Bioavailability Of Insulin-like Growth factor-I Research Articles

Maternal hormones linking maternal body mass index and dietary intake to birth weight

BackgroundObese women often give birth to large-for-gestational age infants (typically defined as a birth weight greater than the 90th percentile), who are at risk of birth injuries and of developing metabolic syndrome later in life. The mechanisms underlying increased fetal growth remain to be established. ObjectiveWe aimed to identify maternal hormones that can explain the link between dietary intake, body mass index (BMI), and birth weight. DesignPregnant women with BMIs (in kg/m2) ranging from 17 to 44 (n = 49) were recruited in gestational weeks 8–12. Serum hormone concentrations were measured and dietary history interviews were performed in the first and third trimesters. Multiple regression models were produced to identify hormones that correlate with birth weight and are influenced by BMI or dietary factors. ResultsWe found a strong positive correlation between BMI and first- and third-trimester insulin and leptin concentrations and a negative correlation between BMI and first-trimester adiponectin and first- and third-trimester insulin-like growth factor binding protein-1 (IGFBP-1). Maternal total fat intake in the first trimester was positively correlated with maternal leptin and inversely correlated with adiponectin. In addition, third-trimester total fat intake was positively correlated with circulating resistin concentrations. First-trimester maternal serum resistin was positively correlated with birth weight, whereas third-trimester maternal IGFBP-1 was negatively correlated with birth weight. ConclusionsHigh first-trimester maternal serum resistin and low third-trimester IGFBP-1 were correlated with increased birth weight. We propose that low serum concentrations of IGFBP-1 represent a link between high BMI and increased fetal growth by increasing the bioavailability of insulin-like growth factor-I, which up-regulates placental nutrient transport.

Raised serum levels of matrix metalloproteinase-9 in women with polycystic ovary syndrome and its association with insulin-like growth factor binding protein-1

Background. It has been suggested in recent studies that matrix metalloproteinases (MMPs) may be implicated in the pathogenesis of polycystic ovary syndrome (PCOS) through regulating ovarian tissue remodeling. In addition to degrading the extracellular matrix, MMPs exhibit the ability to cleave insulin-like growth factor binding protein-1 (IGFBP-1), the major regulator of insulin-like growth factor-I (IGF-I) in serum. The present study aimed to investigate the possible role of MMPs in the pathophysiology of PCOS.Methods. Serum levels of MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), IGF-I and IGFBP-1 were measured in 42 patients with PCOS and 30 healthy women with regular menstruation, matched for age and body mass index. Correlation between IGFBP-1 and other parameters in the PCOS group was analyzed by Pearson's linear correlations.Results. Serum MMP-9 concentrations and MMP-9/TIMP-1 ratios were significantly higher in PCOS women than in controls. Serum levels of IGFBP-1 were markedly lower in the PCOS group. There was a negative correlation between serum IGFBP-1 and MMP-9 in women with PCOS.Conclusion. Our results raise the possibility that MMPs may be implicated in the pathophysiology of PCOS either by regulating ovarian tissue remodeling or indirectly by facilitating IGF-I bioavailability through proteolysis of IGFBP-1.

Intradialytic parenteral nutrition abolishes the increase of insulin-like growth factor binding protein-1 (IGFBP-1) during hemodialysis and elevates the IGF-I/IGFBP-1 ratio, an anticatabolic effect?

Summary Background Malnutrition is a severe clinical problem in hemodialysis (HD) patients. We have earlier shown that insulin-like growth factor binding protein-1 (IGFBP-1) increases during HD and may thus limit the bioavailability of free insulin-like growth factor-I (IGF-I). The present study was performed with the aim to test if intradialytic parenteral nutrition (IDPN) would influence the IGF system in HD patients with the hypothesis that IDPN would attenuate the increase of IGFBP-1 and thus alter the IGF system to give a more anticatabolic effect. Methods Nine HD patients aged 69±3 years were studied during one HD session with IDPN and one without IDPN. The nutritional product used contained 1000 kcal (1000 ml, 53 g amino acids, 75 g glucose and 50 g long chain triglycerides—soybean oil). Blood samples were collected pre- and post-dialysis. Serum concentrations of IGF-I, insulin and IGFBP-1 were determined by RIA. Results During HD without IDPN serum levels of IGFBP-1 increased from 84±21 to 139±26 μg/l ( p =0.01). In contrast IGFBP-1 tended to decrease from 126±37 to 85±18 μg/l ( p =0.087) during HD with IDPN. The difference between post- and pre-HD IGFBP-1 was significantly larger without IDPN than with IDPN (+55±17 vs. −41±21 μg/l, p =0.0056). The ratio IGF-I/IGFBP-1, indicative of free IGF-I, decreased significantly during HD without IDPN (4.5±1.6 vs. 2.8±1.1 p =0.02). In contrast, during IDPN this ratio tended to increase from 2.6±1.0 to 4.3±1.7 ( p =0.059). The difference between post- and pre-HD was −1.7±0.5 without IDPN vs. 1.6±0.7 μg/l with IDPN ( p =0.022). Without IDPN the change in IGF-I was non-significant during HD but on IDPN IGF-I serum levels increased significantly from 156±35 to 193±44 μg/l ( p =0.004). The serum levels of insulin differed significantly during HD with a decrease without IDPN and an increase with IDPN (−17±7 vs. +19±8 μg/l p =0.009). Glucose levels decreased without IDPN but remained unchanged with IDPN (5.9±0.9 to 4.1±0.4 mmol/l p =0.021 vs. 5.8±0.8 to 6.1±0.9 mmol/l NS). Conclusions IDPN blunts the increase of IGFBP-1 and the IGF-I/IGFBP-1 ratio increases. The increased IGF-I bioavailability suggests an anticatabolic effect.

Binding of ADAM28 to P-selectin Glycoprotein Ligand-1 Enhances P-selectin-mediated Leukocyte Adhesion to Endothelial Cells

ADAMs (a disintegrin and metalloproteinases) are a recently discovered gene family of multifunctional proteins with the disintegrin-like and metalloproteinase domains. To analyze the biological functions of ADAM28, we screened binding molecules to secreted-type ADAM28 (ADAM28s) by the yeast two-hybrid system and identified P-selectin glycoprotein ligand-1 (PSGL-1). Binding between the disintegrin-like domain of ADAM28s and the extracellular portion of PSGL-1 was determined by yeast two-hybrid assays, binding assays of the domain-specific recombinant ADAM28s species using PSGL-1 stable transfectants and leukocyte cell lines expressing native PSGL-1 (HL-60 cells and Jurkat cells), and co-immunolocalization and co-immunoprecipitation of the molecules in these cells. Incubation of HL-60 cells with recombinant ADAM28s enhanced the binding to P-selectin-coated wells and P-selectin-expressing endothelial cells. In addition, intravenous injection of ADAM28s-treated HL-60 cells increased their accumulation in the pulmonary microcirculation and alveolar spaces in a mouse model of endotoxin-induced inflammation. These data suggest a novel function that ADAM28s promotes PSGL-1/P-selectin-mediated leukocyte rolling adhesion to endothelial cells and subsequent infiltration into tissue spaces through interaction with PSGL-1 on leukocytes under inflammatory conditions.

Variations in Biological and Immunological Activity of Growth Hormone during the Neonatal Period

Background/Aims: It was postulated that a high growth hormone (GH) bioactivity might explain the rapid growth rate of neonates. The aim of this study is to verify changes in serum GH biological potency (Bio-/Immuno-GH ratio) and their effects on serum growth factors during the first month of life in term and preterm babies. Methods: Blood samples were collected from 10 small-for-gestational-age preterm (SGAPT), 17 appropriate for gestational age preterm (AGAPT) and 26 AGA term (T) neonates on days 4, 15 and 30 of life to evaluate serum GH values measured by IFMA (IFMA-GH) and bioassay (Bio-GH), serum insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3). Results: High serum Bio-GH values on the first few days of life correspond to high IFMA-GH values, suggesting full biological potency of circulating GH. Furthermore, IGF-I/IGFBP-3 molar ratio values in preterm babies were higher than in full-term infants. Conclusions: These data confirmed the hypothesis that the higher growth velocity in the first month of life of preterm neonates is due to an increased bioavailability of IGF-I. A progressive maturation of the hypothalamic-pituitary-IGF-I axis without any alteration in the GH biological potency seems to underpin the increase of the growth factors early in life.

Serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) in IVF patients with polycystic ovary syndrome: correlations with outcome

To evaluate serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) levels during stimulation in polycystic ovary syndrome (PCOS) and control populations as factors predictive of IVF outcome. Observational study. Academic medical center-based IVF practice. Forty-three PCOS and 33 male-factor control patients undergoing IVF from 2002 to 2004. Treatment with a dual suppression protocol incorporating oral contraceptive pills (OCPs) and GnRH agonist suppression followed by low-dose gonadotropin therapy. The PCOS and control patients' serum IGF-I and IGFBP-3 levels were compared and correlated with IVF outcome. PCOS and control patients were comparable in terms of demographics and IVF outcome. In both, mean serum IGF-I levels increased during stimulation. PCOS patients whose IGF-I levels decreased from day 3 to day of hCG had a significantly higher mean number of immature oocytes retrieved (4.8 +/- 1.1 vs. 2.4 +/- 0.4; P=.02). IGFBP-3 levels increased during stimulation in PCOS patients but tended to decrease in control patients. In PCOS patients, an increase in IGFBP-3 levels during stimulation was associated with a greater likelihood of becoming pregnant (P=.03) and of ongoing pregnancy (P=.02). The bioavailability of IGF-I appears to play a key role in oocyte maturation in PCOS patients. Alterations in IGFBP-3 concentration during stimulation may be a critical mechanism in modulating IGF-I activity.

Plasma C‐peptide, insulin‐like growth factor‐I, insulin‐like growth factor binding proteins and risk of colorectal cancer in a nested case‐control study: The Japan public health center‐based prospective study

The physical inactivity and obesity involved in hyperglycemia and hyperinsulinemia is supposed to lead to an increased bioavailability of insulin-like growth factor-I (IGF-I). The carcinogenic effect of IGF-I may be influenced by IGF binding proteins. We investigated the association between plasma levels of C-peptide, a surrogate biomarker of insulin, IGFBP-1, IGF-I or IGFBP-3, and the risk of colorectal cancer in a nested case-control study. During an 11.5-year follow-up, 375 newly diagnosed colorectal cancers were identified in a cohort of 38,373 adults who had returned the baseline questionnaire and provided blood samples. Two matched-controls for each case were selected from the cohort. The odds ratio (OR) of colorectal cancer for plasma levels of each protein was estimated using the conditional logistic regression model adjusted for potential confounding factors. We observed a statistically significant association of plasma C-peptide with colorectal cancer only in men. The ORs were 1.0, 2.3, 2.8 and 3.2 along with quartiles (p trend, 0.0072). The association was stronger in colon cancer (p trend, 0.025) than in rectal cancer (p trend, 0.24). Other peptides were not associated with the risk in either men or women. The results did not change when repeatedly analyzed by tumor invasion levels, tumor sites or follow-up periods. In conclusion, a higher plasma C-peptide may indicate a subsequent risk of colorectal cancer in Japanese men.

The ABCs of IGF-I isoforms: impact on muscle hypertrophy and implications for repair

Insulin-like growth factor I (IGF-I) plays a critical role in the growth and development of many tissues in the body. It is a key regulator of skeletal muscle development, and continues to enhance the ability for muscle to grow and undergo repair throughout life. Although the focus of research has been on the molecular actions and physiological impact of IGF-I, there has also been a growing undercurrent of studies geared toward the characterization of additional potentially active peptides produced by the igf1 gene. Alternative splicing of the gene results in multiple isoforms that retain the identical sequence for mature IGF-I, but also give rise to divergent C-terminal peptides. The peptides might modulate the actions, stability, or bioavailability of IGF-I, or they might have independent activity. These possibilities have gained the attention of the skeletal muscle field, where novel actions of IGF-I could have significant impact on muscle mass, strength, and repair.

ADAM28 Is Overexpressed in Human Breast Carcinomas: Implications for Carcinoma Cell Proliferation through Cleavage of Insulin-like Growth Factor Binding Protein-3

A disintegrin and metalloproteinases (ADAMs) are involved in various biological events including cell adhesion, cell fusion, membrane protein shedding, and proteolysis. In the present study, our reverse transcription-PCR analysis showed that among the 12 different ADAM species with a putative metalloproteinase motif, prototype membrane-anchored ADAM28m and secreted-type ADAM28s are selectively expressed in human breast carcinoma tissues. By real-time quantitative PCR, their expression levels were significantly higher in carcinomas than in nonneoplastic breast tissues. In situ hybridization, immunohistochemistry, and immunoblotting analyses indicated that ADAM28 is predominantly expressed in an active form by carcinoma cells within carcinoma tissues. A direct correlation was observed between mRNA expression levels and proliferative activity of the carcinoma cells. Treatment of ADAM28-expressing breast carcinoma cells (MDA-MB231) with insulin-like growth factor-I (IGF-I) increased cell proliferation, cleavage of IGF binding protein (IGFBP)-3, as well as IGF-I cell signaling; these processes were all significantly inhibited by treatment with ADAM inhibitor or anti-ADAM28 antibody. Down-regulation of ADAM28 expression in MDA-MB231 cells with small interfering RNA significantly reduced cell proliferation, IGFBP-3 cleavage, and growth of xenografts in mice. In addition, cleavage of IGFBP-3 in breast carcinoma tissues was correlated with ADAM28 expression levels and inhibited by treatment with ADAM inhibitor or anti-ADAM28 antibody. These results show that ADAM28 is overexpressed in an activated form in human breast carcinoma cells and suggest that ADAM28 is involved in cell proliferation through enhanced bioavailability of IGF-I released from the IGF-I/IGFBP-3 complex by selective IGFBP-3 cleavage in human breast carcinomas.

Impact of treatment with recombinant human GH and IGF-I on visceral adipose tissue and glucose homeostasis in adults

Supraphysiological doses of growth hormone (GH) therapy are generally thought to antagonize the effects of insulin, whereas the insulin-like growth factor I (IGF-I) potentiates insulin-like actions. Paradoxically, adults with GH deficiency and patients with acromegaly are both predisposed to glucose intolerance and insulin resistance; however, one cannot extrapolate from these pathological conditions to determine the true metabolic roles of GH and IGF-I in glucose homeostasis. Growth hormone also promotes lipolysis, which has been shown to be the principal determinant of its insulin-antagonistic properties; on the other hand, IGF-I, which acts as an insulin sensitizer, does not exert any direct effect on lipolysis or lipogenesis. Under physiological conditions, the insulin-sensitizing effect of IGF-I is evident only after feeding, when the bioavailability of circulating IGF-I is increased. In contrast to supraphysiological GH doses, low doses of GH treatment have been shown to increase circulating IGF-I levels and IGF-I bioavailability and, thus, may theoretically enhance insulin sensitivity without inducing lipolysis. We have recently reported that a fixed administration of a very low GH dose (1.7 μg/kg/day or 0.1 mg/day) improved insulin sensitivity in adults with GH deficiency and increased peripheral glucose uptake in subjects with impaired glucose tolerance and the metabolic syndrome. Our data raise the possibility that this very low GH dose may play a role in maintaining β-cell function and possibly delay the progression to type 2 diabetes in these high-risk patients.

Body mass index, waist circumference and waist–hip ratio and serum levels of IGF-I and IGFBP-3 in European women

To examine the relationship between body mass index (BMI) and waist-hip ratio (WHR) with serum levels of insulin-like growth factor-I (IGF-I), and its binding protein (IGFBP)-3. Cross-sectional study on 2139 women participating in a case-control study on breast cancer and endogenous hormones. Data on lifestyle and reproductive factors were collected by means of questionnaires. Body height, weight, waist and hip circumferences were measured. Serum levels of IGF-I and insulin-like binding protein (IGFBP)-3 were measured by enzyme-linked immunosorbent assays. Adjusted mean levels of IGF-I and IGFBP-3 across quintiles of BMI, waist circumference, and WHR were calculated by linear regression. Results were adjusted for potential confounders associated with IGF-I and IGFBP-3. Adjusted mean serum IGF-I values were lower in women with BMI<22.5 kg/m(2) or BMI>29.2 kg/m(2) compared to women with BMI within this range (P(heterogeneity)<0.0001, P(trend)=0.35). Insulin-like growth factor-I was not related to WHR after adjustment for BMI. IGF-binding protein-3 was linearly positively related to waist and WHR after mutual adjustment. The molar ratio IGF-I/IGFBP-3 had a non-linear relation with BMI and a linear inverse relationship with WHR (P (trend)=0.005). Our data confirm the nonlinear relationship of circulating IGF-I to total adiposity in women. Serum IGFBP-3 was positively related to central adiposity. These suggest that bioavailable IGF-I levels could be lower in obese compared to non-obese women and inversely related to central adiposity.

Age Differences In IGF-I System Responses To Resistance Loading In Human Skeletal Muscle

Skeletal muscle insulin-like growth factor-I (IGF-I) is an autocrine/paracrine factor that is mitogenic to satellite cells and increases protein synthesis in the mature myofiber. We have previously shown in young adults that resistance loading (RL) acutely increases IGF-I and suppresses IGF binding protein-4 (BP4) mRNA levels, presumably leading to greater amounts of bioavailable tissue IGF-I. PURPOSE We tested the hypothesis that age and gender would affect acute RL responses of local IGF-I system components including IGF-I, IGFBP4, and the type 1 IGF receptor (IGFR1) in young (Y) and older (O) males (M) and females (F). METHODS Twenty Y (20–35 yr, 10 YF, 10 YM) and 18 O (60–75 yr, 9 OF, 9 OM) consented to vastus lateralis biopsy before and 24h after a bout of RL (3 sets × 8–12 repetitions to volitional fatigue of squat, leg press, knee extension). Gene expression levels were determined by relative RT-PCR with 18S as an internal standard and analyzed by age × gender × load repeated measures ANOVA. RESULTS A main load effect was found for IGF-I (+34%, p < 0.01), and post hoc testing within groups revealed that the increase was mainly driven by O (+48%, p < 0.05) and M (+43%, p < 0.05). For IGFR1, an age × load interaction (p < 0.05) resulted from a 16% increase in O after RL with no change in Y. A main age effect (p < 0.01) was found for IGFBP4, as higher levels were noted in O (17%). CONCLUSIONS While acute RL increased IGF-I and IGFR1 mRNAs in O, higher levels of IGFBP4 in O may inhibit IGF-I mediated actions and may play a role in attenuating myofiber hypertrophy in older vs. younger adults. Supported by NIH Grant R01 AGI7896 and GCRC M01 RR00032

Age Differences In IGF-I System Responses To Resistance Loading In Human Skeletal Muscle

Skeletal muscle insulin-like growth factor-I (IGF-I) is an autocrine/paracrine factor that is mitogenic to satellite cells and increases protein synthesis in the mature myofiber. We have previously shown in young adults that resistance loading (RL) acutely increases IGF-I and suppresses IGF binding protein-4 (BP4) mRNA levels, presumably leading to greater amounts of bioavailable tissue IGF-I. PURPOSE We tested the hypothesis that age and gender would affect acute RL responses of local IGF-I system components including IGF-I, IGFBP4, and the type 1 IGF receptor (IGFR1) in young (Y) and older (O) males (M) and females (F). METHODS Twenty Y (20–35 yr, 10 YF, 10 YM) and 18 O (60–75 yr, 9 OF, 9 OM) consented to vastus lateralis biopsy before and 24h after a bout of RL (3 sets × 8–12 repetitions to volitional fatigue of squat, leg press, knee extension). Gene expression levels were determined by relative RT-PCR with 18S as an internal standard and analyzed by age × gender × load repeated measures ANOVA. RESULTS A main load effect was found for IGF-I (+34%, p < 0.01), and post hoc testing within groups revealed that the increase was mainly driven by O (+48%, p < 0.05) and M (+43%, p < 0.05). For IGFR1, an age × load interaction (p < 0.05) resulted from a 16% increase in O after RL with no change in Y. A main age effect (p < 0.01) was found for IGFBP4, as higher levels were noted in O (17%). CONCLUSIONS While acute RL increased IGF-I and IGFR1 mRNAs in O, higher levels of IGFBP4 in O may inhibit IGF-I mediated actions and may play a role in attenuating myofiber hypertrophy in older vs. younger adults. Supported by NIH Grant R01 AGI7896 and GCRC M01 RR00032

IGF-I andIGFBP-3 polymorphisms and risk of prostate cancer

Insulin-like growth factor-I (IGF-I) is a potent mitogen for both normal and malignant prostate epithelial cells. The majority of circulating IGF-I is bound in a complex with IGF binding protein-3 (IGFBP-3), which in turn limits IGF-I bioavailability. Multiple studies suggest that higher IGF-I and/or lower IGFBP-3 serum levels are positively associated with prostate cancer risk. Several polymorphisms within the IGF-I and IGFBP-3 coding regions have been associated with increased serum protein levels. To ascertain the potential relationship between serum levels and polymorphism, and prostate cancer risk, we investigated the role of two polymorphisms the IGF-I cytosine-adenosine (CA)-repeat and the IGFBP-3 Ala32Gly, and prostate cancer in a population-based, case-control, study of middle-aged men. We found no significant association between the IGFBP-3 Ala32Gly polymorphism and prostate cancer risk, even though the presence of at least one Gly allele did correlate with increased serum levels of IGFBP-3. For IGF-I, more controls (42%) than cases (38%) were homozygous for 19-CA-repeats (odds ratio, OR = 0.85; 95% confidence interval (CI) = 0.66-1.09). After stratifying by disease characteristics, 19-CA-repeat homozygous men displayed a decreased risk of low-grade disease (OR = 0.50; 95% CI = 0.27-0.93), but no associations were observed with more aggressive features of disease. Additionally, there was no correlation between mean serum IGF-I protein levels and IGF-I genotype in controls. Further evaluation of the IGF-I CA-repeat polymorphism and prostate cancer is necessary to determine if the modest risk reduction associated with the 19-CA-repeat homozygous state is observed in other study populations.

Decreased expression of the insulin-like growth factor-I-binding protein-1 (IGFBP-1) phosphoisoform in pre-eclamptic Wharton's jelly and its role in the regulation of collagen biosynthesis.

Insulin-like growth factor-I (IGF-I) is known as an important stimulator of collagen and glycosaminoglycans (GAGs) biosynthesis in tissues. IGF-I activity is under control of IGF-I-binding proteins (IGFBPs) with different IGF-I-binding affinity. IGFBP-1 is known as an inhibitor of IGF-dependent functions. Some IGFBPs (e.g., IGFBP-1) may undergo phosphorylation that dramatically increases IGFBP affinity for IGF. Wharton's jelly represents a reservoir of IGF-I and its binding proteins (BPs). Pre-eclampsia, the most common, pregnancy-associated pathological syndrome, contributes to a significant decrease in IGF-I and IGFBP-1 content in Wharton's jelly, although it does not affect collagen content in this tissue. In the present study we show that control Wharton's jelly contains phosphorylated forms of IGFBP-1 that are dramatically dephosphorylated during pre-eclampsia. A dramatic decrease in IGF-I binding to immunoprecipitated IGFBP-1 from pre-eclamptic Wharton's jelly compared to the control was observed. Western immunoblot analysis with anti-phosphothreonine antibodies for immunoprecipitated IGFBP-1 from control and pre-eclamptic Wharton's jelly revealed that both tissues contain phosphorylated forms of IGFBP-1. However, a distinct decrease in the expression of phosphorylated IGFBP-1 from pre-eclamptic Wharton's jelly was observed. The functional significance of the phenomenon was found in cultured fibroblasts treated with IGFBP isolated from Wharton's jelly extracts. A significant decrease in collagen biosynthesis was found in the cells treated with IGFBP of control Wharton's jelly, while in the presence of IGFBP from pre-eclamptic Wharton's jelly, the rate of collagen biosynthesis was similar to that in the control cells. The result was corroborated by data showing increase in expression of IGF-I receptor and phosphorylated MAP kinases (ERK1 and ERK2) in fibroblasts cultured in the presence of IGFBP from pre-eclamptic Wharton's jelly, compared to control. The data suggest that the decrease in phosphorylated IGFBP-1 in pre-eclamptic Wharton's jelly may decrease IGF-I-binding affinity for IGF and increase the bioavailability of IGF-I for receptor interaction. This mechanism may facilitate IGF-I-dependent stimulation of fibroblasts to produce extracellular matrix (ECM) components even at a low IGF-I tissue level. Therefore, IGFBP-1 phosphoisoforms in Wharton's jelly may play an important role in the regulation of IGF-I-dependent functions during pre-eclampsia.

Modulation of brain insulin-like growth factor I (IGF-I) binding sites and hypothalamic GHRH and somatostatin levels by exogenous growth hormone and IGF-I in juvenile rats.

The effect of exogenous growth hormone (GH) and insulin-like growth factor I (IGF-I) on brain IGF-I binding sites (IGF-IR), and on the levels of growth hormone-releasing hormone (GHRH) and somatostatin was studied in hypophysectomized and intact juvenile male rats. Animals were injected subcutaneously twice daily (n = 5 each) with recombinant GH (rGH) (2.5 U/kg per day) or rIGF-I (500 microg/kg per day). In the hypophysectomized rats, serum GH and IGF-I levels were markedly suppressed and IGF-I levels were partially restored by GH treatment. There was a significant increase in IGF-IR binding capacity in the IGF-I-treated hypophysectomized rats compared to the saline-treated hypophysectomized animals (150.61 +/- 45.66 vs 41.32 +/- 12.42 fmol/mg, p < 0.05) but no significant difference in IGF-IR mRNA levels. GHRH levels in the saline-treated hypophysectomized group were significantly lower than in the saline-treated intact rats (31.2 +/- 11.2 vs 140.6 +/- 48.1 pg/mg tissue, respectively, p < 0.01); no effect was induced by GH or IGF-I (37.5 +/- 26.8 and 53.8 +/- 22.5 pg/mg tissue, respectively). However, in the intact rats, GH and IGF-I injection led to a decrease in GHRH content, which was significant in the GH-treated compared to the saline-treated animals (33.1 +/- 16.2 vs 140.6 +/- 48.1 pg/mg tissue, p < 0.01). No difference was found in somatostatin levels between intact and hypophysectomized rats (631.2 +/- 81.2 and 625.0 +/- 62.5 pg/mg tissue, respectively). However, in the hypophysectomized animals, GH and IGF-I treatment induced a significant increase in somatostatin levels (1300 +/- 193.7 pg/mg tissue, p < 0.01, and 912.5 +/- 81.2 pg/mg tissue, p < 0.05, respectively). Our findings suggest that the bioavailability of exogenous IGF-I is greater than that of GH-stimulated endogenous IGF-I. Because IGF-I is a potent neurotrophic agent, this effect may have important implications for states of neurodegenerative diseases.

Association between Insulin-Like Growth Factor-I

Several prospective observational studies have suggested that elevated circulating IGF-I levels are associated with an increased risk of cancer. These observations may provide a potential mechanism through which previously identified metabolic and anthropometric factors, such as obesity and elevated insulin and glucose levels, may operate. We therefore examined metabolic and anthropometric influences on circulating levels of insulin-like growth factor-I (IGF-I), insulin-like growth factor-binding protein-1 (IGFBP-1), and the IGF-I:IGFBP-1 ratio in a middle-aged population of 349 men and 492 women. IGF-I showed only modest inverse associations with indices of adiposity. However, we found that low IGFBP-I levels and an increased IGF-I:IGFBP-1 ratio were strongly associated with increased levels of insulin and glucose in men and women. Body mass index was also positively related to the IGF-I:IGFBP-1 ratio in men (P < 0.001) and women (P < 0.001), independent of metabolic correlates of IGFBP-1 and IGF-I. Similarly, waist:hip ratio and waist circumference were also associated with an increased IGF-I:IGFBP-1 ratio and low circulating IGFBP-1 levels. These findings suggest that individuals with greater fat mass and upper body obesity may have elevated levels of bioavailable or free IGF-I, which could, in part, mediate the reported associations among metabolic and anthropometric factors and cancer risk.

Differential effects of progestins on the circulating IGF-I system

Objective: Circulating insulin-like growth factor-I (IGF-I) is mainly produced by the liver under GH stimulation and is influenced by nutrition and insulin. IGF-I bioavailability is regulated by interactions with specific binding proteins (IGFBPs). The objective of this paper is to review available data on modifications of the IGF-I system in menopausal women during HRT, with particular attention on the differential effects of progestins. Method: All available reports on the effects of different forms of HRT have been taken into account. Results: Available data suggest that different kinds of HRT have different effect on the IGF-I system, depending on route of administration, oestrogen dose, basal IGF-I values and type of progestin. Oestrogen administration (oestrogen replacement therapy (ERT)) reduces circulating IGF-I mainly through a hepatocellular effect. The decrease is sharper when oral ERT is used (first pass hepatic effect) and in women with higher basal IGF-I levels. The progestins endowed with androgenic effects—the 19-nortestosterone derivatives and, to a lesser extent, medroxyprogesterone acetate (MPA)—tend to reverse the IGF-I decrease induced by oral oestrogens. In contrast, progestins devoid of androgen-like hepatocellular and metabolic actions (e.g. dydrogesterone) do not interfere with the IGF-I decrease induced by oral oestrogens. Data on the effect of ERT on IGFBP-3 level are not consistent. Oral ERT, via hepatocellular actions (amplified by the first pass hepatic effect) causes a two to three-fold increase in IGFBP-1 levels. Androgenic progestins oppose the IGFBP-1 increase induced by oral oestrogens. Data on the effect of ERT and different progestins on the level of free IGF-I are scant and inconsistent. Conclusion: Even if some aspects need clarification, available data demonstrate that different progestins have differential effects on the circulating IGF-I system.

The role of mitogen-activated protein kinase in insulin and insulin-like growth factor I (IGF-I) signaling cascades for progesterone and IGF-binding protein-1 production in human granulosa cells.

Insulin and IGF-I participate in the regulation of ovulation, steroidogenesis, and IGF-binding protein (IGFBP) production in the ovary. Insulin and IGF-I actions in the ovary are closely related. For example, insulin may amplify IGF-I action in the ovary by up-regulating type I IGF receptors and inhibiting IGFBP-1 production, thus increasing the bioavailability of IGF-I. It is hypothesized that ovarian effects of insulin in insulin-resistant states are mediated via an insulin action pathway(s) distinct from those involved in glucose transport. We previously reported that insulin-induced stimulation of progesterone and inhibition of IGFBP-1 production in the human ovary are mediated by signaling pathways that are independent of phosphatidylinositol 3-kinase, the enzyme whose activation is crucial for glucose transport. We now examined whether activation of MAPK is necessary to mediate insulin-induced or IGF-I-induced stimulation of progesterone or inhibition of IGFBP-1 production in human granulosa cells. Human granulosa cells were obtained during in vitro fertilization. Cells (0.5-1 x 10(5)) were incubated for 24 h in the presence of 0, 10, 10(2), or 10(3) ng/ml insulin or 0, 0.5, 1, 2.5, or 5 ng/ml IGF-I and in the presence or absence of 1 micro M PD98059, a specific inhibitor of ERK1/2 MAPK. The progesterone concentration in the tissue culture medium was measured by RIA (Pantex, Santa Monica, CA), and the IGFBP-1 concentration was measured by immunoradiometric assay (DSL-7800, Diagnostic Systems Laboratories, Inc., Webster, TX). MAPK activity was assessed using the MAPK IP-Kinase assay kit (Upstate Biotechnology, Inc., Lake Placid, NY). ANOVA was used to compare mean values of progesterone or IGFBP-1 concentrations. MAPK was stimulated by insulin up to 350% of the baseline value. Progesterone production in human granulosa cells was stimulated by insulin in a dose-related manner to 123% of the control value (P < 0.001), and IGFBP-1 production was inhibited to 25% of the baseline value (P < 0.001). Despite inhibiting MAPK activity by 99%, PD98059 (1 micro M) did not interfere with insulin-induced stimulation of progesterone or inhibition of IGFBP-1 production. MAPK was stimulated by IGF-I to 730% of the baseline value, with maximal stimulation achieved at 0.5 ng/ml IGF-I. Progesterone production in granulosa cells was stimulated by IGF-I to 130% of the control value (P < 0.001), whereas IGFBP-1 production was inhibited to 44% of the control value (P < 0.001). PD98059 (1 micro M) inhibited IGF-I-induced MAPK activity by 94%. In the presence of 1 micro M PD98059, IGF-I-induced stimulation of progesterone production was inhibited by 96% (P < 0.001). The inhibitory effect of IGF-I on IGFBP-1 production was reduced in the presence of 1 micro M PD98059 by 45% at 5 ng/ml IGF-I and was completely abolished in the presence of 1 micro M PD98059 at concentrations of IGF-I ranging from 0.5-2.5 ng/ml (P < 0.001). We conclude that, under conditions of our experiments, insulin-induced stimulation of progesterone or inhibition of IGFBP-1 production in human granulosa cells does not require MAPK activation, whereas similar effects of IGF-I are largely MAPK dependent.

Free insulin-like growth factor (IGF)-I and IGF binding proteins 2, 5, and 6 in spinal motor neurons in amyotrophic lateral sclerosis

Insulin-like growth factor-I (IGF-I) is a potent survival factor for motor neurons and is being investigated as possible therapeutic agent for amyotrophic lateral sclerosis. However, very little information is available on the components of the IGF-I system in this disease. Insulin-like growth factor binding proteins (IGFBPs) play an important part in regulating the bioavailability of IGF-I. We investigated the components of the IGF-I system in spinal cord sections of ten patients with amyotrophic lateral sclerosis and in ten controls without neurological disease. IGF-I was studied by western immunoblotting. IGFBPs and IGF-I receptors were investigated by immunohistochemistry and Western immunoblotting. Total IGF-I in ventral horn homogenates did not differ between patients and controls. However, free IGF-I was 53% lower in patients than in controls. Compared with controls, immunoreactivity in the spinal motor neurons of patients with amyotrophic lateral sclerosis was 64% higher for IGFBP2, 46% higher for IGFBP5, and 33% higher for IGFBP6, with upregulation of IGF-I receptors. Immunoreactivity for IGFBPs1, 3, and 4 did not differ between patients and controls. In the ventral horns of patients, free IGF-I is reduced, which could be because of specific increases in IGFBPs 2, 5, and 6 in spinal motor neurons. This abnormality might have an important role in the processes leading to motor neuron death, and should be taken into account when developing treatments aimed to stimulate IGF-I receptors in motor neurons.