptors, although intracrine activation of type II IGF receptors may be involved.     

Long [R3] insulin-like growth factor-I reduces growth, plasma growth hormone, IGF binding protein-3 and endogenous IGF-I concentrations in pigs

Growth hormone (GH) improves growth performance in the pig. Analogues of insulin-like growth factor-I (IGF-I) that bind poorly to IGF binding proteins (IGFBP) stimulate growth in the rat but, in contrast, inhibit growth in the pig. This study was designed to determine the effect of IGF peptides alone or in combination with porcine GH (pGH) on growth characteristics and plasma hormone concentrations in finisher pigs. A four-day infusion of Long [R3] IGF-I (LR3IGF-I; 180 micrograms/kg/day) decreased the average daily gain, food intake, and plasma IGFBP-3, IGF-I and insulin concentrations. The mean plasma GH concentration was decreased by 23% and the area under the GH peaks was reduced by 60%. Co-administration of pGH (30 micrograms/kg/day) with LR3IGF-I had no interactive effect on growth performance, and plasma insulin, IGFBP-3 and IGF-I concentrations remained suppressed. The area under the GH peaks was not restored with this combination treatment although mean plasma GH concentrations were elevated in all animals receiving pGH. Infusion of IGF-I (180 micrograms/kg/day) decreased plasma insulin and mean GH concentrations but had no significant effect on IGFBP-3 concentrations. Average daily gain and feed intake were not changed by IGF-I treatment. A combination of IGF-I and pGH injection (30 micrograms/kg/day) increased plasma IGFBP-3 concentrations but plasma insulin levels remained suppressed. Plasma glucose levels were unaffected by any treatment. The study demonstrates that both IGF-I and LR3IGF-I suppress plasma GH concentrations in finisher pigs. This, in turn, may be responsible for the reduction in the plasma concentration of IGF-I, IGFBP-3 and insulin seen in LR3IGF-I-treated animals. The decrease in these parameters may contribute to the inhibitory effect of LR3IGF-I on growth performance in the pig.     

Role of the insulin-like growth factor system in uterine function and placental development in ruminants

Maternal nutrition during pregnancy influences fetal and placental weights. The insulin-like growth factors (IGF) are also important determinants of fetal size. Furthermore, the expression of several components of the IGF system is regulated by nutrition. Effects of nutrition on fetal growth could therefore be mediated by the IGF system in the uterus and placenta. The oviductal mucosa produces IGF-I, which may influence oviductal secretions or act directly on embryonic type 1 IGF receptors. In the uterus, IGF-I mRNA is localized to the stroma surrounding the endometrial glands, which contain high concentrations of IGF type 1 receptors. Uterine IGF-I concentrations fall during pregnancy; therefore, glandular activity is more likely influenced by systemic than local IGF-I production. The IGF-II mRNA is present in both caruncles and fetal placental mesoderm, but concentrations are much higher in the latter. The actions of IGF-I and IGF-II on the endometrium and placenta are influenced by IGF-binding proteins. In the ewe, mRNAs for IGF binding protein-1 and -5 are located in the luminal and glandular epithelia, IGF binding proteins-2 and -4 are produced in the subepithelial stroma, and IGF binding protein-4 is also in the placentome capsule; IGF binding protein-3 is more widely expressed in both maternal and fetal tissues. The IGF binding proteins, therefore, form a major barrier to the passage of IGF between the fetal and maternal circulatory systems.     

Kallikrein gene expression in human pituitary tissues

Somatostatin has been suggested to influence the somatotrophic axis outside the central nervous system, in reducing GH-induced IGF-I mRNA and IGF-I generation. This study aimed to determine whether such effects were mediated via the GH receptor (GHR). GH-deficient dwarf rats aged 45-47 days (n = 8 per group) received twice daily subcutaneous injections of octreotide (1 mg/kg) (group O), saline (group S), octreotide (1 mg/kg) plus bovine GH (0.25 mg/kg) (group OG), or bovine GH (0.25 mg/kg) plus saline (group G) for 10 days. Octreotide-treated animals had less weight gain compared with saline-treated animals, but not when GH cotreated (group OG vs G). Octreotide had an overall effect on decreasing length gain (P < 0.01). Serum IGF-I (ng/ml) was reduced by octreotide (group O 171 +/- 11, group S 239 +/- 20, P < 0.01; group OG 283 +/- 30, group G 362 +/- 10, P < 0.001), as was serum insulin (P < 0.001). A significant decrease in hepatic and muscle IGF-I mRNA expression was found as expected, yet this was not associated with decreased hepatic GHR expression. Rather, an increase in hepatic 125I-bovine GH specific binding was observed (P < 0.001) and, in GH-cotreated animals (OG), hepatic GHR and GH binding protein (GHBP) mRNA expression were also increased by octreotide by approximately 40%. In muscle, octreotide was associated with an approximately 30% decrease in GHBP mRNA and no effect on GHR mRNA. This study suggests that the suppressive effects of octreotide on IGF-I metabolism, at least in liver, are not mediated via down-regulation of GHR expression, but more likely by direct effects on IGF-I expression.