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Background: Hyperplasia of fibroblasts is critical in keloid pathogenesis. Insulin-like growth factor-binding protein 3 (IGFBP3) is an important factor in the regulation of cell growth and type V transforming growth factor-β receptor (TβR-V) is a specific receptor of IGFBP3. However, the role of IGFBP3 in keloid development has not been reported. Objectives: This study aimed to investigate the role of IGFBP3 in keloid pathogenesis and evaluate the effects of TβR-V antagonist on keloid fibroblasts (KFs) activities. Methods: IGFBP3 expression in keloids and its impact on KF proliferation were examined. The effects of TβR-V antagonist on KF cell proliferation, migration, and invasion were also investigated. Differentially expressed genes (DEGs) between TβR-V antagonist treated and nontreated KFs were identified through RNA-sequencing (RNA-seq), followed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein–protein interaction (PPI) network analyses. Results: IGFBP3 was overexpressed in keloids and could promote KF proliferation. TβR-V antagonist suppressed KFs proliferation, migration, and invasion. GO and KEGG analyses showed that the downregulated DEGs revealed by RNA-seq were significantly enriched in terms related to cell proliferation. Interleukin-6 (IL-6) was identified as the only gene interacting with IGFBP3 in the PPI network and was associated with nine hub genes. In vitro assay confirmed the suppression of IL-6 by TβR-V antagonist in KFs. Conclusion: Our study demonstrated that TβR-V antagonist could inhibit keloid growth likely through suppressing IGFBP3 - IL-6 signaling activation. These findings suggest that targeting TβR-V could be a potential therapeutic strategy for keloid treatment. [ABSTRACT FROM AUTHOR]

Background: Hyperplasia of fibroblasts is critical in keloid pathogenesis. Insulin-like growth factor-binding protein 3 (IGFBP3) is an important factor in the regulation of cell growth and type V transforming growth factor-β receptor (TβR-V) is a specific receptor of IGFBP3. However, the role of IGFBP3 in keloid development has not been reported. Objectives: This study aimed to investigate the role of IGFBP3 in keloid pathogenesis and evaluate the effects of TβR-V antagonist on keloid fibroblasts (KFs) activities. Methods: IGFBP3 expression in keloids and its impact on KF proliferation were examined. The effects of TβR-V antagonist on KF cell proliferation, migration, and invasion were also investigated. Differentially expressed genes (DEGs) between TβR-V antagonist treated and nontreated KFs were identified through RNA-sequencing (RNA-seq), followed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein–protein interaction (PPI) network analyses. Results: IGFBP3 was overexpressed in keloids and could promote KF proliferation. TβR-V antagonist suppressed KFs proliferation, migration, and invasion. GO and KEGG analyses showed that the downregulated DEGs revealed by RNA-seq were significantly enriched in terms related to cell proliferation. Interleukin-6 (IL-6) was identified as the only gene interacting with IGFBP3 in the PPI network and was associated with nine hub genes. In vitro assay confirmed the suppression of IL-6 by TβR-V antagonist in KFs. Conclusion: Our study demonstrated that TβR-V antagonist could inhibit keloid growth likely through suppressing IGFBP3-IL-6 signaling activation. These findings suggest that targeting TβR-V could be a potential therapeutic strategy for keloid treatment.

Context: Soluble alpha klotho (sαKL) has been linked to growth hormone (GH) action, but systematic evaluation and comparisons with traditional biomarkers in acromegaly are lacking.Objective: To evaluate the potential of sαKL to aid classification of disease activity.Methods: This retrospective study at 2 academic centers included acromegaly patients before surgery (A, n = 29); after surgery (controlled, discordant, or uncontrolled) without (B1, B2, B3, n = 28, 11, 8); or with somatostatin analogue treatment (C1, C2, C3, n = 17, 11, 5); nonfunctioning pituitary adenomas (n = 20); and healthy controls (n = 31). sαKL was measured by immunoassay and compared with traditional biomarkers (random and nadir GH, insulin-like growth factor I [IGF-I], IGF binding protein 3). Associations with disease activity were assessed.Results: sαKL was correlated to traditional biomarkers, particularly IGF-I (rs=0.80, P <0.0001). High concentrations before treatment (A, median, interquartile range: 4.04 × upper limit of normal [2.26-8.08]) dropped to normal after treatment in controlled and in most discordant patients. A cutoff of 1548 pg/mL for sαKL discriminated controlled (B1, C1) and uncontrolled (B3, C3) patients with 97.8% (88.4%-99.9%) sensitivity and 100% (77.1%-100%) specificity. sαKL was below the cutoff in 84% of the discordant subjects. In the remaining 16%, elevated sαKL and IGF-I persisted, despite normal random GH. Sex, age, body mass index, and markers of bone and calcium metabolism did not significantly affect sαKL concentrations.Conclusion: Our data support sαKL as a biomarker to assess disease activity in acromegaly. sαKL exhibits close association with GH secretory status, large dynamic range, and robustness toward biological confounders. Its measurement could be helpful particularly when GH and IGF-I provide discrepant information. [ABSTRACT FROM AUTHOR]

Steatohepatitis drives fibrogenesis in alcohol-related liver disease. Recent studies have suggested that hepatic stellate cells (HSCs) may regulate the parenchymal cell injury and inflammation that precedes liver fibrosis, although the mechanism remains incompletely defined. Neuropilin-1 (NRP-1) and synectin are membrane proteins implicated in HSC activation. In this study, we disrupted NRP-1 and synectin as models to evaluate the role of HSC activation on the development of steatohepatitis in response to alcohol feeding in mice. Mice with HSC-selective deletion of NRP (ColCre/ Nrp1 loxP) or synectin (ColCre/synectinloxP) vs. paired Nrp1 l oxP or synectinloxP mice were fed a control diet or the chronic/binge alcohol feeding model. Several markers of steatosis and inflammation were evaluated. ColCre/ Nrp1 loxP mice showed less fibrosis, as expected, but also less inflammation and steatosis, with lower hepatic triglyceride content. Similar results were observed in the synectin model. Hepatocytes treated with supernatant of HSCs from ColCre/ Nrp1 loxP mice compared to supernatant from Nrp1 loxP mice were protected against ethanol-induced lipid droplet formation. An adipokine and inflammatory protein array from the supernatant of HSCs with NRP-1 knockdown showed a significant reduction in Igfbp3 (a major insulin-like growth factor-binding protein with multiple metabolic functions) and an increase in SerpinA12 (a serine-protease inhibitor) secretion compared to wild-type HSCs. Recombinant Igfbp3 induced lipid droplets, triglyceride accumulation, and lipogenic genes in hepatocytes in vitro, while SerpinA12 was protective against ethanol-induced steatosis. Finally, Igfbp3 was increased, and SerpinA12 was decreased in serum and liver tissue from patients with alcoholic hepatitis. Selective deletion of NRP-1 from HSCs attenuates alcohol-induced steatohepatitis through regulation of Igfbp3 and SerpinA12 signaling. Hepatic stellate cells are known for their role in fibrosis (scarring of the liver). In this study, we describe their role in the modulation of fat deposition and inflammation in the liver, which occurs secondary to alcohol damage. • HSCs regulate hepatocyte steatosis that precedes liver fibrosis in alcohol-related liver disease. • HSC-derived Igfbp3 and SerpinA12 mediate lipid droplet formation in hepatocytes. • These results are recapitulated in samples from patients with alcoholic hepatitis. [ABSTRACT FROM AUTHOR]

PurposeThe most common single nucleotide polymorphism in the IGFBP3 promoter region occurs at position -202. This polymorphic variation occurs frequently and may influence growth hormone responsiveness and somatic growth. However, the effects of IGFBP3 promoter polymorphism on growth in children are unknown.MethodsRestriction fragment length polymorphism-based genotyping of the -202 single nucleotide polymorphism was performed in 146 Korean girls aged between 15 and 16 years, who were selected randomly from the Seoul School Health Promotion Center. The participants were divided into 3 groups (tall, medium, and short) according to the height percentile established from normal reference values for Korean children. The serum levels of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) were then compared according to genotype.ResultsThe genotype distribution in the participants was 79 AA (54.1%), 60 AC (41.1%), and 7 CC (4.8%). The C allele frequency at the -202 IGFBP3 position was 25.4% in this group. The mean serum IGFBP-3 concentration in girls with the AA genotype was higher than that in girls with the AC genotype in the medium (P=0.047) and short (P=0.035) groups, respectively. There was no difference in the IGF-I to IGFBP-3 molar ratio between the AA and AC genotype groups (P=0.161).ConclusionIn conclusion, the -202 polymorphism in the IGFBP3 promoter region is assumed to affect the serum concentration of IGFBP-3 in children as well as in adults. However, it is unclear whether this affects physical development according to the concentration of IGFBP-3.

Background/Aims: Kabuki syndrome is a multiple congenital malformation syndrome with a variety of clinical features including short stature. The cause of this postnatal short stature remains unknown. Methods: Eighteen children with genetically proven Kabuki syndrome (8 boys and 10 girls; ages 3.3-9.9 years, with a mean of 6.7 years) who underwent growth hormone (GH) stimulation tests were evaluated in a prospective study. Two GH stimulation tests were conducted, including insulin-like growth factor I (IGF-I) and IGFbinding protein 3 (IGFBP-3) serum levels. GH stimulation peaks in relation to age, sex, height, body mass index (BMI), IGF-I, and IGFBP-3 SD scores (SDS) were analyzed. Results: Five of the 18 children (27.8%) were biochemically GH deficient. This was not correlated with BMI SDS. Of all patients, only 1 had an IGF-I below -2 SD and did not fulfill the GH deficiency criteria. The mean IGF-I level was below normal (-0.8 SD). All subjects had normal IGFBP-3 levels. Conclusions: The utility of performing GH stimulation tests on Kabuki syndrome children as an indication of GH status in short stature is questionable. IGF-I levels did correlate neither with the GH stimulation peak nor consequently with the diagnosis of GH deficiency. [ABSTRACT FROM AUTHOR]

Higher levels of insulin-like growth factor-binding protein 3 (IGFBP-3) might raise the risk of type 2 diabetes mellitus (T2DM) via binding of insulin-like growth factor 1 (IGF-1), an insulin-like hormone that is involved in glucose homeostasis. We investigated serum concentrations of IGF-1 and IGFBP-3 and their molar ratio in relation to T2DM incidence in a nested case-cohort study within the European Prospective Investigation Into Cancer and Nutrition-Potsdam Study. We included a randomly selected subcohort of persons without T2DM at the time of blood sampling (n= 2,269) and 776 individuals with incident T2DM identified between 1994 and 2005. For the highest quartile versus lowest, the multivariable-adjusted hazard rate ratios were 0.91 (95% confidence interval (CI): 0.68, 1.23; Pfor trend = 0.31) for IGF-1, 1.33 (95% CI: 1.00, 1.76; Pfor trend = 0.04) for IGFBP-3, and 0.77 (95% CI: 0.57, 1.03; Pfor trend = 0.03) for IGF-1 :IGFBP-3 ratio. IGFBP-3 level remained positively associated with T2DM incidence--and the ratio of IGF-1 to IGFBP-3 was inversely related with T2DM incidence--in models that included adjustment for IGF-1 concentrations (Pfor trend <0.05). Therefore, our findings do not confirm an association between total IGF-1 concentrations and risk of T2DM in the general study population, although higher IGFBP-3 levels might raise T2DM risk independent of IGF-1 levels. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is characterized by the aberrant expression of a number of genes that govern crucial signaling pathways. The insulin-like growth factor (IGF) axis is important in this context, and the precise regulation of expression of members of this axis is known to be lost in HCC. miR-155 is a well-established oncogene in numerous types of cancer. However, to the best of our knowledge, its effect on the regulation of the IGF axis has not been investigated to date. The present study aimed to elucidate the interactions between miR-155 and key components of the IGF axis, in addition to examining its effect on HCC development. Reverse transcription-quantitative polymerase chain reaction was used to measure the expression of miR-155 in HCC and cirrhotic tissues, in addition to HCC cell lines. Furthermore, the effect of the induction of miR-155 expression on the expression of three members of the IGF axis [IGF II, IGF type-1 receptor (IGF-1R) and IGF-binding protein 3 (IGFBP-3)], was analyzed. Finally, the effect of miR-155 on HCC cell proliferation, migration and clonogenicity was also examined. Quantification of the expression of miR-155 demonstrated that it is upregulated in HCC. Induction of the expression of miR-155 in HCC cell lines led to the upregulation of IGF-II and IGF-IR, and the downregulation of IGFBP-3. In addition, the proliferation, migration and clonogenicity of HCC was increased following induction of miR-155 expression. miR-155 is an oncomiR, which upregulates the oncogenes, IGF-II and IGF-IR, and downregulates the tumor suppressor, IGFBP-3, thereby resulting in increased HCC cell carcinogenicity. Therefore, miR-155 may be a therapeutic target in HCC. [ABSTRACT FROM AUTHOR]

Aims: To study the effect of the insulin-like growth factor (IGF) system on growth, adiposity and systolic blood pressure (SBP) in early life in British-born South Asian (SA) and White European (WE) children. Methods: The effect of IGF-1 and insulin-like growth factor-binding protein 3 (IGFBP-3) over the first 4 years in 204 healthy SA and WE children was investigated by mixed linear regression modelling. This enabled inclusion of all follow-up observations and adjustment for repeated measures. Results: At birth, SA babies were shorter and lighter than WE babies. Over 4 years, SA ethnicity was associated with lower height, weight and body mass index (BMI) standard deviation score (SDS), higher subscapular/triceps skinfold thickness (Ss/Tr SFT) and lower SBP (all p < 0.01). IGF-1 was associated with greater height (p = 0.03), weight (p < 0.001) and BMI SDS (p < 0.001), and IGFBP-3 with greater weight SDS (p < 0.001), BMI SDS (p = 0.001), Ss/Tr SFT (p = 0.003) and SBP (p = 0.023). Conclusions: Over this first 4-year period of life, SA ethnicity was associated with being shorter, lighter, having more superficial truncal adiposity and lower SBP. IGFBP-3 (and not IGF-1) was independently associated with both superficial truncal adiposity and SBP, suggesting that IGFBP-3 is a potential metabolic and cardiovascular marker in healthy children in the early years of life. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aim: This study was designed to estimate the percentage of growth hormone (GH)-treated children born small for gestational age (SGA), with serum IGF-1 >2 SDS before and after GH dose adaptation. Methods: SGA boys aged 4-9 and girls aged 4-7 with a height <-2 SDS and an annual growth rate below the mean received a subcutaneous GH dose of 57 μg/kg/day for 2 years. The GH dose was to be decreased by 30% in children with serum IGF-1 >2 SDS at 12 months and on the previous sample. The GH dose could be reduced a second time to 35 μg/kg·day. IGF-1 and IGFBP-3 dosages were centralized. Results: Among the 49 (21 boys) children included in the study, 8 (16.3%) had an IGF-1 >2 SDS consecutively at 9 and 12 months (95% CI 7.3, 29.7). The GH dose was decreased in 6/8 children. However, IGF-1 levels were elevated at several nonconsecutive determinations in 45% (95% CI 28.4, 56.6) of the patients. Conclusion: A high IGF-1 level is observed in 45% of the GH SGA-treated children with a relatively high dose of GH. A 30% reduction in the GH dose causes a decrease in IGF-1 below 2 SDS in most children. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Insulin-like growth factors (IGF) regulate growth and development and enhance cellular proliferation. IGF-binding protein-3 (IGFBP-3) inhibits IGF action by competitively binding IGFs that prevents their binding to the IGF cell surface receptor. Altered expression and serum levels of IGFBP-3 are associated with a number of malignancies. Study addressing the effect of IGFBP-3 gene polymorphism on bladder cancer is lacking. The aim of this study was to examine the effect of -202 A/C polymorphism of IGFBP-3 gene on development of bladder transitional cell carcinoma (TCC) and its correlation with serum concentration of IGF-1 and IGFBP-3 and with clinicopathological characteristics. One single nucleotide polymorphism ( rs2854744) was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RLFP) technique. One hundred and sixty-two bladder cancer patients were genotyped for this SNP. The genotypes were compared with those of a random sample of 324 age-matched controls of the general population. Serum levels of IGF-I and IGFBP-3 were also determined. We found statistically significant differences in the genotypic distribution between the cases and the control subject (χ = 6.43, df = 2.0, P = 0.028). Using CC genotype as a reference, the odds ratio for the subjects with AC genotype was 1.76 (95% CI: 1.27-2.84; P = 0.038). We detected a significantly decreased risk of bladder cancer associated with the AA genotype (adjusted OR = 0.48; 95% CI = 0.24-0.64; P = 0.001) compared with the CC genotype. This decreased risk was more pronounced for invasive bladder cancer. Age-adjusted mean serum IGFBP-3 levels were lowest in the individuals with the CC genotype. We found a positive correlation between age-adjusted serum IGFBP-3 levels and circulating IGF-1 concentrations (16% difference in IGFBP-3 in top vs. bottom tertiles of IGF-1, P for trend = 0.001), which was comparable across genotypes at the -202 IGFBP-3 locus (interaction term, F = 0.10, P = 0.87). Genetic polymorphism of the IGFBP-3 gene may be involved in the etiology of bladder TCC, and our results need further confirmation by larger studies. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) appear to influence breast cancer risk and are hypothesized to mediate the effects of several cancer risk factors that depend on menopausal status. We investigated associations among cancer risk factors and plasma IGF-I and IGFBP-3 in 882 healthy control women (426 premenopausal, 456 postmenopausal) from two population-based breast cancer case–control studies. Interactions with menopausal status were statistically tested. We observed associations with non-modifiable (age, benign breast disease) and modifiable factors [body mass index (BMI), physical activity, smoking habits, alcohol consumption]. Furthermore, we demonstrated statistical interactions with menopausal status. Premenopausal IGFBP-3 levels increased and postmenopausal levels decreased with age ( p-interaction = 0.001). Overweight postmenopausal women had higher IGF-I ( p = 0.049) and IGFBP-3 ( p = 0.005) levels than women with lower BMI. Postmenopausal IGF-I levels were positively associated with physical activity ( p-trend = 0.012, p-interaction = 0.050). Postmenopausal current smokers had lower IGF-I ( p = 0.014) and IGFBP-3 levels ( p = 0.011). Increasing alcohol consumption was associated with lower premenopausal IGF-I ( p-trend = 0.002, p-interaction = 0.004) and higher postmenopausal IGFBP-3 levels ( p = 0.019). Benign breast disease was associated with higher premenopausal ( p = 0.044) and postmenopausal ( p = 0.002) IGF-I levels. IGF-I and/or IGFBP-3 potentially mediate changes in breast cancer risk associated with BMI, benign breast disease, and perhaps alcohol consumption. Other observed associations suggest that neither IGF-I nor IGFBP-3 alone acts as mediator. Consideration of menopausal status may help disentangle carcinogenic pathways involving IGF proteins. [ABSTRACT FROM AUTHOR]

Pituitary dysfunction including growth hormone (GH) deficiency may be associated with non-alcoholic fatty liver disease (NAFLD). Since the relationships among GH, IGF-1, IGFBP-3, and development of NAFLD without hypopituitarism are unclear, we examined the role of these hormones in the development of NAFLD based on clinical, laboratory and liver histology data. A total of 55 consecutive patients (20 males and 35 females) with NAFLD. Aspartate amino transferase (AST), AST/ALT, platelet count and IGF-1, levels were significantly associated with differences in fibrosis, since these variables differed between stage 0–1 and stage 2–3 NAFLD. In multivariate analysis, platelet count ( P = 0.0223, relative risk (RR), 5.899; 95% confidence interval (CI), 1.288–27.017), and IGF-1 ( P = 0.0363, RR, 4.568; 95% CI, 1.101–18.945) showed significant associations with stage 2–3 NAFLD. Additionally, hyaluronic acid levels had a negative relationship with IGF-1 and the IGF-1/IGFBP-3 ratio. There was no relationship of fibrosis with GH level, but decreased GH ( P = 0.0414, RR, 0.199; 95% CI, 0.042–0.989) was significantly associated with steatosis of stage 2–3. Low GH/IGF-1 and GH/IGFBP-3 ratios were found in advanced steatosis. GH, IGF-1 and IGFBP-3 are associated with hepatic fibrosis and steatosis in NAFLD. Low levels of IGF-1 might be associated with fibrosis while low level of GH with hepatic steatosis. [ABSTRACT FROM AUTHOR]

Abstract: Insulin and insulin-like growth factors (IGFs) have critical functions in growth regulatory signalling pathways. They are part of a tightly controlled network of ligands, receptors, binding proteins and their proteases. However, the system becomes uncontrolled in neoplasia. The insulin-like growth factor binding protein 3 (IGFBP-3) and the insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) have unique properties among the sixteen known members of the IGFBP superfamily. IGFBP-3 has very high affinity for IGFs (k d ∼10−10 M), it transports>75% of serum IGF-I and -II, whereas it’s affinity for insulin is very low. On the other hand, IGFBP-rP1 binds insulin with very high affinity (500-fold higher compared to other IGFBPs), but has low affinity for IGF-I and -II proteins (k d =3×10−8 M). In this review, we have examined the roles of IGFBP-3 and IGFBP-rP1 in breast cancer, and discuss the potential impact of these two proteins in mammary carcinoma risk assessment and the development of treatments for breast cancer. [Copyright &y& Elsevier]

Background: The diagnosis of growth hormone deficiency (GHD) in infancy is difficult, and no specific cutoff value during GH provocative testing is recommended in early life. Methods: Serum insulin-like growth factor I (IGF-I) and serum IGF-binding protein 3 (IGFBP-3) levels were evaluated as diagnostic markers of GHD. Measurements of IGF-I and IGFBP-3 during the 1st year of life were analyzed in 11 patients clinically suspected of having GHD (neonatal hypoglycemia, micropenis, or evidence of other pituitary hormone deficiencies), in whom the diagnosis was later verified. A prospective cohort of 51 healthy infants served as controls. Results: The sensitivity of IGF-I as a diagnostic marker of GHD was 90% (10 out of 11 patients) with a cutoff value of –2 standard deviations (SD), and the sensitivity of IGFBP-3 measurements was 81% (9 out of 11 patients) with a cutoff value below –2 SD. One patient had serial measurements before initiation of GH treatment where the IGF-I was fluctuating (3 of 6 slightly above –2 SD), whereas all IGFBP-3 measurements were below –2 SD. Conclusions: The IGF-I had a high sensitivity in detecting infants with GHD. The combination of IGF-I and IGFBP-3 increased the diagnostic sensitivity. We speculate that assessment of IGF-I and IGFBP-3 may add diagnostic value in infants suspected of having GHD and furthermore that values below –2 SD are highly suggestive of GHD. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Several studies show that in elderly men bone mineral density (BMD) is not correlated with the insulin-like growth factor (IGF-I) level, but data are scanty in young men. Results of studies correlating insulin-like growth factor binding protein 3 (IGFBP-3) and BMD in men are discordant. As different hypotheses can explain the discordant results, we evaluated the correlation of BMD with serum IGF-I, IGFBP-3, and IGF-I/IGFBP-3 index in a large cohort of 721 men aged 19–85 years taking into account age, body weight, 17β-estradiol, free testosterone, and parathyroid hormone. Serum IGF-I and IGFBP-3 decreased with age (r = -0.44 and r = -0.36, P = 0.0001). After adjustment for confounding variables, IGF-I correlated weakly positively with BMD and with bone mineral apparent density (BMAD) of hip as well as with cortical thickness of femoral neck, both of which are determined mainly by bone resorption, but not with bone size determined by periosteal apposition. IGF-I correlated weakly positively with BMD at the whole body and at the third lumbar vertebra IGFBP-3 and IGF-I/IGFBP-3 index did not correlate with densitometric parameters. In men aged 19–60 years, IGF-I correlated with BMD and BMAD of total hip and with cortical thickness of femoral neck positively and more strongly than in the entire cohort but not with the size of proximal femur. BMD of total hip was 6% higher in men in the highest quartile of IGF-I than in men in the lowest quartile. IGF-I, IGFBP-3, and IGF-I/IGFBP-3 index did not correlate with densitometric parameters of other sites. In the men aged more than 60 years, neither IGF-I nor IGFBP-3 nor IGF-I/IGFBP-3 index correlated with BMD, BMAD, or bone size. In men aged 19–60 years, the most significant hormonal determinants of BMD and BMAD of the hip and of the cortical thickness of femoral neck were 17β-estradiol and IGF-I (P < 0.05–0.0001). In men aged more than 60 years, the most significant determinants of hip BMD were 17β-estradiol and PTH. In conclusion, IGF-I seems to contribute to the inhibition of bone resorption and to maintaining bone mass of the proximal femur during the phase of slow bone loss in men aged less than 60 years. IGFBP-3 and IGF-I/IGFBP-3 index were not correlated with BMD or bone size. [ABSTRACT FROM AUTHOR]

The insulin-like growth factor I (IGF-I) generation test has the potential to assess the ability of an individual to respond to an acute bolus of growth hormone (GH), in terms of IGF-I, IGF-binding protein 3 and acid-labile subunit responses. This article will discuss something of the history of the IGF-I generation test, and review some of the major studies to date. The IGF-I generation test was first used in adults by Lieberman et al., who studied the effects of ageing and oestrogen administration, and suggested that decreased responsiveness to GH occurs with increasing age and oral oestrogen administration. Our results, however, show that, while activity of the GH/IGF-I axis declines with age, peripheral responsiveness to GH is not affected. As in the Lieberman study, we found that oral oestrogen replacement reduces responses of GH-dependent peptides to GH stimulation in healthy post-menopausal women. Transdermal oestrogen administration also reduced responsiveness to GH, although to a lesser degree than orally administered oestrogen. In addition, utilizing a non-weight-based dose of GH we have demonstrated that obese individuals produce greater increases in IGF-I following an acute bolus of GH. In GH deficiency (GHD), data suggesting enhanced peripheral responsiveness should be interpreted with caution, and with awareness of differences between these groups in terms of age and obesity. The IGF-I generation test may allow a fresh approach to unanswered questions in the field of GHD, but as the IGF-I response to GH is not strictly associated with protein anabolism or clinical benefit, the question remains whether this test will predict the effect of longer-term GH administration. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Purpose: The most common single nucleotide polymorphism in the IGFBP3 promoter region occurs at position -202. This polymorphic variation occurs frequently and may influence growth hormone responsiveness and somatic growth. However, the effects of IGFBP3 promoter polymorphism on growth in children are unknown., Methods: Restriction fragment length polymorphism-based genotyping of the -202 single nucleotide polymorphism was performed in 146 Korean girls aged between 15 and 16 years, who were selected randomly from the Seoul School Health Promotion Center. The participants were divided into 3 groups (tall, medium, and short) according to the height percentile established from normal reference values for Korean children. The serum levels of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) were then compared according to genotype., Results: The genotype distribution in the participants was 79 AA (54.1%), 60 AC (41.1%), and 7 CC (4.8%). The C allele frequency at the -202 IGFBP3 position was 25.4% in this group. The mean serum IGFBP-3 concentration in girls with the AA genotype was higher than that in girls with the AC genotype in the medium ( P =0.047) and short ( P =0.035) groups, respectively. There was no difference in the IGF-I to IGFBP-3 molar ratio between the AA and AC genotype groups ( P =0.161)., Conclusion: In conclusion, the -202 polymorphism in the IGFBP3 promoter region is assumed to affect the serum concentration of IGFBP-3 in children as well as in adults. However, it is unclear whether this affects physical development according to the concentration of IGFBP-3., Competing Interests: Conflict of interest: No potential conflict of interest relevant to this article was reported.

Introduction: Adenotonsillar hypertrophy (ATH) may present with growth retardation. Insulin-like growth factor 1 (IGF-1) mediates the anabolic effects of growth hormone (GH) on tissues. Most of the circulating IGF-1 molecules are bound to insulin-like growth factor-binding protein 3 (IGFBP-3). IGF-1 and IGFBP-3 serum levels reflect the levels of daily mean serum GH and are used as indices for evaluating the serum level of GH. This study aimed to determine the effect of adenotonsillectomy on IGF-1 and IGFBP-3 serum levels in patients with ATH or recurrent tonsillitis. Furthermore, we aimed to investigate the effect of adenotonsillectomy on growth indices such as weight and height., Materials and Methods: A total of 100 randomly selected children with a diagnosis of ATH or recurrent tonsillitis with a mean age of 10.2 ± 1.4 years (range, 3-17 years) were enrolled in the intervention group. Of those, 53 were boys and 47 were girls. The control group included 100 healthy children (62 boys and 38 girls) with a mean age of 8.5 ± 1.5 years (range, 4-15 years). Growth indices such as weight and height were measured and documented at the time of surgery and 6 months after the operation. Blood samples were taken preoperatively and repeated 6 months after adenotonsillectomy. The coated-tube immunoradiometric (IRMA) method was used to measure IGF-1 and IGFBP-3 levels., Results: Postoperative IGF-1 and IGFBP-3 serum levels as well as weight and height showed were significantly greater in comparison with preoperative measurements in both the intervention and control groups (P<0.001). At the end of study, the intervention group showed significantly greater changes from baseline in IGF-1 and IGFBP-3 serum levels, weight, and height in comparison with the control group (P< 0.001)., Conclusions: This study shows that adenotonsillectomy in children with ATH or recurrent tonsillitis increases IGF-1 and IGFBP-3 serum levels in comparison with preoperative levels by affecting the GH-IGF-1 axis, and subsequently leads to a faster increase in growth indices compared with healthy peers during the same period.

Congenital disorders of glycosylation (CDG) are a growing group of inherited metabolic disorders where enzymatic defects in the formation or processing of glycolipids and/or glycoproteins lead to variety of different diseases. The deficiency of GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase, encoded by the human ortholog of ALG1 from yeast, is known as ALG1-CDG (CDG-Ik). The phenotypical, molecular and biochemical analysis of a severely affected ALG1-CDG patient is the focus of this paper. The patient's main symptoms were feeding problems and diarrhea, profound hypoproteinemia with massive ascites, muscular hypertonia, seizures refractory to treatment, recurrent episodes of apnoea, cardiac and hepatic involvement and coagulation anomalies. Compound heterozygosity for the mutations c.1145T>C (M382T) and c.1312C>T (R438W) was detected in the patient's ALG1-coding sequence. In contrast to a previously reported speculation on R438W we confirmed both mutations as disease-causing in ALG1-CDG., (© 2013.)

T-cell acute lymphoblastic leukemia (T-ALL) is characterized as a high-risk stratified disease associated with frequent relapse, chemotherapy resistance, and a poorer prognostic outlook than B-precursor ALL. Many of the challenges in treating T-ALL reflect the lack of prognostic cytogenetic or molecular abnormalities on which to base therapy, including targeted therapy. Notch1 activating mutations were identified in more than 50% of T-ALL cases and can be therapeutically targeted with γ-secretase inhibitors (GSIs). Mutant Notch1 can activate cMyc and PI3K-AKT-mTOR1 signaling in T-ALL. In T-ALLs with wild-type phosphatase and tensin homolog deleted on chromosome ten (PTEN), Notch1 transcriptionally represses PTEN, an effect reversible by GSIs. Notch1 also promotes growth factor receptor (IGF1R and IL7Rα) signaling to PI3K-AKT. Loss of PTEN is common in primary T-ALLs due to mutation or posttranslational inactivation and results in chronic activation of PI3K-AKT-mTOR1 signaling, GSI-resistance, and repression of p53-mediated apoptosis. Notch1 itself might regulate posttranslational inactivation of PTEN. PP2A is activated by Notch1 in PTEN-null T-ALL cells, and GSIs reduce PP2A activity and increase phosphorylation of AKT, AMPK, and p70S6K. This review focuses on the central role of the PI3K-AKT-mTOR1 signaling in T-ALL, including its regulation by Notch1 and potential therapeutic interventions, with emphasis on GSI-resistant T-ALL., (© 2013.)

Autophagy is an evolutionarily conserved process that promotes the lysosomal degradation of intracellular components including organelles and portions of the cytoplasm. Besides operating as a quality control mechanism in steady-state conditions, autophagy is upregulated in response to a variety of homeostatic perturbations. In this setting, autophagy mediates prominent cytoprotective effects as it sustains energetic homeostasis and contributes to the removal of cytotoxic stimuli, thus orchestrating a cell-wide, multipronged adaptive response to stress. In line with the critical role of autophagy in health and disease, defects in the autophagic machinery as well as in autophagy-regulatory signaling pathways have been associated with multiple human pathologies, including neurodegenerative disorders, autoimmune conditions and cancer. Accumulating evidence indicates that the autophagic response to stress may proceed in two phases. Thus, a rapid increase in the autophagic flux, which occurs within minutes or hours of exposure to stressful conditions and is entirely mediated by post-translational protein modifications, is generally followed by a delayed and protracted autophagic response that relies on the activation of specific transcriptional programs. Stress-responsive transcription factors including p53, NF-κB and STAT3 have recently been shown to play a major role in the regulation of both these phases of the autophagic response. Here, we will discuss the molecular mechanisms whereby autophagy is orchestrated by stress-responsive transcription factors., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objectives: To compare the response between Chinese children with growth hormone deficiency (GHD) born either small for gestational age (SGA) or appropriate for gestational age (AGA) after 4 weeks of recombinant human growth hormone (r-hGH) therapy., Methods: This was a phase IV, open-label, multicenter, interventional study (NCT01187550). Prepubertal children with GHD received open-label treatment with daily r-hGH (0.033 mg/kg) for 4 weeks. Serum levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor-binding protein 3 (IGFBP3), and metabolic markers (including fasting glucose, insulin, total cholesterol, and homeostasis model assessment of insulin resistance) were assessed at baseline and after 4 weeks of treatment, and were analyzed according to patient subgroup (SGA or AGA)., Results: A total of 205 children with GHD (mean age 10.4 years; 175 AGA, 30 SGA) were included in the analysis. Mean baseline serum IGF-I and IGFBP3 standard deviation scores (SDS) across the whole patient population were lower than the population norms (mean values: -2.1 SDS for IGF-I and -1.2 SDS for IGFBP3), with no significant differences between the two patient subgroups. After 4 weeks, IGF-I and IGFBP3 levels increased by 1.0 SDS (p < 0.001) and 0.34 SDS (p < 0.001), respectively, but no significant differences were found between the two patient subgroups for growth-related or metabolic markers., Conclusions: For children with GHD born SGA, IGF-I and IGFBP3 are short-term biomarkers of responsiveness to treatment with growth hormone, as for children with GHD born AGA.