Insulin-like Growth factor-I Synthesis Research Articles

Are the Effects of Oral and Vaginal Contraceptives on Bone Formation in Young Women Mediated via the Growth Hormone-IGF-I Axis?

Purpose: Combined hormonal contraceptive therapy has been associated with negative bone mineral density outcomes that may be route-dependent [i.e., combined oral contraception (COC) vs. contraceptive vaginal ring (CVR)] and involve the hepatic growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. The objective of the pilot study was to assess the impact of route of contraceptive administration on IGF-I and procollagen type I N-terminal propeptide (PINP) responses to an IGF-I Generation Test. We hypothesized that the peak rise in IGF-I and PINP concentration and area under the curve (AUC) would be attenuated following COC, but not CVR, use.Methods: Healthy, premenopausal women not taking hormonal contraception were recruited. Women were enrolled in the control group (n = 8) or randomly assigned to COC (n = 8) or CVR (n = 8) for two contraceptive cycles. IGF-I Generation Tests were used as a probe to stimulate IGF-I release and were completed during the pre-intervention and intervention phases. Serum IGF-I and PINP were measured during both IGF-I Generation Tests. The study was registered at ClinicalTrials.gov (NCT02367833).Results: Compared to the pre-intervention phase, peak IGF-I concentration in response to the IGF-I Generation Test in the intervention phase was suppressed in the COC group (p < 0.001), but not the CVR or Control groups (p > 0.090). Additionally, compared to the pre-intervention phase, PINP AUC during the intervention phase was suppressed in both COC and CVR groups (p < 0.001), while no difference was observed in the control group (p = 0.980).Conclusion: These data suggest that changes in recombinant human GH-stimulated hepatic IGF-I synthesis in response to combined hormonal contraception (CHC) use are dependent on route of CHC administration, while the influence on PINP is route-independent. Future research is needed to expand these results with larger randomized control trials in all age ranges of women who utilize hormonal contraception.Clinical Trial Registration: www.ClinicalTrials.gov registration NCT02367833.

Application of Growth Hormone in in vitro Fertilization.

Growth hormone (GH) is a peptide hormone secreted mainly by the anterior part of the pituitary gland and plays a critical role in cell growth, development, and metabolism throughout the body. GH can not only directly influence human oocytes and cumulus cells but also indirectly improve oocyte quality through activating synthesis of insulin-like growth factor-I or promoting follicle-stimulating hormone-induced ovarian steroidogenesis. Since GH can regulate female and male infertility, it has been applied in the management of infertility for many years, especially in patients with poor ovarian response or poor prognosis. During ovarian stimulation, GH administration might improve the success rate of in vitro fertilization (IVF) probably through the beneficial effects of GH on oocyte quality as indicated by a higher number of mature oocytes and embryos arriving at the transfer stage and a higher fertility rate in GH-treated patients. However, there is still great controversy in the application of GH in IVF. While some researchers showed that pregnancy, implantation and live birth rates could be increased by ovarian pretreatment with GH, others did not support GH as an effective adjuvant for infertility treatment because the live birth rate was not increased. This study reviewed and summarized recent advancements and benefits in clinical application of GH, trying to reach a just unbiased conclusion regarding the effect of GH therapy in IVF.

Mel1c Mediated Monochromatic Light-Stimulated IGF-I Synthesis through the Intracellular Gαq/PKC/ERK Signaling Pathway.

Previous studies have demonstrated that monochromatic light affects plasma melatonin (MEL) levels, which in turn regulates hepatic insulin-like growth factor I (IGF-I) secretion via the Mel1c receptor. However, the intracellular signaling pathway initiated by Mel1c remains unclear. In this study, newly hatched broilers, including intact, sham operation, and pinealectomy groups, were exposed to either white (WL), red (RL), green (GL), or blue (BL) light for 14 days. Experiments in vivo showed that GL significantly promoted plasma MEL formation, which was accompanied by an increase in the MEL receptor, Mel1c, as well as phosphorylated extracellular regulated protein kinases (p-ERK1/2), and IGF-I expression in the liver, compared to the other light-treated groups. In contrast, this GL stimulation was attenuated by pinealectomy. Exogenous MEL elevated the hepatocellular IGF-I level, which is consistent with increases in cyclic adenosine monophosphate (cAMP), Gαq, phosphorylated protein kinase C (p-PKC), and p-ERK1/2 expression. However, the Mel1c selective antagonist prazosin suppressed the MEL-induced expression of IGF-I, Gαq, p-PKC, and p-ERK1/2, while the cAMP concentration was barely affected. In addition, pretreatment with Ym254890 (a Gαq inhibitor), Go9863 (a PKC inhibitor), and PD98059 (an ERK1/2 inhibitor) markedly attenuated MEL-stimulated IGF-I expression and p-ERK1/2 activity. These results indicate that Mel1c mediates monochromatic GL-stimulated IGF-I synthesis through intracellular Gαq/PKC/ERK signaling.

Regulatory Role for Growth Hormone in Statural Growth: IGF-Dependent and IGF-Independent Effects on Growth Plate Chondrogenesis and Longitudinal Bone Growth.

It was initially thought that the growth-promoting effects of GH were exclusively mediated by liver-derived Insulin-like Growth Factor-I (IGF-I). Subsequent studies demonstrated that GH promotes IGF-I synthesis and activity in other organs and in the growth plate. GH has also IGF-I-independent growth-promoting effects. In Igf1 null mice, high circulating GH levels may be responsible for normal chondrocyte proliferation. Furthermore, tibial growth is reduced more in Ghr null mice than in Igf1 null mice, while the body of mice lacking both Ghr and Igf1 is smaller than that of mice lacking Igf1 or Ghr. The increased IGF-II expression in the growth plate in Igf1 null mice suggests that the IGF-I-independent effects of GH may be mediated by IGF-II. The effects of Igf1 receptor (Igf1r) gene deletion in chondrocytes indicate that GH may promote growth directly at the growth plate even when the local effects of IGF-I and IGF-II are abrogated.

Insulin-like growth factor- I and factors affecting it in thalassemia major.

Despite improvement of blood transfusion regimens and iron chelation therapy growth and maturational delay, cardiomyopathy, endocrinopathies and osteoporosis still occur in good number of thalassemic patients. Decreased IGF-1 secretion occurs in the majority of the thalassemic patients particularly those with growth and pubertal delay. Many factors contribute to this decreased synthesis of IGF-I including disturbed growth hormone (GH) - insulin-like growth factor - I (IGF-I) axis. The possible factors contributing to low IGF-I synthesis in thalassemia and the possible interaction between low IGF-I secretion and the occurrence of these complications is discussed in this mini-review. Improvement of IGF-I secretion in thalassemic patients should be intended to improve linear growth and bone mineral accretion in thalassemic patients. This can be attained through adequate correction of anemia and proper chelation, nutritional supplementation (increasing caloric intake), correction of vitamin D and zinc deficiencies, induction of puberty and correction of hypogonadism at the proper time and treating GH deficiency. This review paper provides a summary of the current state of knowledge regarding IGF-I and factors affecting it in patients with thalassaemia major (TM). Search on PubMed and reference lists of articles with the term ‘IGF-I, GH, growth, thalassemia, thyroxine, anemia, vitamin D, and zinc’ was carried out. A hundred and forty-eight articles were found and used in the write up and the data analyzed was included in this report.

Longitudinal Study on Liver Functions in Patients with Thalassemia Major before and after Deferasirox (DFX) Therapy.

By performing regular blood transfusion and iron chelation therapy, most patients with beta thalassemia major (BTM) now survive beyond the third decade of life. Liver disease is becoming an important cause of morbidity and mortality in these patients. Chronic hepatitis and/or severe iron overload are both important causes of liver pathology. Iron chelation with desferrioxamine (DFO) reduces excessive body iron, but its efficacy is limited by poor compliance and dose related toxicity. The recent use of Deferasirox ( DFX ), an oral single dose therapy, has improved the compliance to chelation.AimsTo study the long-term liver functions in BMT patients, seronegative for liver infections before versus after DFX treatment in relation to ferritin level.MethodsOnly BTM patients with hepatitis negative screening (checked every year) and on treatment with DFO for at least five years and with DFX for four years were enrolled. Liver function tests including serum bilirubin, alanine transferase (ALT), aspartate transferase (AST), albumin, insulin-like growth factor – I (IGF-I) and serum ferritin concentrations were followed every six months in 40 patients with BTM.ResultsDFX treatment (20 mg/kg/day) significantly decreased serum ferritin level in patients with BTM; this was associated with a significant decrease in serum ALT, AST, ALP and increase in IGF-I concentrations. Albumin concentrations did not change after DFX treatment. ALT and AST levels were correlated significantly with serum ferritin concentrations ( r = 0.45 and 0.33 respectively, p < 0.05). IGF-I concentrations were correlated significantly with serum ALT (r= 0.26, p = 0.05) but not with AST, ALP, bilirubin or albumin levels.The negative correlation between serum ferritin concentrations and ALT suggests that the impairment of hepatic function negatively affect IGF-I synthesis in these patients due to iron toxicity, even in the absence of hepatitis.ConclusionsSome impairment of liver function can occur in hepatitis negative thalassemic patients with iron overload. The use of DFX was associated with mild but significant reduction of ALT, AST and ALP and increase in IGF-I levels. The negative correlation between IGF-I and ALT concentrations suggest that preventing hepatic dysfunction may improve the growth potential in these patients.

Methionine improves the performance and breast muscle growth of broilers with lower hatching weight by altering the expression of genes associated with the insulin-like growth factor-I signalling pathway

The present study aimed to investigate the responses of broilers with different hatching weights (HW) to dietary methionine (Met). A total of 192 1-d-old Arbor Acres broiler chicks with different HW (heavy: 48·3 (sem 0·1)g and light: 41·7 (sem 0·1)g) were allocated to a 2 (HW)×2 (Met) factorial arrangement with six replicates of eight chicks. Control starter (1-21d) and finisher (22-42d) diets contained 0·50 and 0·43% Met, respectively. Corresponding values for a high-Met treatment were 0·60 and 0·53%. Light chicks had poorer (P<0·05) growth performance and breast muscle weight and lower (P<0·05) insulin-like growth factor-I (IGF-I) concentration and mRNA level in breast muscle than heavy chicks when both were fed the control diets. High-Met diets improved performance and promoted breast muscle growth and IGF-I concentration in light chicks (P<0·05). Increased IGF-I and target of rapamycin (TOR) mRNA levels as well as decreased eIF4E-binding protein 1 (4EBP1), atrogin-1 and forkhead box O 4 (FOXO4) mRNA levels were induced by high-Met diets in light chicks (P<0·05). In conclusion, the Met requirement of broilers might depend on their HW and Met levels used in the control diets in the present study were adequate for heavy chicks but inadequate for light chicks, resulting in poorer performance and breast muscle growth, which were improved by increasing dietary Met supply presumably through alterations in IGF-I synthesis and gene expression of the TOR/4EBP1 and FOXO4/atrogin-1 pathway.

GH receptor blocker administration and muscle–tendon collagen synthesis in humans

ContextThe growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis stimulates collagen synthesis in tendon and skeletal muscle, but no studies have investigated the effect of reducing IGF-I on collagen synthesis in healthy humans. ObjectiveWe hypothesised, that a GH blockade would decrease IGF-I and collagen synthesis in the connective tissue of skeletal muscle and tendon. DesignThe study was randomised and double blinded. Participants20 healthy young males completed the study. InterventionThe participants were randomised to 2weeks of GH receptor blocker supplementation (pegvisomant, 5mg/day, n=9) or placebo (n=11). Main outcome measuresSerum levels of GH, IGF-I and IGF-binding protein 3 (IGFBP-3) were measured before and after pegvisomant/placebo supplementation. Fractional synthesis rates (FSR) for collagen and myofibrillar protein were determined with stable isotopes in tendon and muscle, and mRNA for collagen (COL1A1 and COL3A1) as well as IGF-I isoforms (Ea and Ec) were measured in skeletal muscle. ResultsPegvisomant decreased serum IGF-I by 20% (p<0.01) and serum IGFBP-3 by 10% (p<0.05). Pegvisomant supplementation had no effect on collagen synthesis in tendon and skeletal muscle, nor was muscle myofibrillar protein synthesis affected. Similarly, pegvisomant supplementation had no effect on mRNA expression of IGF-I and collagen in skeletal muscle. ConclusionGH receptor blocker administration in healthy humans resulted in a moderate decrease in serum IGF-I. Collagen synthesis in tendon and skeletal muscle, as well as skeletal muscle IGF-I and collagen mRNA expression, was unaffected by GH receptor blocker supplementation.

Involvement of Insulin-Like Growth Factor-I Secretion and All-Trans-Retinoic Acid-Induced Decrement in Viability in MCF-7 Cells

Background/Aim: Insulin-like growth factor-I (IGF-I) is associated with survival, apoptosis and proliferation in MCF-7 cells. All-trans-retinoic acid (RA) is used as a cancer therapeutic, but the use of RA in cancer therapy is limited by the unpredictable resistance of cancer cells to drug action. Furthermore, the relationship of IGF-I with RA-induced decrement in cell viability has yet to be elucidated. Materials and Methods: MCF-7 cells were grown as confluent monolayers. To demonstrate the signaling pathways and roles of IGF-I, we suppressed endogenous target IGF-I with specific small interfering RNA treatment. Protein kinase C-δ and insulin receptor substrate 1 (IRS-1) protein levels were analyzed by Western blot. Radioimmunoassays were used to assess the concentration of endogenous IGF-I, and RT-PCR was used to assess IGF-I mRNA expression. Cell viability was analyzed with the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay. Results: We showed that RA treatment resulted in a dose- and time-dependent decrease in the secretion and synthesis of IGF-I. Subsequently, we found that suppression of IGF-I and IRS-1 protein decreased cell viability. In contrast, suppression of protein kinase C-δ and stimulation of IGF-I protected cells from RA-induced decrement in cell viability. The combination of RA treatment with IGF-I or IRS-1 small interfering RNA resulted in an additive decrease in cell viability. Conclusion: These results indicate that IGF-I plays an important role in the effect of RA and that suppression of IGF-I is implicated in the RA-induced inhibition of cell viability in MCF-7 cells.

Effects of acetic, propionic and butyric acids given intraruminally at different molar proportions or individually on rumen papillae growth and IGF-I and IGFBP-3 in plasma, liver and rumen tissue in growing sheep nourished by total intragastric infusions

Two experiments were conducted to evaluate effects of acetic, propionic and butyric acids given intraruminally at different molar proportions or individually on the rumen papillae growth and insulinlike growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3), growth hormone (GH) and insulin in plasma and/or tissues in growing sheep nourished by total intragastric infusions. The animals were daily infused with volatile fatty acids (VFA) mixtures at different molar proportions or individual VFA, casein, glucose and corn oil for a total of 1.2 times of maintenance requirement of energy and protein for 12 days. At the end of each experiment, the sheep were slaughtered and blood and tissue samples were obtained for determination of rumen papillae growth and hormones mentioned above. The present study indicated that the papillae growth and IGF-I concentration in rumen tissue of growing sheep nourished by intragastric infusions were not affected significantly by VFA mixtures with different molar proportions or by acetic, propionic and butyric acids individually (P > 0.05) when they were supplied at the same energy level and the synthesis and secretion of IGF-I could be more associated with the energy level rather than energy source of VFA.

Influences of the environment on the endocrine and paracrine fish growth hormone–insulin‐like growth factor‐I system

Insulin-like growth factor-I (IGF-I) is a key component of the complex system that regulates differentiation, development, growth and reproduction of fishes. The IGF-I gene is mainly expressed in the liver that represents the principal source of endocrine IGF-I but also in numerous other organs where the hormone most probably acts in an autocrine-paracrine manner. The primary stimulus for synthesis and release of IGF-I is growth hormone (GH) from the anterior pituitary. Thus, in analogy to mammals, it is usual to speak of a fish 'GH-IGF-I axis'. The GH-IGF-I system is affected by changes in the environment and probably represents a target of endocrine disrupting compounds (EDC) that impair many physiological processes in fishes. Thus, the review deals with the influences of changes in different environmental factors, such as food availability, temperature, photoperiod, season, salinity and EDCs, on GH gene expression in pituitary, IGF-I gene expression in liver and extrahepatic sites and the physiological effects resulting from the evoked alterations in endocrine and local IGF-I. Environmental influences certainly interact with each other but for convenience of the reader they will be dealt with in separate sections. Current trends in GH-IGF-I research are analysed and future focuses are suggested at the end of the sections.

Oxidative stress in MCF-7 cells is involved in the effects of retinoic acid-induced activation of protein kinase C-δ on insulin-like growth factor-I secretion and synthesis

It is known that all- trans retinoic acid (RA) is a useful therapeutic anticancer agent in breast cancer that acts by inducing apoptosis and growth inhibition. Insulin-like growth factor-I (IGF-I) is also known to be a growth hormone that plays an important role in cell proliferation and apoptosis. We examined the relationships between RA-induced protein kinase C (PKC)-δ, the secretion and synthesis of IGF-I, and oxidative stress. RA at 10 −8 M and 10 −7 M increased PKC-δ phosphorylation (the ratio of phosphorylated to total PKC-δ) ( p < 0.05) and decreased the secretion and synthesis of IGF-I ( p < 0.05) compared to control, with the effects peaking for treatment with 10 −7 M RA for 72 h. The silencing of PKC-δ prevented the RA-induced inhibition of the secretion and synthesis of IGF-I and cell viability ( p < 0.05). Application of 10 −7 M RA for 72 h increased the level of thiobarbituric-acid-reactive substances and the expression of inducible nitric oxide synthase relative to control ( p < 0.05). These increases were blocked by suppressing PKC-δ and by pretreatment with the antioxidants glutathione and diphenyleneiodonium ( p < 0.05). These antioxidants also reversed the RA-induced inhibition of the secretion and synthesis of IGF-I and cell viability to control levels ( p < 0.05). The effects of suppressing IGF-I demonstrate that IGF-I plays a critical role in the RA-induced inhibition of the cell viability. These results indicate that the anticancer effects of RA are mediated by inhibition of the secretion and synthesis of IGF-I, and involve a PKC-δ-dependent mechanism, and they provide evidence of an interaction between PKC-δ and reactive oxygen species.

Insulin‐like growth factor I messenger RNA and protein are expressed in the human lymph node and distinctly confined to subtypes of macrophages, antigen‐presenting cells, lymphocytes and endothelial cells

Insulin-like growth factor I (IGF-I) is a potent hormone that stimulates growth and differentiation and inhibits apoptosis in numerous tissues. Preliminary evidence suggests that IGF-I exerts differentiating, mitogenic and restoring activities in the immune system but the sites of synthesis of local IGF-I are unknown. Identification of these sites would allow the functional role of local IGF-I to be clarified. The presence of IGF-I in non-immune cells suggests that it acts as a trophic factor, while its occurrence in subtypes of lymphocytes or antigen-presenting cells indicates paracrine/autocrine direct regulatory involvement of IGF-I in the human immune response. The present study investigated the location of IGF-I messenger RNA and protein on archival human lymph node samples by in situ hybridization, immunohistochemistry and double immunofluorescence staining using an IGF-I probe and antisera specific for human IGF-I and CD3 (T lymphocytes), CD20 (B lymphocytes), CD68 (macrophages), CD21 (follicular dendritic cells), S100 (interdigitating dendritic cells) and podoplanin (fibroblastic reticular cells). Numerous cells within the B- and T-cell compartments expressed the IGF-I gene, and the majority of these cells were identified as macrophages. Solitary follicular dendritic cells exhibited IGF-I. A few T lymphocytes, and no B lymphocytes, contained IGF-I immunoreactive material. Furthermore, IGF-I immunoreactive cells outside the follicles that did not react with CD3, CD20, S100 or podoplanin markers were identified as high-endothelial venule (HEV) cells. From this we conclude that the main task of IGF-I in human non-tumoral lymph node may be autocrine and paracrine regulation of the differentiation, stimulation and survival of lymphocytes, antigen-presenting cells and macrophages and the differentiation and maintenance of HEV cells.

IGF-I measurements in the diagnosis of adult growth hormone deficiency

Although serum insulin-like growth factor I (IGF-I) concentrations have utility as a screening test for growth hormone (GH) deficiency in children and young adults, they are less accurate for screening in adults over 40 years of age. There are two main limitations in the clinical use of IGF-I levels as a marker of GH secretion. First, IGF-I synthesis is not only regulated by GH but also by nutrient supply and by other hormones; second, low IGF-I levels in the presence of normal or increased GH secretion may reflect a peripheral resistance to GH action. Although serum IGF-I cannot be used as a stand-alone test for the diagnosis of adult GH deficiency, very low IGF-I levels in the context of documented hypothalamic or pituitary disease may be helpful in identifying patients with a high probability of GH deficiency. In the presence of two or more additional pituitary hormone deficiencies, an IGF-I level <84 microg/l (assayed by Esoterix Endocrinology, Inc. Calabasas Hills, CA, USA) indicates a 99% probability of GH deficiency. As this cut-off value has not been validated for other IGF-I assays, an IGF-I standard deviation score (SDS) of <-3 may be considered in adults over age 28; an even lower IGF-I SDS is needed for diagnosis in younger adults. In clinical practice, other causes of low serum IGF-I such as malnutrition, diabetes, hypothyroidism, liver disease, etc., should be excluded before applying these diagnostic criteria.

Serum Concentrations of Insulin-Like Growth Factor-I (IGF-I) as a Marker of Liver Fibrosis in Patients With Chronic Hepatitis C

Liver biopsy was until recently the only way of evaluating liver fibrosis. Noninvasive tests for hepatic fibrosis, without potential risks, are desired by clinicians as well as patients. Insulin-like growth factor-I (IGF-I) synthesis is disturbed in liver fibrosis and reflects the severity of the clinical stage. We assessed serum IGF-I levels in patients with chronic hepatitis C (CHC) to correlate with liver fibrosis and antiviral therapy. Forty patients with CHC and persistently abnormal alanine aminotransferase values were enrolled and treated with peginterferon alpha-2a 180 microg per week plus ribavirin for 24 (n=20) or 48 (n=20) weeks. All patients underwent liver biopsy before treatment (METAVIR fibrosis stage F0, n=13; F1-F2, n=14; F3, n=7; F4, n=6). Serum IGF-I was measured at baseline, at the end of treatment period, and 24 weeks after finishing treatment. Mean IGF-I values were significantly lower in patients with advanced fibrosis (F4, 65.9+/-17.9 ng/mL) than in the others (F0, 145.2+/-47.1; F1-F2, 150.3+/-89.6; and F3, 121.4+/-35.2 ng/mL; P < .05). Serum IGF-I levels increased during combined therapy, being this increment markedly higher in patients with sustained virologic response. In conclusion, IGF-I synthesis is disturbed in CHC and reflects the severity of the liver fibrosis. Combined therapy improves serum IGF-I levels. IGF-I could represent a good, noninvasive marker of liver fibrosis.

Modulation of circulating IGF-I and IGFBP-3 levels by hormonal regulators of energy homeostasis in obese children

Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are key factors in the control of somatic growth. Recent work revealed a critical role for the transcription factor STAT5b in GH stimulated IGF-I gene expression. In obesity, the normal regulation of the GH/IGF-I axis is disturbed, with normal levels of circulating IGF-I despite blunted GH secretion. We hypothesized that leptin or other hormonal regulators of energy homeostasis, which can activate Stat5b-regulated gene expression or exert an effect on GH secretion, might be able to substitute for GH in terms of IGF-I synthesis. Thus, the aim of this study was to identify potential regulators of IGF-I serum levels in obesity with a particular focus on the interaction of leptin and IGF-I. In a cross-sectional study, we measured hormonal and auxiological parameters in 99 obese children who were referred to our obesity outpatient clinic and analysed correlations between unadjusted hormone levels and between hormone concentrations expressed as SDS values, adjusted for sex, age, and/or puberty and BMI. Serum concentrations of IGF-I correlated highly significant with IGFBP-3, leptin, fasting ghrelin and insulin (p<0.001). However, when expressing hormone levels as SDS values, only leptin SDS and IGFBP-3 SDS correlated significantly with IGF-I SDS (p<0.01). This correlation between leptin SDS and IGF-I SDS was more pronounced in prepubertal and in male subjects, with increasing IGF-I SDS values paralleling an increase in leptin SDS tertiles in prepubertal subjects. In linear regression analyses, leptin SDS, IGFBP-3 SDS and BMI SDS contributed significantly to the variation of IGF-I SDS values, and explained 53.3% of the variability of IGF-I SDS levels in male subjects. In summary, we demonstrated a strong correlation of age and sex-adjusted standard deviation scores (SDS) for IGF-I and leptin in obese children, which is modulated by sex, pubertal stage and body weight. Whether this association results from a direct induction of hepatic IGF-I gene expression by leptin or reflects a more complex interrelationship between IGF-I and obesity-related factors should be subject of future research.

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.

The Role of Insulin-Like Growth Factor I Components in the Regulation of Vitamin D

Several factors are known to be involved in the regulation of vitamin D and sunlight and diet are the two sources in humans, but the relative importance of each of them is not well defined. Vitamin D, parathyroid hormone and serum insulin-like growth factor-I (IGF-I) were found to be independent predictors of total bone density. Thus, the growth hormone (GH)/IGF-I is thought to play an important role in the regulation of bone mineral density and the skeleton is second only to the liver as a source of circulating levels of IGF-I. The mechanisms by which IGF-I may influence bone metabolism is not fully understood but they are a predictor of bone mass density and are positively associated with vitamin D concentrations. There is a physiological decline of the GH/IGF axis with ageing. The high affinity IGF-binding proteins (IGFBP-I to 6) have also been involved in IGF-I regulation, and it is important to include the IGF-independent properties, particularly those of IGFBP3 that may be involved in the osteoblastic differentiation observed in human bone marrow stromal cell cultures. These hormones have been shown to up regulate each other. 1,25-(OH) D(3) has been shown to promote the action of IGF-I by increasing IGF-I receptors and IGF-I can also elevate 1,25-(OH) D(3) concentrations by stimulating the hydroxylation of 25-(OH) D(3) in the active 1,25-(OH) D(3) hormone. Both GH and IGF-I significantly increased renal 1alpha-hydroxylase expression and serum 1, 25-(OH) D(3) concentrations. In prostate cells, 1,25-(OH) D(3) is growth inhibitory for many established cell lines and the role of IGFBPs, especially IGFBP-3, can be growth inhibitory or stimulatory and IGFBP-3 expression increases in response to 1,25-(OH) D(3), or its analogs, in established prostate cancer cell lines. Body fat is inversely associated with 25-(OH) D(3) in relation to with anthropometric measures, indicating a specific role of adipose tissue. IGF-I may be involved in both normal and abnormal fetal growth and stimulation of IGF-I synthesis during normal pregnancy may be associated with an increase in GH production by the placenta. Thus, maternal and umbilical cord serum IGF-I and 1,25-(OH) D(3) concentrations are lower in preeclampsia and umbilical cord serum IGF-I, IGFBP-1 and IGFBP-3 concentrations are associated with low newborn birth weights.

Anti-tumor necrosis factor agent PEG-sTNFRI improves the growth hormone/insulin-like growth factor-I system in adjuvant-induced arthritic rats

Adjuvant-induced arthritis is associated with body weight loss and decreased pituitary growth hormone (GH) and hepatic insulin-like growth factor-I (IGF-I) synthesis. Cytokines as tumor necrosis factor (TNF) mediate wasting associated with chronic inflammation. The aim of this study was to analyse whether the inhibition of TNF is able to revert the decrease in the body weight and the GH/IGF-I axis in arthritic rats. Male Wistar rats were injected with Freund's adjuvant, and 15 days later arthritic and control rats were daily injected with polyethylene glycol linked to soluble TNF receptor p55 (PEG-sTNFRI) (1 mg/kg, s.c.) or saline for 8 days. There was a significant decrease in pituitary GH mRNA ( P < 0.05), hepatic IGF-I mRNA ( P < 0.01) and serum concentrations of IGF-I ( P < 0.01) in arthritic rats. The 8-day administration of PEG-sTNFRI resulted in an increase in food intake ( P < 0.05) and body weight gain ( P < 0.01) in arthritic but not in control rats. There was an increase in pituitary GH mRNA after PEG-sTNFRI treatment both in control and in arthritic rats. There was a significant increase in IGF-I serum concentrations ( P < 0.05) and hepatic IGF-I mRNA expression ( P < 0.05) in control rats treated with PEG-sTNFRI, whereas the effect of this anti-TNF agent in arthritic rats was only statistically significant in hepatic IGF-I mRNA expression ( P < 0.05). These data suggest that TNF seems to be involved in the decrease in GH and IGF-I synthesis in arthritic rats.

Serum insulin-like growth factor I in brain function

Insulin-like growth factor I (IGF-I) is present at high concentrations in the circulation. Tissue-specific genetic ablation has shown that the majority of serum IGF-I is secreted by liver cells, although all major organs synthesize it. IGF-I is an important signal during development, including brain growth. Although the biological role of IGF-I in organs such as muscle or ovary is reasonably well established, its biological significance in the adult brain is far from clear. In this regard, while local IGF-I synthesis decreases during brain development, protein levels remain relatively constant throughout life until old age, where a decline is found, not only in the brain but also in the bloodstream. This mismatch between declining local synthesis early after birth and steady protein levels may be explained by the ability of serum IGF-I to access the brain across the blood-brain-barrier. This peripheral IGF-I input to the brain is a physiologically meaningful process of potential impact in brain diseases. Numerous brain mechanisms are regulated by serum IGF-I. Many of these, such as cell energy modulation or growth and survival are common to other IGF-I target tissues but there are also a number of brain-specific mechanisms regulated by IGF-I which likely underlie the ability of serum IGF-I to modulate the major function of the brain: cognition. We propose that serum IGF-I forms part of the mechanisms involved in the "cognitive reserve" concept of brain responses to homeostasis breakdown. Based on IGF-I pleiotropy not only in brain but elsewhere, we consider that loss of IGF-I function is an important step towards disease.