Decreased Serum IGF-I Research Articles

Decreased Circulating Insulin-Like Growth Factor 1 Levels Are Associated with Cardiac Diastolic Dysfunction in Small for Gestational Age Infants

To evaluate the impact of serum insulin-like growth factor-1 (IGF-1) levels on cardiac function in small for gestational age (SGA) infants. This is a prospective, observational study. Serum IGF-1 levels at birth and echocardiography measurements at 1 week of age were compared between SGA and appropriate for gestational age (AGA) infants. Thirty-one SGA infants and 27 AGA infants were enrolled. Serum IGF-1 levels were lower in the SGA infants than in the AGA infants. SGA infants had lower mitral lateral annular systolic (S') and early diastolic (E') tissue Doppler imaging velocities compared with AGA infants (S', 5.1 ± 0.9 vs 5.7 ± 1.2 cm/s; E', 6.1 ± 1.5 cm/s vs 7.1 ± 1.3 cm/s; p < 0.05). Serum IGF-1 levels positively correlated with E' velocity in the entire population (r = 0.44, p < 0.001) and in SGA infants (r = 0.39, p < 0.05). In multivariate linear regression analysis, serum IGF-1 and S' velocity were independently associated with E' velocity in the entire population and in SGA infants. Decreased serum IGF-I levels could account for cardiac diastolic dysfunction in SGA infants.

Skeletal Response of Male Mice to Anabolic Hormone Therapy in the Absence of theIgfalsGene

IGF-I is a critical regulator of skeletal acquisition, which acts in endocrine and autocrine/paracrine modes. In serum, IGF-I is carried by the IGF-binding proteins in binary complexes. Further stabilization of these complexes is achieved by binding to the acid labile subunit (ALS) in a ternary complex (of IGF-I-IGF-binding protein 3/5-ALS). Ablation of the Igfals gene in humans (ALS deficiency) and mice (ALS knockout [ALSKO]) leads to markedly decreased serum IGF-I levels, growth retardation, and impaired skeletal acquisition. To investigate whether hormonal replacement therapy would improve the skeletal phenotype in cases of Igfals gene ablation, we treated male ALSKO mice with GH, IGF-I, or a combination of both. Treatments were administered to animals between 4 and 16 weeks of age or from 8 to 16 weeks of age. Although all treatment groups showed an increase (20%) in serum IGF-I levels, there was no increase in body weight, weight gain, or bone length in either age group. Despite the blunted linear growth in response to hormone therapy, ALSKO mice treated with GH showed radial bone growth, which contributed to bone strength tested by 4-point bending. We found that ALSKO mice treated with GH showed increased total cross-sectional area, cortical bone area, and cortical thickness by microtomography. Dynamic histomorphometry showed that although GH and double treatment groups resulted in trends towards increased bone formation parameters, these did not reach significance. However, bone resorption parameters were significantly increased in all treatment groups. ALSKO mice treated between 4 and 16 weeks of age showed minor differences in bone traits compared with vehicle-treated mice. In conclusion, treatment with GH and IGF-I do not work synergistically to rescue the stunted growth found in mice lacking the Igfals gene. Although GH alone appears to increase bone parameters slightly, it does not affect body weight or linear growth.

DNA Methylation Analysis of the Insulin-like Growth Factor-1 (IGF1) Gene in Swedish Men with Normal Glucose Tolerance and Type 2 Diabetes

Objective: Recent genetic studies have demonstrated that Single Nucleotide Polymorphism (SNP) rs35767(C/T) in the IGF1 gene promoter is associated with insulin resistance and serum IGF-I levels and thereby implicated that IGF1 has genetic effect in Type 2 Diabetes (T2D). The present study aimed to investigate the alteration of DNA methylation levels of the IGF1 gene in T2D. Subjects and methods: A total of 688 Swedish men with Normal Glucose Tolerance (NGT) or T2D were selected from Stockholm Diabetes Prevention Program. DNA methylation levels at rs35767 SNP-CpG site and other three CpG sites (P1-P3) in the IGF1 gene promoter region were analyzed with PyroMark Assays and bisulfite pyrosequencing. Fasting serum IGF-I levels were measured with an in-house radio-immunoassay. Results: DNA methylation levels at CpG site P3 of the IGF1 gene promoter were increased in T2D patients compared with NGT subjects (84.8% vs. 74.2%, P<0.001), while serum IGF-I levels were lower in T2D than that in NGT subjects (152 μg/l vs 169 μg/l, P=0.029). In SNP rs35767(C/T), the carriers with CC genotype had higher DNA methylation levels at SNP-CpG site compared with the carriers with CT and TT genotypes in both NGT and T2D. Conclusions: The present study provides the first evidence that increased DNA methylation levels of the IGF1 gene and decreased serum IGF-I protein concentration are associated with T2D, and suggests that DNA methylation in the IGF1 gene may interact with SNP rs35767 (C/T) in the gene promoter region.

Dietary Energy Balance Modulation of Kras- and Ink4a/Arf+/−-Driven Pancreatic Cancer: The Role of Insulin-like Growth Factor-I

New molecular targets and intervention strategies for breaking the obesity-pancreatic cancer link are urgently needed. Using relevant spontaneous and orthotopically transplanted murine models of pancreatic cancer, we tested the hypothesis that dietary energy balance modulation impacts pancreatic cancer development and progression through an insulin-like growth factor (IGF)-I-dependent mechanism. In LSL-Kras(G12D)/Pdx-1-Cre/Ink4a/Arf(lox/+) mice, calorie restriction versus overweight- or obesity-inducing diet regimens decreased serum IGF-I, tumoral Akt/mTOR signaling, pancreatic desmoplasia, and progression to pancreatic ductal adenocarcinoma (PDAC), and increased pancreatic tumor-free survival. Serum IGF-I, Akt/mTOR signaling, and orthotopically transplanted PDAC growth were decreased in liver-specific IGF-I-deficient mice (vs. wild-type mice), and rescued with IGF-I infusion. Thus, dietary energy balance modulation impacts spontaneous pancreatic tumorigenesis induced by mutant Kras and Ink4a deficiency, the most common genetic alterations in human pancreatic cancer. Furthermore, IGF-I and components of its downstream signaling pathway are promising mechanistic targets for breaking the obesity-pancreatic cancer link.

Short-term growth hormone or IGF-I administration improves the IGF-IGFBP system in arthritic rats

ObjectiveAdjuvant-induced arthritis is an experimental model of rheumatoid arthritis that inhibits the GH-IGF-I axis and decreases body weight gain and muscle mass. Although chronic GH or IGF-I treatment increases body weight gain in arthritic rats, muscle resistance to GH and IGF-I is a very common complication in inflammatory diseases. In this study we examine the effect of short-term administration of rhGH and rhIGF-I on liver and muscle IGF-I, IGFBP-3 and −5 as well as on the ubiquitin-ligases MuRF1 and atrogin-1 in the muscle of arthritic rats. DesignArthritis was induced in adult male Wistar rats by an intradermal injection of 4mg of Freund's adjuvant. Fifteen days after adjuvant injection, 300μg/kg of rhGH or 200μg/kg of rhIGF or saline was administrated 18 and 3h before decapitation. A pair-fed group injected with saline was included in order to discard a possible effect of decreased food intake. Gene expression of IGF-I, GHR, IGFBP-3, IGFBP-5, atrogin-1 and MuRF1 were quantified using RT-PCR. In serum, IGF-I was measured by radioimmunoassay (RIA) and IGFBP-3 by ligand blot. ResultsArthritis decreased serum IGF-I and IGF mRNA in liver (P<0.05), but not in skeletal muscle. In arthritic rats, rhGH increased serum IGF-I and liver IGF-I mRNA similar to the levels of pair-fed rats. Arthritis increased atrogin-1, MuRF1, IGFBP-3 and IGFBP-5 mRNA in muscle (P<0.01). IGFBP-3 mRNA was downregulated by rhIGF-I, but not by rhGH, administration in control and arthritic rats (P<0.05). Administration of rhGH and rhIGF-I increased IGFBP-5 in the gastrocnemius of arthritic rats. ConclusionsShort-term rhGH and rhIGF-I administration was found to increase muscle IGFBP-5 mRNA, whereas only rhIGF-I administration decreased muscle IGFBP-3 mRNA in control and arthritic rats. These data suggest that arthritis does not induce GH or IGF-I resistance in skeletal muscle.

Cytoplasmic and Nuclear STAT3 in GH-Stimulated Fibroblasts of Children with Idiopathic Short Stature

Background: STAT5, which plays an important role in GH signal transduction, has been studied extensively in children with growth retardation, but there is scarce information regarding STAT3. Aim: We determined total and phosphorylated STAT3 after GH stimulation in fibroblasts from children with idiopathic short stature (ISS) and control children with normal stature. Subjects and Methods: We studied 15 prepubertal children (age 7.6 ± 0.4 years) with short stature (height –2.8 ± 0.2 SDS), decreased growth velocity (<p10), a GH response of >10 ng/ml to the clonidine stimulation test and decreased serum IGF-I concentrations (<–1 SDS), and 19 control children with normal stature (age 6.7 ± 0.3 years). We determined the levels of total and phosphorylated STAT3 in the cytoplasmic and nuclear fractions of fibroblast cultures obtained from a skin biopsy, stimulated with GH (200 ng/ml) for 15–60 min. Results: We observed a reduction in nuclear pSTAT3 levels and a lower nuclear/cytoplasmic STAT3 phosphorylated ratio in 3 patients from the study group compared to the control children. Conclusion: These results suggest that some children with ISS may exhibit a reduction in the nuclear content of their phosphorylated STAT3.

Effects of ractopamine and sex on serum metabolites and skeletal muscle gene expression in finishing steers and heifers

We evaluated growth-related responses to ractopamine in steers and heifers. Sixteen Angus steers (512 kg) and 16 Angus heifers (473 kg) housed in individual pens were used in a complete block design. At 90 to 97 d before the experiment, steers were implanted with 120 mg of trenbolone acetate and 24 mg of estradiol-17beta (Component TE-S) and heifers were implanted with 140 mg of trenbolone acetate and 14 mg of estradiol-17beta (Component TE-H). Treatments were arranged as a 2 x 2 factorial and included sex (steer vs. heifer) and ractopamine-HCl (0 or 200 mg/d). Cattle were fed a diet based on steam-flaked corn once daily. Blood and LM and biceps femoris (BF) biopsy samples were collected on d 0 (before ractopamine feeding) and after 14 and 28 d of ractopamine feeding. Serum insulin concentrations were not affected by ractopamine or sex. Serum IGF-I concentrations were greater in steers than heifers (P < 0.001), and steers demonstrated greater IGF-I mRNA expression in BF than heifers (P = 0.05). Ractopamine decreased serum IGF-I concentrations in heifers on d 14, but increased serum IGF-I concentrations in steers on d 28 (sex x ractopamine x day interaction; P = 0.03). Ractopamine did not affect (P >or= 0.19) mRNA expression of IGF-I, IGFBP-3, or calpastatin in BF or LM. However, ractopamine led to increases in LM expression of IGFBP-5 in heifers, but to decreases in expression in steers (ractopamine x sex interaction; P = 0.04). Ractopamine decreased myosin heavy chain IIA mRNA expression in BF (P = 0.04) but not in LM (P = 0.99). Ractopamine decreased beta(2)-receptor mRNA expression in LM of steers on d 14, but not on d 28; in contrast, expression of beta(2)-receptor mRNA in LM of heifers was not affected by ractopamine (sex x ractopamine x day interaction; P = 0.03). Although there were a few criteria for which ractopamine led to differences in response between steers and heifers, there were no striking disparities to suggest that the effectiveness of ractopamine would markedly differ between sexes.

Reduction of serum IGF-I levels in patients affected with Monoclonal Gammopathies of undetermined significance or Multiple Myeloma. Comparison with bFGF, VEGF and K-ras gene mutation

BackgroundSerum levels of IGF-I in patients affected with multiple myeloma (MM) have been scarcely studied. The present study is aimed to explore this point comparing 55 healthy subjects, 71 monoclonal gammopaties of uncertain significance (MGUS) and 77 overt MM patients. In the same subjects, basic FGF and VEGF, have been detected. All three mediators were analyzed in function of K-ras mutation and melphalan response. Concerning IGF-I, two representative monitoring examples have also been added.MethodsCytokine determinations were performed by commercially available ELISA kits, while K12-ras mutation was investigated on genomic DNA isolated from bone marrow cell specimens by RFLP-PCR assay.ResultsSignificant reductions of IGF-I levels were observed in MGUS and MM as compared with healthy controls. In addition, MM subjects showed significantly decreased serum IGF-I levels than MGUS. Conversely, increasing levels were observed for bFGF and VEGF, molecules significantly correlated. A multivariate analysis corrected for age and gender confirmed the significant difference only for IGF-I values (P = 0.01). K12-ras mutation was significantly associated with malignancy, response to therapy and with significantly increased serum bFGF levels.ConclusionIGF-I reduction in the transition: Controls→MGUS→MM and changes observed over time suggest that IGF-I should be furtherly studied in future clinical trials as a possible monitoring marker for MM.

Strain-Specific Effects of Rosiglitazone on Bone Mass, Body Composition, and Serum Insulin-Like Growth Factor-I

Activation of peroxisome proliferator activated receptor-gamma (PPARG) is required for the differentiation of marrow mesenchymal stem cell into adipocytes and is associated with the development of age-related marrow adiposity in mice. Thiazolidinediones are agonists for PPARG and have a heterogeneous effect on bone mineral density (BMD). We postulated that genetic determinants influence the skeletal response to thiazolidinediones. We examined the effects of rosiglitazone (3 mg/kg . d for 8 wk) on BMD, body composition, and serum IGF-I in adult female mice from four inbred strains. C3H/HeJ mice showed the most significant response to treatment, exhibiting decreased femoral and vertebral BMD, reduced distal femoral bone volume fraction and a decrease in serum IGF-I. In DBA/2J, there were no changes in femoral BMD or bone volume fraction, but there was a decrease in vertebral BMD. C57BL/6J mice showed increases in marrow adiposity, without associated changes in trabecular bone volume; the skeletal effects from rosiglitazone in A/J mice were minimal. No association between trabecular bone volume and marrow adiposity was found. The effect of rosiglitazone on gene expression in the femur was then examined in the C3H/HeJ and C57BL/6J strains by microarray. Increased gene expression was observed in the PPARG signaling pathway and fatty acid metabolism in both C3H/HeJ and C57BL/6J, but a significant down-regulation of genes associated with cell cycle was noted only in the C3H/HeJ strain. The divergent skeletal responses to rosiglitazone in this study suggest the existence of a strong genetic background effect.

Loss of sexually dimorphic liver gene expression upon hepatocyte-specific deletion of Stat5a-Stat5b locus.

Hepatocyte-specific, albumin-Cre recombinase-mediated deletion of the entire mouse Stat5a-Stat5b locus was carried out to evaluate the role of signal transducer and activator of transcription 5a and 5b (STAT5ab) in the sex-dependent transcriptional actions of GH in the liver. The resultant hepatocyte STAT5ab-deficient mice were fertile, and unlike global STAT5b-deficient male mice, postnatal body weight gain was normal, despite a 50% decrease in serum IGF-I. Whole-liver STAT5ab RNA decreased by approximately 65-85%, and residual STAT5 immunostaining was observed in a minority of the hepatocytes, indicating incomplete excision by Cre-recombinase. Quantitative PCR analysis of 20 sexually dimorphic, liver-expressed genes revealed significant down-regulation of 10 of 11 male-specific genes in livers of male hepatocyte STAT5ab-deficient mice. Class I female-specific liver genes were markedly up-regulated (de-repressed), whereas the expression of class II female genes, belonging to the Cyp3a subfamily, was unaffected by the loss of hepatocyte STAT5ab. STAT5ab is thus required in the liver for positive regulation of male-specific genes and for negative regulation of a subset of female-specific genes. Continuous GH infusion strongly induced (>500-fold) the class II female gene Cyp3a16 in both wild-type and hepatocyte STAT5ab-deficient male mice, indicating sex-specific transcriptional regulation by GH that is STAT5ab independent. In contrast, hepatocyte STAT5ab deficiency abolished the strong suppression of the male-specific Cyp2d9 by continuous GH seen in control mouse liver. Analysis of global STAT5a-deficient mice indicated no essential requirement of STAT5a for expression of these sex-specific liver Cyp genes. Thus, the major loss of liver sexual dimorphism in hepatocyte STAT5ab-deficient mice can primarily be attributed to the loss of STAT5b.

Endocrine, liver-derived IGF-I is of importance for spatial learning and memory in old mice

IGF-I is a neuroprotective hormone, and neurodegenerative disorders, including Alzheimer's disease, have been associated with decreased serum IGF-I concentration. In this study, IGF-I production was inactivated in the liver of adult mice (LI-IGF-I(-/-)), resulting in an approximately 80-85% reduction of circulating IGF-I concentrations. In young (6-month-old) mice there was no difference between the LI-IGF-I(-/-) and the control mice in spatial learning and memory as measured using the Morris water maze test. In old (aged 15 and 18 months) LI-IGF-I(-/-) mice, however, the acquisition of the spatial task was slower than in the controls. Furthermore, impaired spatial working as well as reference memory was observed in the old LI-IGF(-/-) mice. Histochemical analyses revealed an increase in dynorphin and enkephalin immunoreactivities but decreased mRNA levels in the hippocampus of old LI-IGF-I(-/-) mice. These mice also displayed astrocytosis and increased metabotropic glutamate receptor 7a-immunoreactivity. These neurochemical disturbances suggest synaptic dysfunction and early neurodegeneration in old LI-IGF-I(-/-) mice. The decline in serum IGF-I with increasing age may therefore be important for the age-related decline in memory function.

Relative Impact of Androgen and Estrogen Receptor Activation in the Effects of Androgens on Trabecular and Cortical Bone in Growing Male Mice: A Study in the Androgen Receptor Knockout Mouse Model

The relative importance of AR and ER activation has been studied in pubertal male AR knockout and WT mice after orchidectomy and androgen replacement therapy, either with or without an aromatase inhibitor. AR activation dominates normal trabecular bone development and cortical bone modeling in male mice. Moreover, optimal periosteal bone expansion is only observed in the presence of both AR and ER activation. Androgen receptor (AR)-mediated androgen action has traditionally been considered a key determinant of male skeletal growth. Increasing evidence, however, suggests that estrogens are also essential for normal male bone growth. Therefore, the relative importance of AR-mediated and estrogen receptor (ER)-mediated androgen action after aromatization remains to be clarified. Trabecular and cortical bone was studied in intact or orchidectomized pubertal AR knockout (ARKO) and male wildtype (WT) mice, with or without replacement therapy (3-8 weeks of age). Nonaromatizable (dihydrotestosterone [DHT]) and aromatizable (testosterone [T]) androgens and T plus an aromatase inhibitor (anastrazole) were administered to orchidectomized ARKO and WT mice. Trabecular and cortical bone modeling were evaluated by static and dynamic histomorphometry, respectively. AR inactivation or orchidectomy induced a similar degree of trabecular bone loss (-68% and -71%, respectively). Both DHT and T prevented orchidectomy-induced bone loss in WT mice but not in ARKO mice. Administration of an aromatase inhibitor did not affect T action on trabecular bone. AR inactivation and orchidectomy had similar negative effects on cortical thickness (-13% and -8%, respectively) and periosteal bone formation (-50% and -26%, respectively). In orchidectomized WT mice, both DHT and T were found to stimulate periosteal bone formation and, as a result, to increase cortical thickness. In contrast, the periosteum of ARKO mice remained unresponsive to either DHT or T. Interestingly, administration of an aromatase inhibitor partly reduced T action on periosteal bone formation in orchidectomized WT mice (-34% versus orchidectomized WT mice on T), but not in ARKO mice. This effect was associated with a significant decrease in serum IGF-I (-21% versus orchidectomized WT mice on T). These findings suggest a major role for AR activation in normal development of trabecular bone and periosteal bone growth in male mice. Moreover, optimal stimulation of periosteal growth is only obtained in the presence of both AR and ER activation.

An investigation into the mechanisms of action of Revalor-S and Optaflexx in growing steers (2006)

An experiment was conducted to evaluate the interaction between steroidal implantation and feeding ractopamine on nitrogen retention, blood metabolites, and messenger RNA (mRNA) expression. Six Holstein steers (initially weighing 509 lb) were implanted or not with Revalor-S (120 mg trenbolone acetate plus 24 mg estradiol-17β), and all were fed no ractopamine for the initial 28 days and then 2 grams per steer daily of Optaflexx (200 mg/day ractopamine-HCl) on days 29 through 56. Implantation increased nitrogen retention. Optaflexx increased nitrogen retention in nonimplanted steers, but did not significantly increase retained nitrogen in implanted steers. Implantation increased serum insulin-like growth factor (IGF)-I concentration. Optaflexx, however, numerically decreased serum IGF-I concentrations. Implantation numerically increased IGF-I mRNA in the longissimus muscle, but expression of IGF-I mRNA was significantly decreased when Optaflexx was fed. Both growth promotants increased nitrogen retention in steers, but, despite perceived differences in their mode of action, the combination yielded a less than additive response for nitrogen retention.

Interactive responses in gut immunity, and systemic and local changes in the insulin-like growth factor system in nursery pigs in response to Salmonella enterica serovar Typhimurium,

Abstract In recent years, we have sought to understand how disparate endocrine and immune signals converge in response to Salmonella enterica serovar Typhimurium (ST) to affect growth and the IGF system in the nursery pig. The enteric pathogen ST interacts with gut epithelium to rapidly upregulate the chemoattractive chemokines IL-8 and chemokine ligand-20, and to selectively affect toll-like receptors. Activation of these components of the innate immune system seems to confine the immune response largely to the gut mucosa and mesenteric lymph nodes, as evidenced by the lack of systemic elevation of proinflammatory cytokines. Despite the apparent restriction of proinflammatory signals to the gut-associated lymphoid tissue, ST provokes peripheral sequelae consistent with danger signaling, including the febrile response and activation of the adrenal axis. In addition, pigs undergoing ST-induced febrile responses experience a consistent period of inappetence that is independent of changes in leptin. Moreover, this period of decreased intake is invariably accompanied by an unmistakable decrease in serum IGF-I and, less consistently, with parallel reductions in circulating IGFBP-3. More recently, we characterized changes in expression of components of the IGF system within skeletal muscle of pigs undergoing ST-associated enteric disease. Despite the characteristic decrease in circulating IGF-I, the relative abundance of skeletal muscle IGF-I and IGFBP-3 mRNA was unaffected by ST. However, mRNA for IGFBP-5 was decreased in the skeletal muscle of ST-challenged pigs, suggesting a possible effect of the enteric disease on IGF availability. Taken together, oral challenge with ST engages elements of the mucosal innate immune system that seem to contain the spread of systemic proinflammatory cytokine signals. Even so, ST challenge is associated with parallel changes in both systemic and local IGF systems that may affect pig growth.

Effect of cattle disease on carcass traits

Abstract The movement to price an increasing percentage of fed cattle on carcass merit grids has renewed interest in the effect of cattle disease on carcass traits. There is growing evidence that disease has the potential to affect not only carcass weight, but also the quantity, location, and ratio of muscle, fat, and water. A clear mechanistic pathway linking disease to changes in carcass traits has not been made. Three theories considered in this review are 1) a change in metabolic signals, such as cytokines and cortisol, could affect carcass composition through modification of hypothalamic secretions of thyrotropin-releasing hormone, by inhibition of IGF-I and insulin actions on muscle and fat tissues, and by direct protein catabolism and lipolysis; 2) disease-induced anorexia causing a decrease in serum IGF-I and an increase in serum GH, which induces a change in the partitioning of nutrients for tissue deposition; and 3) an indirect (and reversible) effect of anorexia, whereby sick cattle are on feed for fewer effective days than pen mates that do not become sick. Other pathogen or immune-mediated responses to disease, as well as interactions among hormones and cytokines, may influence nutrient partitioning and body composition but have yet to be described. The use of carcass merit to determine the value of fed cattle provides an improved economic signal of the cost of cattle disease. The value of disease avoidance as well as rapid diagnosis and treatment of disease increases when cattle are sold on carcass merit basis because of the negative effects of disease on carcass traits.

Inhibition of TNF-alpha production by pentoxifylline does not prevent endotoxin-induced decrease in serum IGF-I.

Sepsis and endotoxin (LPS or lipopolysaccharide) injection induce a state of growth hormone (GH) resistance leading to decreased circulating insulin-like growth factor (IGF)-I. Because the proinflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta inhibit the GH-stimulated IGF-I expression in vitro, it was tempting to speculate that these two cytokines might play an important role in the reduction of circulating IGF-I levels caused by LPS. Pentoxifylline, a methylxanthine usually used in the treatment of peripheral arterial circulatory disorders, has been reported to inhibit TNF-alpha synthesis. The goal of our study was to investigate whether inhibition of TNF-alpha production by pentoxifylline could prevent the decrease in IGF-I and the GH resistance caused by LPS injection. Because previous studies demonstrated that pentoxifylline can reduce muscle catabolism induced by sepsis, we also assessed whether pentoxifylline could exert its anticatabolic effect by preventing the decrease in circulating IGF-I. LPS injection in rats decreased serum IGF-I (-45% at 12 h; P<0.01 vs time 0) and its liver mRNA (-67% at 12 h; P<0.01 vs time 0) while it induced circulating TNF-alpha and IL-1beta and their hepatic expression (P<0.01). Pretreatment of LPS-treated animals by pentoxifylline abolished the LPS-induced rise in serum TNF-alpha (-98% at 90 min; P<0.001 vs LPS alone) and to a lesser extent in serum IL-1beta (-44% at 3 h; not significant vs LPS alone). Despite its dramatic inhibitory effect on TNF-alpha induction, however, pentoxifylline failed to suppress both the decrease in IGF-I and the GH resistance induced by LPS in rats. These results suggest that mediators other than TNF-alpha, in particular IL-1beta or IL-6, could contribute to the GH resistance induced by LPS. They also suggest that the anticatabolic effect of pentoxifylline is not due to prevention of the decline of circulating IGF-I.

Vitamin A Deficiency Reduces Insulin-Like Growth Factor (IGF)-I Gene Expression and Increases IGF-I Receptor and Insulin Receptor Gene Expression in Tissues of Japanese Quail (Coturnix coturnix japonica)

The insulin-like growth factor (IGF) system is regulated by various stimuli, including hormones, growth factors and nutritional status. We examined the effects of vitamin A on components of the IGF system in Japanese quail. Male quail (1 d old) fed a vitamin A-deficient diet for 14 or 21 d developed vitamin A deficiency, as confirmed by a depletion of serum retinol and hepatic retinyl palmitate. Consuming the vitamin A-deficient diet for 14 d did not affect growth rate, but decreased the serum IGF-I concentrations by 22% compared with the control group. The decreased serum IGF-I levels were accompanied by 21-52% lower levels of IGF-I mRNA in the testis, lung, liver and heart, whereas IGF-I receptor (IGF-IR) and insulin receptor (IR) gene expressions were unaffected in these tissues. Continuous feeding of the vitamin A-deficient diet for 21 d retarded growth and further decreased the levels of serum IGF-I and tissue IGF-I mRNA. Serum IGF-I levels were reduced by approximately 50%; IGF-I mRNA levels were > 90% lower in the liver and lung and approximately 60% lower in the heart and testis. In contrast, levels of the IGF-IR and IR mRNAs were approximately 100% greater in some tissues examined. When vitamin A-deficient quail received a single injection of retinol or retinoic acid (0.1 mg/bird), tissue IGF-I, IGF-IR and IR gene expressions did not change after 4 h. These results suggest a possible physiologic role of the IGF system in mediating vitamin A-supported growth of Japanese quail.

Effect of thyroxine administration on the IGF/IGF binding protein system in neonatal and adult thyroidectomized rats.

The effects of different doses of thyroxine (T(4)) delivered by injection or s.c. pellet implantation on alterations of the IGF/IGF binding protein (IGFBP) system were studied in neonatal and adult thyroidectomized (Tx) rats. Body weight, blood glucose, plasma insulin, TSH and GH and pituitary GH content, as well as serum IGF-I, IGF-II, IGFBP-1, -2 and -3 and their liver mRNA expression were assayed. Pellet implantation with the smaller dose of T(4) (1.5 microg/100 g body weight (b.w.) per day) in Tx neonatal rats decreased serum IGF-I, -II and the 30 kDa complex of IGFBPs (IGFBP-1 and -2), and increased serum IGFBP-3. Only the larger dose of T(4) (3 microg/100 g b.w. per day) recovered liver mRNA expression of IGF-I and ensured euthyroid status as shown by the normalized levels of plasma TSH. The rapid increase of body weight and serum GH after T(4) administration indicated a high sensitivity to T(4) during the neonatal period. Serum and liver mRNA expression of IGFs and plasma insulin and GH recovered in adult Tx rats after pellet implantation of 1.75 microg/100 g b.w. per day throughout 10 days. The continuous replacement of T(4) by pellet seems to be the most suitable method for thyroid rehabilitation. A very good correlation was found between insulin and IGF-II in Tx neonates treated with T(4) but not between insulin and IGF-I in Tx adults. IGFBP-2 seems to be up-regulated by T(4) deprivation in neonatal and adult rats. Finally, a good correlation as well as a partial correlation were found between IGFs and thyroid hormones in both neonatal and adult Tx populations, suggesting a direct effect in vivo of T(4) on the hepatic secretion of IGFs, as previously suggested in vitro.

Continuation of Growth Hormone (GH) Replacement in GH-Deficient Patients during Transition from Childhood to Adulthood: A Two-Year Placebo-Controlled Study

Previous studies have demonstrated beneficial effects of GH replacement, in adults with GH deficiency (GHD), on body composition, physical fitness, and quality of life. These studies, however, concern patients with adult-onset GHD or childhood-onset (CO) patients enrolled several years after withdrawal of initial therapy. So far, the effects of continuation of GH-administration in patients with CO-GHD have not been examined. We studied a group of nineteen young adults (13 males+ 6 females; 16–26 yr old; mean age, 20.2 ± 0.65 yr) with CO-GHD, in a randomized, parallel, double-blind, placebo-controlled trial for 1 yr, followed by an open phase with GH for 1 yr. All patients received GH therapy at the start of study, and trial medication (GH/placebo) was given in a similar dose. Patients randomized to continued GH treatment exhibited no significant changes in any parameters tested, but intra- and interindividual variations in insulin-like growth factor (IGF)-I levels could suggest compliance problems. Discontinuation of GH for 1 yr resulted in a decrease in serum IGF-I, from 422.0 ± 56.8 to 147.8 ± 33.4 μg/L, in the placebo group (P = 0.003). After discontinuation of GH for 1 yr, an increase in total body fat (TBF, kg), measured by dual-energy x-ray absorptiometry scan, was seen[ placebo: 22.7 ± 2.7 to 26.5 ± 2.5 (P = 0.01); GH:16.2 ± 2.1 to 17.2 ± 2.1 (not significant)]. Resumption of GH after placebo was followed by increments in serum IGF-I (μg/L) [from 147.8 ± 33.4 to 452 ± 76 (P = 0.001)] and IGF-binding protein 3, as well as in fasting glucose (mmol/L) [4.9 ± 0.2 vs. 5.3 ± 0.2 (P = 0.03)]. After resumption of GH lean body mass (kg) increased [52.4 ± 4.9 vs. 60.7 ± 5.6 (P = 0.006)]. Likewise, resumption of GH therapy increased thigh muscle volume and thigh muscle/fat ratio, as assessed by computed tomography [muscle volume (cm2/10 mm): 118.2 ± 11.7 vs. 130.0 ± 10.9 (P = 0.002); muscle/fat ratio: 1.33 ± 0.24 vs. 1.69 ± 0.36 (P = 0.02)]. In conclusion, discontinuation of GH treatment in GHD patients, during the transition from childhood to adulthood, induces significant and potentially unfavorable changes in IGF-I and body composition, both of which are reversed after resumption of GH treatment. By contrast, continuation of GH therapy results in unaltered IGF-I and body composition. We recommend continuation of GH therapy in these patients, to be undertaken in collaboration between pediatricians and adult endocrinologists.

Potentiation of the inhibitory effect of growth hormone-releasing hormone antagonists on PC-3 human prostate cancer by bombesin antagonists indicative of interference with both IGF and EGF pathways.

In view of the involvement of various neuropeptides and growth factors in the progression of androgen-independent prostate cancer, we investigated the effects of antagonists of growth hormone-releasing hormone (GHRH) alone or in combination with an antagonist of bombesin/gastrin-releasing peptide (BN/GRP) on PC-3 human prostate cancers. Nude mice implanted with PC-3 tumors received GHRH antagonists MZ-5-156 or JV-1-38, each at 20 microgram/day s.c. In experiment 2, treatment consisted of daily injections of JV-1-38 (20 microgram), BN/GRP antagonist RC-3940-II (10 microgram), or a combination of JV-1-38 and RC-3940-II. Serum IGF-I levels, expression of mRNA for IGF-II, and characteristics of BN/GRP and EGF receptors in tumor tissue were investigated. JV-1-38 induced a greater inhibition of tumor growth and suppression of IGF-II mRNA than MZ-5-156, both compounds causing a similar decrease in serum IGF-I. In experiment 2, JV-1-38 and RC-3940-II produced a comparable reduction in tumor volume (65% and 61%, respectively), but a combination of both antagonists augmented tumor inhibition to 75%. Combined treatment with JV-1-38 and RC-3940-II also led to a greater suppression of IGF-II mRNA (92%), as compared with JV-1-38 (72%) or RC-3940-II (77%). Serum IGF-I concentration was lowered only in mice treated with JV-1-38, while the downregulation of BN/GRP and EGF receptors was specific for groups receiving RC-3940-II. The inhibitory effects of GHRH antagonists on PC-3 human androgen-independent prostate cancer can be potentiated by concomitant use of BN/GRP antagonists. The combination of both types of analogs apparently interferes with both IGF and bombesin/EGF pathways, and might be clinically useful for the management of androgen-independent prostate cancer.