Insulin-like Growth factor-I Production Research Articles

Advantages and disadvantages of GH/IGF-I combination treatment

Growth hormone (GH) is the primary regulator of insulin-like growth factor-I (IGF-I) production in a wide variety of tissues. There is much overlap in the endocrine, metabolic and anabolic effects of GH and IGF-I but both hormones have divergent effects on glucose metabolism, insulin sensitivity and differentiation of prechondrocytes. Theoretically combined administration of GH and IGF-I may be more effective than GH alone or IGF-I alone. Arguments in favor for this are: 1] Clearance of IGF-I may be markedly altered by the co-administration of GH and this will provide sustained actions of IGF-I. 2] Higher serum IGF-I levels are achieved with a combination treatment of GH and IGF-I than with GH treatment alone or IGF-I alone. In addition, combination therapy may have additive or synergistic effects. 3] The combination GH and IGF-I counteracts disadvantageous effects on glucose metabolism of either GH alone or IGF-I alone. 4] GH may exert direct actions on tissues independently from IGF-I. 5] Combination of GH and IGF-I may be more effective in improving tissue IGF-I levels. The combination therapy of GH and IGF-I might be beneficial in growth retardation, in certain specific subgroups of critically ill or catabolic patients and in the treatment of GH-deficient subjects with the metabolic syndrome and/or manifest diabetes. It is at present unknown whether an optimal balance between safety and efficacy can be achieved with the combination therapy of GH and IGF-I, since this combination has been evaluated in only a small number of patient populations and in studies of a relatively short duration. In addition, a disadvantage may be the financial costs of combination therapy of GH and IGF-I. In conclusion, there are many reasons for believing that administration of the combination therapy of GH and IGF-I could have advantages above GH alone or IGF-I alone. However, determination of whether co-administration of GH and IGF-I indeed is superior to either agent alone awaits further study.

Effect of topical application of raspberry ketone on dermal production of insulin-like growth factor-I in mice and on hair growth and skin elasticity in humans

Sensory neurons release calcitonin gene-related peptide (CGRP) on activation. We recently reported that topical application of capsaicin increases facial skin elasticity and promotes hair growth by increasing dermal insulin-like growth factor-I (IGF-I) production through activation of sensory neurons in mice and humans. Raspberry ketone (RK), a major aromatic compound contained in red raspberries ( Rubus idaeus), has a structure similar to that of capsaicin. Thus, it is possible that RK activates sensory neurons, thereby increasing skin elasticity and promoting hair growth by increasing dermal IGF-I production. In the present study, we examined this possibility in mice and humans. RK, at concentrations higher than 1 μM, significantly increased CGRP release from dorsal root ganglion neurons (DRG) isolated from wild-type (WT) mice and this increase was completely reversed by capsazepine, an inhibitor of vanilloid receptor-1 activation. Topical application of 0.01% RK increased dermal IGF-I levels at 30 min after application in WT mice, but not in CGRP-knockout mice. Topical application of 0.01% RK increased immunohistochemical expression of IGF-I at dermal papillae in hair follicles and promoted hair re-growth in WT mice at 4 weeks after the application. When applied topically to the scalp and facial skin, 0.01% RK promoted hair growth in 50.0% of humans with alopecia ( n = 10) at 5 months after application and increased cheek skin elasticity at 2 weeks after application in 5 females ( p < 0.04). These observations strongly suggest that RK might increase dermal IGF-I production through sensory neuron activation, thereby promoting hair growth and increasing skin elasticity.

Antithrombin prevents reperfusion-induced hepatic apoptosis by enhancing insulin-like growth factor-I production in mice

Antithrombin (AT) reduces ischemia/reperfusion-induced liver injury by increasing release of calcitonin gene-related peptide (CGRP) from sensory neurons. Because CGRP increases the production of insulin-like growth factor-I (IGF-I), an antiapoptotic factor, it is possible that AT prevents apoptosis by increasing IGF-I production. We examined this possibility in the present study. Prospective, randomized, controlled study. University laboratory. Male C57BL/6 wild-type mice and alphaCGRP-deficient mice weighing 16-23 g. AT (250 units/kg) was intravenously administered to mice subjected to hepatic ischemia/reperfusion. Liver injury was evaluated by determining changes in serum levels of alanine aminotransferase after ischemia/reperfusion. Hepatic apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining. AT reduced ischemia/reperfusion-induced liver injury and enhanced increases in hepatic tissue levels of IGF-I in wild-type mice, although it did not reduce liver injury or enhance increases in hepatic tissue levels of IGF-I in alphaCGRP-deficient mice. Reperfusion-induced hepatic apoptosis was markedly suppressed by AT in wild-type mice, but not in alphaCGRP-deficient mice. Pretreatment with anti-IGF-I antibody completely reversed therapeutic effects of AT in wild-type mice. Both CGRP and IGF-I showed therapeutic effects similar to those of AT in wild-type and alphaCGRP-deficient mice. : These observations suggested that AT may prevent reperfusion-induced hepatic apoptosis by enhancing IGF-I production through promotion of sensory neuron activation, thereby reducing ischemia/reperfusion-induced liver injury.

Lycopene inhibits IGF-I signal transduction and growth in normal prostate epithelial cells by decreasing DHT-modulated IGF-I production in co-cultured reactive stromal cells

Prostate stromal and epithelial cell communication is important in prostate functioning and cancer development. Primary human stromal cells from normal prostate stromal cells (PRSC) maintain a smooth muscle phenotype, whereas those from prostate cancer (6S) display reactive and fibroblastic characteristics. Dihydrotestosterone (DHT) stimulates insulin-like growth factor-I (IGF-I) production by 6S but not PSRC cells. Effects of reactive versus normal stroma on normal human prostate epithelial (NPE or PREC) cells are poorly understood. We co-cultured NPE plus 6S or PRSC cells to compare influences of different stromal cells on normal epithelium. Because NPE and PREC cells lose androgen receptor (AR) expression in culture, DHT effects must be modulated by associated stromal cells. When treated with camptothecin (CM), NPE cells, alone and in stromal co-cultures, displayed a dose-dependent increase in DNA fragmentation. NPE/6S co-cultures exhibited reduced CM-induced cell death with exposure to DHT, whereas NPE/PRSC co-cultures exhibited CM-induced cell death regardless of DHT treatment. DHT blocked CM-induced, IGF-I-mediated, NPE death in co-cultured NPE/6S cells without, but not with, added anti-IGF-I and anti-IGF-R antibodies. Lycopene consumption is inversely related to human prostate cancer risk and inhibits IGF-I and androgen signaling in rat prostate cancer. In this study, lycopene, in dietary concentrations, reversed DHT effects of 6S cells on NPE cell death, decreased 6S cell IGF-I production by reducing AR and beta-catenin nuclear localization and inhibited IGF-I-stimulated NPE and PREC growth, perhaps by attenuating IGF-I's effects on serine phosphorylation of Akt and GSK3beta and tyrosine phosphorylation of GSK3. This study expands the understanding of the preventive mechanisms of lycopene in prostate cancer.

Novel Splice Site Mutation in the Growth Hormone Receptor Gene in Turkish Patients with Laron-type Dwarfism

Growth hormone (GH) is involved in growth, and fat and carbohydrate metabolism. Interaction of GH with the GH receptor (GHR) is necessary for systemic and local production of insulin-like growth factor-I (IGF-I) which mediates GH actions. Mutations in the GHR cause severe postnatal growth failure; the disorder is an autosomal recessive genetic disease resulting in GH insensitivity, called Laron syndrome. It is characterized by dwarfism with elevated serum GH and low levels of IGF-I. We analyzed the GHR gene for mutations and polymorphisms in eight patients with Laron-type dwarfism from six families. We found three missense mutations (S40L, V125A, I526L), one nonsense mutation (W157X), and one splice site mutation in the extracellular domain of GHR. Furthermore, G168G and exon 3 deletion polymorphisms were detected in patients with Laron syndrome. The splice site mutation, which is a novel mutation, was located at the donor splice site of exon 2/ intron 2 within GHR. Although this mutation changed the highly conserved donor splice site consensus sequence GT to GGT by insertion of a G residue, the intron splicing between exon 2 and exon 3 was detected in the patient. These results imply that the splicing occurs arthe GT site in intron 2, leaving the extra inserted G residue at the end of exon 2, thus changing the open reading frame of GHR resulting in a premature termination codon in exon 3.

Intravenous immunoglobulin reduces the ischemia/reperfusion-induced renal injury by increasing insulin-like growth factor-I production in mice

Sensory neurons release calcitonin gene-related peptide (CGRP) upon activation. We have previously reported that activation of sensory neurons increases insulin-like growth factor-I (IGF-I) production, thereby reducing ischemia/reperfusion (I/R)-induced liver injury in mice. Although immunoglobulin has been shown to reduce organ failures by attenuating inflammatory responses in various animal models of sepsis, its therapeutic molecular mechanism(s) is not fully understood. Since sensory neurons have an Fcγ receptor, it is possible that intravenous immunoglobulin reduces reperfusion-induced renal injury by increasing IGF-I production through sensory neuron activation. We examined this possibility in the present study.

Antagonists of growth-hormone-releasing hormone: an emerging new therapy for cancer

This article reviews the potential clinical uses of antagonists of growth-hormone-releasing hormone (GHRH) for tumor therapy. GHRH antagonists suppress the growth of various human cancer lines xenografted into nude mice; such tumors include breast, ovarian, endometrial and prostate cancers, lung cancers (small-cell lung carcinomas and non-small-cell lung carcinomas), renal, pancreatic, gastric and colorectal carcinomas, brain tumors (malignant gliomas), osteogenic sarcomas and non-Hodgkin's lymphomas. The antitumor effects of GHRH antagonists are exerted in part indirectly through the inhibition of the secretion of GH from the pituitary and the resulting reduction in the levels of hepatic insulin-like growth factor I (IGF-I). The main effects of the GHRH antagonists are, however, exerted directly on tumors. GHRH ligand is present in various human cancers and might function as an autocrine and/or paracrine growth factor. Pituitary-type GHRH receptors and their splice variants are also found in many human cancers. The inhibitory effects of GHRH antagonists seem to be due to the blockade of action of tumoral GHRH. Antagonists of GHRH can also suppress cancer growth by blocking production of IGF-I and/or IGF-II by the tumor. Further development of GHRH antagonists that are still-more potent should lead to potential therapeutic agents for various cancers.

Excess Mortality in Acromegaly

Background: Increased production of growth hormone (GH) and insulin-like growth factor-I (IGF-I) in patients with acromegaly is associated with a twofold increase in mortality compared with the general population. The range of standardised mortality rates in various studies ranges from 1.2 to 3.6. Predictors of Mortality: Multivariate analysis has indicated that post-treatment serum GH levels and, in a number of studies, serum IGF-I levels are the most powerful predictors of outcome. Normal IGF-I concentrations and random GH levels <2.5 µg/l measured by polyclonal radioimmunoassay result in optimal outcome. Other factors adversely influencing mortality include hypertension and a long interval between onset of the disorder and diagnosis. Conclusions: Analysis of recent reports suggests that adoption of treatment guidelines with appropriate post-treatment target ranges for GH and IGF-I, together with the availability of newer methods to control GH oversecretion, has significantly improved patient outcomes.

Somatostatin inhibits basal and growth hormone-stimulated hepatic insulin-like growth factor-I production

Growth of vertebrates is controlled by the growth hormone (GH)-insulin-like growth factor-I (IGF-I) system, and somatostatins (SSs) have been shown to inhibit growth by reducing the release of growth hormone (GH) from the pituitary. In this study, we used rainbow trout to assess the effects of SSs on the production of IGF-I. Somatostatin-14 (SS-14-I) implantation for 15 days significantly reduced steady-state levels of IGF-I mRNA in liver and lowered IGF-I concentration in plasma compared to control animals. The direct effects of SSs were examined on hepatocytes incubated in vitro. SS-14-I inhibited basal and GH-stimulated IGF-I mRNA expression. SS-14-I inhibition of GH-stimulated IGF-I expression was concentration- and time-dependent; the ED 50 was ca. 40 ng/ml and the maximum response was observed after 6 h. All SS isofoms tested, including the N-terminally extended form of SS-14-I, SS-28-I, and the [Tyr 7, Gly 10]-substituted forms of SS, SS-14-II, SS-25-II and SS-28-II, inhibited GH-stimulated IGF-I mRNA expression. The inhibitory effects of SS-14-I on steady-state levels of IGF-I mRNA resulted from reduced IGF-I mRNA transcription and not from altered mRNA stability. SS-14-I also reduced basal and GH-stimulated release of IGF-I into culture medium. These results indicate that SSs regulate growth in an extrapituitary manner by reducing hepatic IGF-I biosynthesis and secretion.

Prostate cancer prevention by nutritional means to alleviate metabolic syndrome

In 1987 when Reaven introduced syndrome X (metabolic syndrome, or MS), we were studying skeletal muscle insulin resistance and found that when rodents were fed a high-fat, refined-sugar (HFS) diet, insulin resistance developed along with aspects of MS, including hyperinsulinemia, hypertension, hypertriglyceridemia, and obesity. MS was controlled in rodents by switching them to a low-fat, starch diet and was controlled in humans with a low-fat starch diet and daily exercise (Pritikin Program). Others reported inverse relations between serum insulin and sex hormone–binding globulin (SHBG). When subjects were placed on the Pritikin Program, insulin fell and SHBG rose and it was suggested that prostate cancer might also be an aspect of MS. A bioassay was developed with tumor cell lines grown in culture and stimulated with serum before and after a diet and exercise intervention. Diet and exercise altered serum factors that slowed the growth rate and induced apoptosis in androgen-dependent prostate cancer cells. Changes in serum with diet and exercise that might be important include reductions in insulin, estradiol, insulin-like growth factor-I (IGF-I), and free testosterone with increases in SHBG and IGF binding protein-1. Hyperinsulinemia stimulates liver production of IGF-I, plays a role in the promotion of prostate cancer, and thus is the cornerstone for both MS and prostate cancer. Adopting a low-fat starch diet with daily exercise controls MS and should reduce the risk of prostate cancer.

Effect of capsaicin on plasma and tissue levels of insulin-like growth factor-I in spontaneously hypertensive rats

Objective Plasma levels of insulin-like growth factor-I (IGF-I), an important substance for maintaining cardiovascular homeostasis, are lower in spontaneously hypertensive rats (SHR) than in normotensive Wistar Kyoto rats (WKY). Calcitonin gene-related peptide (CGRP) increases IGF-I production in vitro and in vivo, suggesting that stimulation of sensory neurons might increase the production of IGF-I in SHR. Design Levels of CGRP and IGF-I in plasma, kidneys and heart in WKY and SHR and cellular cyclic AMP levels in dorsal root ganglion neurons (DRGs) isolated from WKY and SHR were measured by an ELISA-based method. Results Levels of CGRP and IGF-I in plasma, kidneys and heart of SHR were about half of those of WKY. Administration of capsaicin significantly increased levels of CGRP and IGF-I in plasma and tissues of SHR to the levels in WKY and these increases were completely reversed by pretreatment with capsazepine, an inhibitor of vanilloid receptor-1 activation. CGRP release and cellular levels of cAMP in DRGs isolated from SHR were significantly lower than those in DRGs isolated from WKY. Capsaicin increased both CGRP release and cellular cAMP levels in DRGs isolated from SHR to the levels in DRGs isolated from WKY. Conclusions Sensory neuron activation might be lower in SHR than in WKY probably due to decreased production of cAMP in sensory neurons, explaining why IGF-I levels in plasma and tissues are lower in SHR than in WKY.

Administration of capsaicin and isoflavone promotes hair growth by increasing insulin-like growth factor-I production in mice and in humans with alopecia

Objective Insulin-like growth factor-I (IGF-I) plays an important role in hair growth. Capsaicin activates vanilloid receptor-1, thereby increasing the release of calcitonin gene-related peptide (CGRP) from sensory neurons, and CGRP has been shown to increase IGF-I production. We recently reported that isoflavone, a phytoestrogen, increases production of CGRP by increasing its transcription in sensory neurons. These observations raise the possibility that administration of capsaicin and isoflavone might promote hair growth by increasing IGF-I production. In the present study, we examined this possibility in mice and humans with alopecia. Design Dermal IGF-I levels, immunohistochemical expression of IGF-I in the skin and hair regrowth were examined after capsaicin and isoflavone administration to wild-type (WT) mice and CGRP-knockout mice. Plasma levels of IGF-I and promotion of hair growth were evaluated in 48 volunteers with alopecia after administration of capsaicin and isoflavone for 5 months. Results Subcutaneous administration of capsaicin significantly increased dermal IGF-I levels at 30 min after administration in WT mice ( p < 0.01), but not in CGRP-knockout mice. Dermal levels of IGF-I were significantly higher in WT mice administered capsaicin and isoflavone for 4 wks than in those administered capsaicin alone for 4 wks ( p < 0.01) and in those administered neither of them ( p < 0.01). Immunohistochemical expression of IGF-I at dermal papillae in hair follicles was increased in WT mice administered capsaicin and isoflavone and in those administered capsaicin alone at 4 wks. Hair regrowth was clearly more accelerated in WT mice administered capsaicin and isoflavone for 4 wks than in those administered capsaicin alone for 4 wks and in those administered neither of them. Plasma levels of IGF-I were significantly increased from baseline levels in 31 volunteers with alopecia at 5 months after oral administration of capsaicin (6 mg/day) and isoflavone (75 mg/day) ( p < 0.01), while they were not increased in 17 volunteers with alopecia administered placebo. The number of volunteers with alopecia who showed promotion of hair growth at 5 months after administration was significantly higher among volunteers administered capsaicin and isoflavone (20/31: 64.5%) than among those administered placebo (2/17: 11.8%) ( p < 0.01). Conclusions These observations strongly suggested that combined administration of capsaicin and isoflavone might increase IGF-I production in hair follicles in the skin, thereby promoting hair growth. Such effects of capsaicin and isoflavone might be mediated by sensory neuron activation in the skin.

The influence of social status on the rate of growth, eye color pattern and Insulin-like Growth Factor-I gene expression in Nile tilapia, Oreochromis niloticus

Many aspects of teleost physiology are subject to regulation by social interactions. To evaluate the relationship of social status with growth, eye color pattern and hepatic Insulin-like Growth Factor-I (IGF-I) mRNA expression, 30 Oreochromis niloticus were isolated for 10 days and were used in a social pair study. Results revealed that growth of both dominant (except 1 day after social interaction) and subordinate individuals was suppressed, but growth suppression was greater in the subordinates. The dominant fish completely inhibited the feeding of the subordinate individuals during and 1 day after they were introduced into the aquaria together. After that, a pattern of highly aggressive attacks by dominant fish only partially inhibited feeding by the subordinates. Differential alterations in growth rate between dominants and subordinates were attributed more to behavioral changes (i.e., feeding) as transduced by physiological regulators (i.e., IGF-I level and possibly serotonin and/or neuropeptide Y) but may also be due to changes in metabolism. The fish's relative position in the social hierarchy consistently influenced the levels of IGF-I mRNA in the liver and the eye color pattern. Lower social status depressed hepatic IGF-I levels while dominant status stimulated hepatic IGF-I production, possibly in response to inhibition of somatostatin release in the hypothalamus, leading to greater secretion of pituitary growth hormone (GH). A significant positive association was detected between the IGF-I mRNA expression of the dominant fish and the level of aggression (number of attacks) during the encounter. Social status also influenced the eye color pattern of the fish. During aggressive interactions, most of the fish (22 out of 24) displayed decreased eye darkening. At the later part of the encounter, all subsequent subordinates displayed eye-darkening patterns which acted as a social signal announcing social submission. After the encounter dominant fish had paler eye color pattern than subordinates.

Effect of topical application of capsaicin and its related compounds on dermal insulin-like growth factor-I levels in mice and on facial skin elasticity in humans

Capsaicin increases calcitonin gene-related peptide (CGRP) release from sensory neurons by stimulating vanilloid receptor-1 (VR-1). Since CGRP increases production of insulin-like growth factor-I (IGF-I) in fetal osteoblasts in vitro, it is possible that sensory neuron activation by capsaicin increases production of IGF-I. In the present study, we attempted to determine whether topical application of capsaicin and related compounds increases dermal IGF-I level in mice and whether it increases facial skin elasticity in humans. Topical application of 0.01% capsaicin significantly increased dermal IGF-I levels from 30 to 180 min ( p < 0.01), but not at 360 min, after application in mice. Topical application of 0.01% capsaicinoids (dihydrocapsaicin and nordihydrocapsaicin), 0.01% capsinoids (capsiate, dihydrocapsiate and nordihydrocapsiate), 0.01% anandamide (an endogenous agonist of VR-1), and 0.01% nonylic acid vanillylamide (a synthetic capsaicin) significantly increased dermal IGF-I levels at 30 min after topical application in mice ( p < 0.01). Topical application of 0.01% capsaicin to faces of 17 healthy female volunteers for seven days significantly increased cheek skin elasticity ( p < 0.01). These observations suggest that topical application of capsaicin and related compounds might be useful in the treatment of detrimental morphological changes of the skin in patients with growth hormone deficiency and those in the elderly by increasing dermal IGF-I levels.

RETRACTED: Stimulation of sensory neurons by capsaicin increases tissue levels of IGF-I, thereby reducing reperfusion-induced apoptosis in mice

Calcitonin gene-related peptide (CGRP) increases insulin-like growth factor-I (IGF-I) production in fetal rat osteoblasts in vitro, suggesting that stimulation of sensory neurons might increase IGF-I production, thereby preventing apoptosis. We examined whether stimulation of sensory neurons by capsaicin might reduce reperfusion-induced hepatic apoptosis by increasing IGF-I production. Administration of capsaicin increased tissue levels of IGF-I and IGF-I mRNA in various organs in wild-type (WT) mice, but not in CGRP-knock-out (CGRP-/-) mice. Administration of CGRP increased tissue levels of IGF-I and IGF-I mRNA in both WT and CGRP-/- mice. Increases in hepatic tissue levels of TNF, serum levels of transaminases, hepatic apoptosis and hepatic tissue levels of caspase-3 after hepatic ischemia/reperfusion (I/R) were more marked in CGRP-/- mice than in WT mice. Hepatic IGF-I levels were increased in WT mice after reperfusion, while they were not changed in CGRP-/- mice. Although administration of capsaicin enhanced increases in IGF-I levels and reduced reperfusion-induced events in WT mice, it had no effect in CGRP-/- mice. Administration of CGRP and IGF-I reduced reperfusion-induced effects in both strains of mice. These observations suggested that capsaicin-induced sensory neuron activation, which leads to release of CGRP, might increase IGF-I production, thereby reducing reperfusion-induced liver injury by reducing apoptosis.

A Novel Immune-Based Therapy for Stroke Induces Neuroprotection and Supports Neurogenesis

The ability of the central nervous system to cope with stressful conditions was shown to be dependent on proper T-cell-mediated immune response. Because the therapeutic window for neuroprotection after acute insults such as stroke is relatively narrow, we searched for a procedure that would allow the relevant T cells to be recruited rapidly. Permanent middle cerebral artery occlusion was induced in adult rats. To facilitate a rapid poststroke T cell activity, rats were treated with poly-YE using different regimens. Control and poly-YE-treated rats were assessed for functional recovery using neurological severity score and Morris water maze. Neuroprotection, neurogenesis, growth factor expression, and microglial phenotype were assessed using histological and immunofluorescence methods. Administration of poly-YE as late as 24 hours after middle cerebral artery occlusion yielded a beneficial effect manifested by better neurological performance, reduced neuronal loss, attenuation of behavioral deficits, and increased hippocampal and cortical neurogenesis. This compound affected the subacute phase by modulating microglial response and by increasing local production of insulin-like growth factor-I, known to be a key player in neuronal survival and neurogenesis. The relative wide therapeutic window, coupled with its efficacy in attenuating further degeneration and enhancing restoration, makes poly-YE a promising immune-based candidate for stroke therapy.

Autocrine Production of Insulin-like Growth Factor-I (IGF-I) Affects Paracellular Transport Across Epithelial CellsIn Vitro

Autocrine production of growth factors can have significant effects on cell activity. We report for the first time that autocrine production of insulin-like growth factor-I (IGF-I) alters paracellular transport across bovine mammary epithelial cells in vitro. Paracellular transport was assessed by measuring phenol red transport across mammary alveolar cells-large T antigen (MAC-T cells) derived from parental mammary epithelial cells, cultured on porous membranes and compared with two different transfected MAC-T cell lines that constitutively secrete IGF-I. Phenol red transport was essentially blocked in parental cell culture after six days, while IGF-I secreting cells provided essentially no barrier. Surprisingly, neither co-culture studies between parental and IGF-I-secreting cells nor addition of exogenous IGF-I or IGF-binding protein-3 reversed the phenol red transport properties. IGF-I-secreting cells did however express lower levels of the junction components occludin and E-cadherin than parental cells, suggesting that localized autocrine IGF-I activity might lead to increased permeability via changes in both the tight and adherens junction protein levels.

Recombinant Human Insulin-Like Growth Factor I (rhIGF-I) and rhIGF-I/rhIGF-Binding-Protein-3: New Growth Treatment Options?

INSULIN-LIKE GROWTH FACTOR I (IGF-I) AND GROWTH he growth effect that gives growth hormone (GH) its name is the result of GH stimulation of IGF-I production in the liver (endocrine IGF-I) and peripheral tissues, particularly bone and muscle (autocrine/paracrine IGF-I). Hepatic IGF-I circulates almost entirely ( 99%) bound to IGF-binding proteins (IGFBPs). The IGFBPs are a family of six tructurally related proteins with a high affinity for binding IGF. The principal BP, IGFBP-3, which binds 75% to 90% of irculating IGF-I, is a large ternary complex consisting of IGFBP-3, acid labile subunit (ALS), and IGF molecules. ALS and GFBP-3 are produced in the liver as a direct effect of GH. The ALS stabilizes the IGF–IGFBP-3 complex, reduces the passage f IGF-I to the extravascular compartment, and extends its half-life. The remainder of bound IGF-I is mostly with IGFBP-1 nd IGFBP-2. IGFBP-1 concentrations are controlled by nutritional status as reflected in insulin levels, with the highest GFBP-1 concentrations found in the fasting, hypoinsulinemic state. Similarly, circulating concentration of IGFBP-2 is under egative control by GH directly, independently of IGF-I, and is elevated with GH deficiency or resistance; the positive effect f IGF-I on IGFBP-2 results in further elevation when patients who are GH receptor deficient (GHRD, Laron syndrome) are reated with IGF-I. The IGFBPs modulate IGF action by controlling storage and release of IGF-I in the circulation and nfluencing its binding to its receptor, facilitating storage of IGF-I in extracellular matrices, and they also exert independent ctions. IGF-I binds to the type 1 IGF receptor with high affinity and to the structurally similar insulin receptor with an affinity hat is approximately 100-fold less that of insulin. Because IGF-I is present in the circulation at molar concentrations that are 000 times those of insulin, even a small insulin-like effect of IGF-I as a result of its binding to the insulin receptor could be ore important than that of insulin itself, were it not for the IGFBPs that control the availability and activity of IGF-I, and dapt to changing energy status. The importance of IGF-I in normal intrauterine growth in humans has been demonstrated in a patient with a homozygous artial deletion of the IGF-I gene, in a patient with mutation of the IGF-I gene resulting in high circulating levels of an neffective IGF-I, and in patients with mutations of the IGF-I receptor, who all had severe intrauterine growth retardation. ntrauterine IGF-I synthesis, however, does not appear to be GH dependent because most patients with genetically determined evere IGF-I deficiency have normal or only minimally reduced intrauterine growth. Standard deviation score (SDS) for length eclines rapidly after birth in these conditions, demonstrating the immediate need for GH-stimulated IGF-I synthesis for ostnatal growth. Growth velocity in the absence of GH is typically half normal, but it has been reported to be normal or upranormal despite absence of GH in some hypothalamic conditions characterized by hyperphagia, with obesity or rapid weight ain. A similar phenomenon was described in a placebo-controlled study of rhIGF-I treatment of patients with severe IGF-I eficiency from GHRD, in which 3 of the 9 placebo-treated subjects grew over the -month study period at an accelerated rate comparable with that of the rhIGF-I–treated ubjects, attributed to improved nutrition in the investigative milieu.

Effects of fasting on growth hormone, growth hormone receptor, and insulin-like growth factor-I axis in seawater-acclimated tilapia, Oreochromis mossambicus

Effects of fasting on the growth hormone (GH)–growth hormone receptor (GHR)–insulin-like growth factor-I (IGF-I) axis were characterized in seawater-acclimated tilapia ( Oreochromis mossambicus). Fasting for 4 weeks resulted in significant reductions in body weight and specific growth rate. Plasma GH and pituitary GH mRNA levels were significantly elevated in fasted fish, whereas significant reductions were observed in plasma IGF-I and hepatic IGF-I mRNA levels. There was a significant negative correlation between plasma levels of GH and IGF-I in the fasted fish. No effect of fasting was observed on hepatic GHR mRNA levels. Plasma glucose levels were reduced significantly in fasted fish. The fact that fasting elicited increases in GH and decreases in IGF-I production without affecting GHR expression indicates a possible development of GH resistance.

Insulin-like growth factor-I, its binding proteins (IGFBP-1 and IGFBP-3), and growth hormone and breast cancer risk in The Nurses Health Study II

Earlier data suggest that the relationship between circulating insulin-like growth factor I (IGF-I) levels and breast cancer risk differs according to menopausal status. We evaluated the association between IGF levels as well as the primary regulator of IGF-I production, growth hormone (GH), and breast cancer risk in the Nurses' Health Study II (NHS II) cohort, a large cohort of primarily premenopausal women. We conducted a case-control study nested within the prospective NHS II cohort. Plasma concentrations of IGF-I, IGF binding protein (IGFBP)-3, IGFBP-1, and GH were measured in blood samples collected between 1996 and 1999. Totally 317 women were identified who had a diagnosis of invasive or in situ breast cancer between the date of blood collection and June 1 2003; 75% of these women were premenopausal at blood collection. To each of the 317 women, two controls were age-matched for a total of 634 controls. We used conditional logistic regression models to estimate the relative risk of breast cancer. Overall, plasma IGF-I, IGFBP-1, IGFBP-3, and GH levels were not associated with breast cancer risk (relative risks, top vs bottom quartile; IGF-I, 0.98, 95% confidence interval (CI), 0.69-1.39; IGFBP-1, 0.95, 95% CI, 0.63-1.41; IGFBP-3, 1.10, 95% CI, 0.78-1.54; GH, 1.09, 95% CI, 0.82-1.46). These risks were similar for premenopausal women of age 45 years or less. Further adjustment for additional breast cancer risk factors did not change these estimates. In conclusion, circulating IGF-I, IGFBP-1, IGFBP-3, and GH levels appear to have no important association with breast cancer risk in a large cohort of premenopausal women.