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Concept: IGFBP3

170

Measurement of insulin-like growth factor-1 (IGF-I) has utility for the diagnosis and management of growth disorders, but inter-assay comparison of results has been complicated by a multitude of reference standards, antibodies, detection methods, and pre-analytical preparation strategies. We developed a quantitative LC-MS method for intact IGF-I, which has advantages in throughput and complexity when compared to mass spectrometric approaches that rely on stable isotope dilution analysis of tryptic peptides. Since the method makes use of full-scan data, the assay was easily extended to provide quantitative measurement of IGF-II using the same assay protocol. The validated LC-MS assay for IGF-I and IGF-II provides accurate results across the pediatric and adult reference range and is suitable for clinical use.

Concepts: Immune system, Mass spectrometry, Insulin-like growth factor 1, Growth hormone, Growth factors, Insulin-like growth factor, Peptide hormones, IGFBP3

168

Insulin-like growth factor II (IGF-II) is a major embryonic growth factor belonging to the insulin-like growth factor family which includes insulin and IGF-I. Its expression in humans is tightly controlled by maternal imprinting, a genetic restraint which is lost in many cancers, resulting in upregulation of both mature IGF-II mRNA and protein expression. Additionally, increased expression of several longer isoforms of IGF-II, termed pro- and big-IGF-II, has been observed. To date, it is ambiguous as to what role these IGF-II isoforms have in initiating and sustaining tumorigenesis and whether they are bioavailable. We have expressed each individual IGF-II isoform in their proper O-glycosylated format and established that all bind to the IGF-IR, IR-A and IR-B receptors, resulting in their activation and subsequent stimulation of fibroblast proliferation. We also confirmed that all isoforms are able to be sequestered into binary complex with several IGF binding proteins (IGFBP-2, IGFBP-3 and IGFBP-5). In contrast to this, ternary complex formation with IGFBP-3/IGFBP-5 and the auxillary protein, acid labile subunit (ALS) was severely diminished. Furthermore, big-IGF-II isoforms bound much more weakly to purified ectodomain of the natural IGF-II scavenging receptor, IGF-IIR. IGF-II isoforms thus possess unique biological properties which may enable them to escape normal sequestration avenues and remain bioavailable in vivo in order to sustain oncogenic signaling.

Concepts: DNA, Proteins, Protein, Molecular biology, Signal transduction, Hormone, Insulin-like growth factor 1, IGFBP3

28

Growth regulation in adult Atlantic salmon (1.6 kg) was investigated during 45 days in seawater at 13, 15, 17, and 19 °C. We focused on feed intake, nutrient uptake, nutrient utilization, and endocrine regulation through growth hormone (GH), insulin-like growth factors (IGF), and IGF-binding proteins (IGFBP). During prolonged thermal exposure, salmon reduced feed intake and growth. Feed utilization was reduced at 19 °C after 45 days compared with fish at lower temperatures, and body lipid storage was depleted with increasing water temperature. Although plasma IGF-1 concentrations did not change, 32-Da and 43-kDa IGFBP increased in fish reared at ≤17 °C, and dropped in fish reared at 19 °C. Muscle igf1 mRNA levels were reduced at 15 and 45 days in fish reared at 15, 17, and 19 °C. Muscle igf2 mRNA levels did not change after 15 days in response to increasing temperature, but were reduced after 45 days. Although liver igf2 mRNA levels were reduced with increasing temperatures after 15 and 45 days, temperature had no effect on igf1 mRNA levels. The liver igfbp2b mRNA level, which corresponds to circulating 43-kDa IGFBP, exhibited similar responses after 45 days. IGFBP of 23 kDa was only detected in plasma in fish reared at 17 °C, and up-regulation of the corresponding igfbp1b gene indicated a time-dependent catabolic response, which was not observed in fish reared at 19 °C. However, higher muscle ghr mRNA levels were detected in fish at 17 and 19 °C than in fish at lower temperatures, indicating lipolytic regulation in muscle. These results show that the reduction of muscle growth in large salmon is mediated by decreased igf1 and igf2 mRNA levels in addition to GH-associated lipolytic action to cope with prolonged thermal exposure. Accordingly, 13 °C appears to be a more optimal temperature for the growth of adult Atlantic salmon at sea.

Concepts: Liver, Insulin-like growth factor 1, Growth hormone, Ocean, Insulin-like growth factor, Atlantic salmon, Anabolism, IGFBP3

28

Background:In preterm infants, low levels of insulin-like growth factor-I (IGF-I) and IGF binding protein 3 (IGFBP-3) are associated with impaired brain growth and retinopathy of prematurity (ROP). Treatment with IGF-I/IGFBP-3 may be beneficial for brain development and may decrease the prevalence of ROP.Methods:In a phase II pharmacokinetics and safety study, five infants (three girls) with a median (range) gestational age (GA) of 26 wk + 6 d (26 wk + 0 d to 27 wk + 2 d) and birth weight of 990 (900-1,212) g received continuous intravenous infusion of recombinant human (rh)IGF-I/rhIGFBP-3. Treatment was initiated during the first postnatal day and continued for a median (range) duration of 168 (47-168) h in dosages between 21 and 111 µg/kg/24 h.Results:Treatment with rhIGF-I/rhIGFBP-3 was associated with higher serum IGF-I and IGFBP-3 concentrations (P < 0.001) than model-predicted endogenous levels. Of 74 IGF-I samples measured during study drug infusion, 37 (50%) were within the target range, 4 (5%) were above, and 33 (45%) were below. The predicted dose of rhIGF-I/rhIGFBP-3 required to establish circulating levels of IGF-I within the intrauterine range in a 1,000 g infant was 75-100 µg/kg/24 h. No hypoglycemia or other adverse effects were recorded.Conclusion:In this study, continuous intravenous infusion of rhIGF-I/rhIGFBP-3 was effective in increasing serum concentrations of IGF-I and IGFBP-3, and was found to be safe.

Concepts: Pregnancy, Childbirth, Embryo, Fetus, Obstetrics, Insulin-like growth factor 1, Growth hormone, IGFBP3

28

The IGF system plays important roles in growth. Nevertheless, few data have been reported so far on the expression of IGF system members and their relationship with growth in domestic animals, especially pigs. In this study, hepatic transcript level of IGF1, IGF2, IGF binding protein 2 (IGFBP2), IGFBP3 and IGF 1 receptor (IGF1R), plasma protein level of IGF1 and IGFBP3, and eight growth or carcass traits, including chest circumference, body length, body height (BH), body weight, carcass weight, loin muscle area (LMA), back fat thickness and average daily gain, were measured in fast-growing Landrace and slow-growing Lantang pigs at the age of 1, 27, 90, 150 and 180 days. The results showed that liver mRNA level of IGF1, IGF2 and IGF1R, and blood protein level of IGF1 have a similar developmental profile in both Landrace and Lantang pigs. Their levels were higher at the early age than that at other older ages. Hepatic transcript abundances of the two growth inhibitors, IGFBP2 and IGFBP3, were mostly higher in Lantang pigs than that in Landrace pigs, at 5 examined postnatal stages. The IGF system members' liver mRNA level and/or serum protein level have significant correlation with each other in different age of Landrace or Lantang pigs. Hepatic mRNA level or serum protein level of IGF system members also has significant correlation with investigated traits, especially with BH and LMA, in different age of Lantang or Landrace pigs. Our results revealed the change profiles of porcine IGF system members' liver transcript level and plasma protein level between different pig breeds and different postnatal developmental ages. Moreover, the correlation analysis results suggest that the IGF system members act coordinately to regulate the growth performance and carcass composition in pigs. The information obtained from the present study is important for elucidation of the regulatory mechanism of IGF system underlying growth, and for genetic improvement in pigs.

Concepts: Protein, Genetics, Transcription, Liver, Insulin-like growth factor 1, Insulin-like growth factor, IGFBP3, Serum protein electrophoresis

27

OBJECTIVE: Insulin-like growth factor (IGF) levels, their binding proteins (IGFBPs), and high-dose statin therapy, have all been linked to the development of diabetes. We aimed to identify whether atorvastatin caused dose-related changes in IGF proteins. DESIGN AND METHODS: We measured IGF1, IGF2, IGFBP1 and IGFBP3 concentrations at baseline, 6 months and 12 months in PANDA trial participants with type 2 diabetes randomised to 10mg (n=59) vs 80mg (n=60) of atorvastatin (N=119; mean (SD): age 64(10) years; 83% male; HbA1c 61(10) mmol/mol; blood pressure 131/73 mmHg. RESULTS: Atorvastatin was associated with overall reductions in circulating IGF1, IGF2 and IGFBP3 concentrations. The adjusted mean (95% CI) between-group differences that indicate dose-related changes in IGF proteins were not significant for: IGF1: -3 (-21 to 14) ng/ml; IGF2: -23 (-65 to 18) ng/ml; and IGFBP3: -0.34 (-0.71 to 0.03) µg/ml; negative values indicating numerically greater lowering with high-dose). The IGFBP1 concentration did not change overall with atorvastatin therapy overall but the adjusted mean (95% CI) between-group difference indicating a dose-related change in log IGFBP1 was highly significant -0.41 (-0.69 to 0-0.13, p=0.004). CONCLUSION: IGF1, IGF2 and IGFBP3 concentrations all decreased following atorvastatin therapy. A differential effect of low vs high dose atorvastatin on IGFBP1 concentrations was observed with likely implications for IGF bioavailability. The dose-related differential impact of atorvastatin treatment on concentration of IGF proteins merits investigation as a mechanism to explain the worsening of glucose tolerance with statin therapy.

Concepts: Hypertension, Diabetes mellitus, Glucose, Statin, Insulin-like growth factor 1, Growth factors, Insulin-like growth factor, IGFBP3

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Objectives. The aim of this study was to determine the normal values of serum IGF-1 and IGFBP-3 in Turkish children and adults (1-79 years). Material and methods. The study included 571 healthy children and 625 healthy adults from the West Black Sea region of Turkey. Serum IGF-1 and IGFBP-3 concentrations were determined using a chemiluminescent immunometric assay on an Immulite 1000 analyzer. Results. IGF-1 and IGFBP-3 levels tended to be higher in girls compared to boys among the children. The differences were statistically significant in puberty from age 12-14 years for IGF-1 and prepubertally from age 9-10 years for IGFBP-3. Peaks of serum IGF-1 levels were observed 2 years earlier in girls (14 years) than boys (16 years). The general pattern of IGFBP-3 was similar to IGF-1 during puberty. In adults, IGF-1 and IGFBP-3 levels decreased by age. There was no significant difference in IGF-1 and IGFBP3 values between men and women in any age group. Conclusions. This study established age- and sex-specific reference values for serum IGF-1 and IGFBP-3 in healthy Turkish children and adults.

Concepts: Statistical significance, Insulin-like growth factor 1, Difference, Growth factors, Turkey, Insulin-like growth factor, IGFBP3, Black Sea

3

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype-phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci.

Concepts: DNA, Gene, Gene expression, Bioinformatics, Insulin-like growth factor 1, Genome-wide association study, C-reactive protein, IGFBP3

0

Insulin-like growth factor binding proteins (IGFBPs) play crucial roles in regulating the availability of IGFs to receptors and prolong the half-lives of IGFs. There are six IGFBPs present in the mammalian circulation with IGFBP-3 being most abundant. In mammals IGFBP-3 is the major carrier of circulating IGFs, facilitated by forming a ternary complex with IGF and an acid-labile subunit (ALS). IGFBP-1 is generally inhibitory to IGF action by preventing it from interacting with its receptors. In teleosts, the third-round of vertebrate whole genome duplication created paralogs of each IGFBP, except IGFBP-4. In the fish circulation, three major IGFBPs are typically detected at molecular ranges of 20-25, 28-32 and 40-50 kDa. However, their identities are not well established. Three major circulating IGFBPs in Chinook salmon have been identified through protein purification and cDNA cloning. Salmon 28- and 22-kDa IGFBPs are co-orthologs of IGFBP-1, termed IGFBP-1a and -1b, respectively. They are induced under catabolic conditions such as stress and fasting but their responses are somewhat different, with IGFBP-1b being the most sensitive of the two. Cortisol stimulates production and secretion of these IGFBP-1 subtypes while, unlike in mammals, insulin may not be a primary suppressor. Salmon 41-kDa IGFBP, a major carrier of IGF-I, is not IGFBP-3, as might be expected extrapolating from mammals, but is in fact IGFBP-2b. Salmon IGFBP-2b levels in plasma are high when fish are fed, and GH treatment increases its circulating levels similar to mammalian IGFBP-3. These findings suggest that salmon IGFBP-2b acquired the role and regulation similar to mammalian IGFBP-3. Multiple replication of fish IGFBPs offer a unique opportunity to investigate molecular evolution of IGFBPs.

Concepts: DNA, Protein, Hormone, Insulin-like growth factor 1, Gene duplication, Salmon, IGFBP3, Insulin-like growth factor binding protein

0

The aim of this investigation was to compare serum growth hormone (GH), insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-3 (IGFBP-3) in response to a combined sprint and resistance training (CSRT) program in young and middle-aged men.Thirty-eight healthy, moderately trained men participated in this study. Young and middle-aged men were randomly assigned to, a young training group (YT = 10, 21.4±1.2yrs) ora young control group (YC = 9, 21.6±1.8 yrs), a middle-aged training group (MAT = 10, 40.4±2.1 yrs) or a middle-aged control group (MAC = 9, 40.5±1.8 yrs). Participants performed the Wingate Anaerobic Test (WAnT) before and after a 13-week CSRT program (three sessions per week). Blood samples were collected at rest, after warm-up, immediately post-WAnT, and 10 min post-WAnT. CSRT induced increases in GH at rest and in response to the WAnT in YT and MAT (P<0.05). CSRT-induced increases were observed for IGF-1 and IGFBP-3 at rest in MAT only (P<0.05). Pre-training, GH, IGF-1 and IGFBP-3 were significantly higher at rest and in response to the WAnT in young participants as compared to their middle-aged counterparts (P<0.05). Post-training, YT and MAT had comparable basal GH (P>0.05). In response to the WAnT, amelioration of the age-effect was observed between YT and MAT for IGF-1 and IGF-1/IGFBP-3 ratio following CSRT (P>0.05). These data suggest that CSRT increases the activity of the GH/IGF-1 axis at rest and in response to the WAnT in young and middle-aged men. In addition, CSRT reduces the normal age-related decline of somatotropic hormones in middle-age men.

Concepts: Immune system, Hypothalamus, Insulin-like growth factor 1, Growth hormone, Endocrine gland, IGFBP3