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Concept: Insulin-like growth factor 1

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Insulin-like growth factor 1 (IGF-1), the most abundant growth factor in the bone matrix, maintains bone mass in adulthood. We now report that IGF-1 released from the bone matrix during bone remodeling stimulates osteoblastic differentiation of recruited mesenchymal stem cells (MSCs) by activation of mammalian target of rapamycin (mTOR), thus maintaining proper bone microarchitecture and mass. Mice with knockout of the IGF-1 receptor (Igf1r) in their pre-osteoblastic cells showed lower bone mass and mineral deposition rates than wild-type mice. Further, MSCs from Igf1rflox/flox mice with Igf1r deleted by a Cre adenovirus in vitro, although recruited to the bone surface after implantation, were unable to differentiate into osteoblasts. We also found that the concentrations of IGF-1 in the bone matrix and marrow of aged rats were lower than in those of young rats and directly correlated with the age-related decrease in bone mass. Likewise, in age-related osteoporosis in humans, we found that bone marrow IGF-1 concentrations were 40% lower in individuals with osteoporosis than in individuals without osteoporosis. Notably, injection of IGF-1 plus IGF binding protein 3 (IGFBP3), but not injection of IGF-1 alone, increased the concentration of IGF-1 in the bone matrix and stimulated new bone formation in aged rats. Together, these results provide mechanistic insight into how IGF-1 maintains adult bone mass, while also providing a further rationale for its therapeutic targeting to treat age-related osteoporosis.

Concepts: Bone, Stem cell, Mesenchymal stem cell, Bone marrow, Skeletal system, Cellular differentiation, Insulin-like growth factor 1, Insulin-like growth factor

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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

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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

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The NEPROCHECK test (Astute Medical, San Diego, CA, USA) combines urinary tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) to identify patients at high risk for acute kidney injury (AKI). In a US Food and Drug Administration registration trial (NCT01573962), AKI was determined by a three-member clinical adjudication committee. The objectives were to examine agreement among adjudicators as well as between adjudicators and consensus criteria for AKI and to determine the relationship of biomarker concentrations and adjudicator agreement.

Concepts: Blood, Insulin-like growth factor 1, California, Adjudicator

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Although both growth hormone (GH) and insulin-like growth factor 1 (IGF-1) signaling were shown to regulate life span in lower organisms, the role of GH signaling in human longevity remains unclear. Because a GH receptor exon 3 deletion (d3-GHR) appears to modulate GH sensitivity in humans, we hypothesized that this polymorphism could play a role in human longevity. We report a linear increased prevalence of d3-GHR homozygosity with age in four independent cohorts of long-lived individuals: 841 participants [567 of the Longevity Genes Project (LGP) (8% increase; P = 0.01), 152 of the Old Order Amish (16% increase; P = 0.02), 61 of the Cardiovascular Health Study (14.2% increase; P = 0.14), and 61 of the French Long-Lived Study (23.5% increase; P = 0.02)]. In addition, mega analysis of males in all cohorts resulted in a significant positive trend with age (26% increase; P = 0.007), suggesting sexual dimorphism for GH action in longevity. Further, on average, LGP d3/d3 homozygotes were 1 inch taller than the wild-type (WT) allele carriers (P = 0.05) and also showed lower serum IGF-1 levels (P = 0.003). Multivariate regression analysis indicated that the presence of d3/d3 genotype adds approximately 10 years to life span. The LGP d3/d3-GHR transformed lymphocytes exhibited superior growth and extracellular signal-regulated kinase activation, to GH treatment relative to WT GHR lymphocytes (P < 0.01), indicating a GH dose response. The d3-GHR variant is a common genetic polymorphism that modulates GH responsiveness throughout the life span and positively affects male longevity.

Concepts: Immune system, Gene, Genetics, Allele, Signal transduction, Insulin-like growth factor 1, Growth hormone, Heterozygote advantage

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BACKGROUND: The ability of an intermittent fasting (IF)-calorie restriction (CR) regimen (with or without liquid meals) to modulate adipokines in a way that is protective against coronary heart disease (CHD) has yet to be tested. OBJECTIVE: Accordingly, we examined the effects of an IFCR diet on adipokine profile, body composition, and markers of CHD risk in obese women. METHODS: Subjects (n = 54) were randomized to either the IFCR-liquid (IFCR-L) or IFCR-food based (IFCR-F) diet for 10 weeks. RESULTS: Greater decreases in body weight and waist circumference were noted in the IFCR-L group (4 +/- 1 kg; 6 +/- 1 cm) versus the IFCR-F group (3 +/- 1 kg; 4 +/- 1 cm). Similar reductions (P < 0.0001) in fat mass were demonstrated in the IFCR-L (3 +/- 1 kg) and IFCR-F group (2 +/- 1 kg). Reductions in total and LDL cholesterol levels were greater (P = 0.04) in the IFCR-L (19 +/- 10%; 20 +/- 9%, respectively) versus the IFCR-F group (8 +/- 3%; 7 +/- 4%, respectively). LDL peak particle size increased (P < 0.01) in the IFCR-L group only. The proportion of small LDL particles decreased (P < 0.01) in both groups. Adipokines, such as leptin, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and insulin-like growth factor-1 (IGF-1) decreased (P < 0.05), in the IFCR-L group only. CONCLUSION: These findings suggest that IFCR with a liquid diet favorably modulates visceral fat and adipokines in a way that may confer protection against CHD.

Concepts: Cholesterol, Nutrition, Atherosclerosis, Obesity, Mass, Adipose tissue, Insulin-like growth factor 1, LDL

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HT042, a new herbal prescription consisting of Astragalus membranaceus, Phlomis umbrosa and Eleutherococcus senticosus, is used in traditional Korean medicine to stimulate growth in children. This study was conducted to investigate the effects of HT042 on skeletal growth, insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) levels, and oestrogenic activity in female rats. Female Sprague-Dawley rats were divided into control, recombinant human growth hormone (rhGH; 20 µg/kg/day), and HT042 (100 mg/kg/day) groups and treated for 3 weeks. Axial skeletal growth, femur length, and growth plate length were measured every 3 weeks. The serum IGF-1 and IGFBP-3 levels were analysed. Moreover, the oestrogenic activity of the herbal extracts in the immature and ovariectomized rats was tested. The nose-anus, nose-tail, femur and growth-plate lengths were increased significantly in the HT042 group. Both IGF-1 and IGFBP-3 were highly expressed in the hypertrophic zone of the growth plate. The serum IGF-1 levels were increased. Moreover, HT042 had no uterotrophic effects in the rats. Consequently, HT042 promoted longitudinal bone growth by stimulating cell proliferation in the epiphyseal plate and inducing the expression of IGF-1 without an oestrogenic response. HT042 may be helpful in stimulating growth in children with short stature. Copyright © 2012 John Wiley & Sons, Ltd.

Concepts: Immune system, Insulin-like growth factor 1, Growth hormone, Growth factors, Endochondral ossification, Insulin-like growth factor, Idiopathic short stature, Long bone

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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

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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

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Liver resection offers a chance of cure for patients with hepatocellular carcinoma (HCC). Hepatic pedicle clamping (HPC) is commonly used to reduce blood loss during hepatectomy. Hepatic ischemia-reperfusion (I/R) injury has recently been reported to be a major factor in accelerated tumor growth. We therefore evaluated the effect of intermittent HPC on the prognosis of patients after liver resection.

Concepts: Cancer, Iron, Red blood cell, Cirrhosis, Platelet, Insulin-like growth factor 1, Hepatitis C, Liver transplantation