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Oral ghrelin receptor agonist MK-0677 increases serum insulin-like growth factor 1 in hemodialysis patients: a randomized blinded study.
Campbell, GA, Patrie, JT, Gaylinn, BD, Thorner, MO, Bolton, WK
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2018;(3):523-530
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Abstract
BACKGROUND Protein-energy wasting (PEW) in end-stage renal disease (ESRD) patients is associated with increased morbidity and mortality, but options for treatment are limited. Growth hormone (GH) increases insulin-like growth factor 1 (IGF-1), with improved nutritional parameters, but must be given subcutaneously and does not provide normal GH secretion patterns. MK-0677, an oral ghrelin receptor agonist (GRA), maintains normal GH secretion and increases lean body mass in normal subjects; it has not been studied in dialysis patients, an essential step in assessing efficacy and safety prior to clinical trials. METHODS We performed a randomized crossover double-blind study in assessing the effect of MK-0677 versus placebo on IGF-1 levels, the primary outcome, in hemodialysis patients. In total, 26 subjects enrolled and 22 completed the 3-month crossover study. RESULTS The geometric mean IGF-1 was 1.07-fold greater [95% confidence interval (CI) 0.89-1.27; P = 0.718] after placebo. In patients receiving MK-0677, the geometric mean IGF-1 were 1.76-fold greater (95% CI 1.48-2.10; P < 0.001) following MK-0677. When the data were adjusted for preintervention IGF-1 concentration, the ratio of geometric means (MK-0677 relative to placebo) for the pre- versus postintervention change in the IGF-1 was 1.65 (95% CI 1.33-2.04; P < 0.001). These data demonstrate a 65% greater increase (95% CI 33-104%) in IGF-1 in MK-0677-dosed subjects compared with placebo. There were no serious adverse effects attributable to MK-0677. CONCLUSIONS MK-0677 increased serum IGF-1 levels with minimal adverse effects in hemodialysis subjects. Studies are needed to evaluate whether long-term therapy with MK-0677 improves PEW, lean body mass, physical strength, quality of life and survival in CKD/ESRD patients.
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Effects of dietary advice on insulin-like growth factors among healthy newborns.
Bulduk, EÖ, Bulduk, S, Coşkun, BB
Archives of gynecology and obstetrics. 2018;(3):637-643
Abstract
OBJECTIVES In fetal life, insulin, insulin-like growth factor (IGF) 1, IGF 2 and IGF-binding protein (IGFBP) 3 are essential growth factors. The purpose of this study is to investigate the effects of dietary intervention on insulin-like growth factors in the cord blood of neonates. METHODS The study involved 52 pregnant women who were followed up in Gazi University Medical School Hospital at Ankara, Turkey. They were randomly divided into two groups: The experimental group was involved in nutrition education. We measured IGF 1, IGF 2 and IGFBP 3 concentrations in cord blood from 52 neonates. RESULTS In the experimental group, cord serum levels of IGF 1, IGF 2 were observed to be higher than that of control group. CONCLUSION Dietary advice had positive effects on the cord serum IGF 1 and IGF 2 concentrations. Dietary advice during pregnancy proved to be effective in fetal development.
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Treatment of growth failure in the absence of GH signaling: The Ecuadorian experience.
Guevara-Aguirre, J, Guevara, A, Guevara, C
Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. 2018;:53-56
Abstract
Recombinant human insulin-like growth factor-1 (rhIGF-1) treatment studies of growth failure in absence of growth hormone (GH) signaling (GH insensitivity -GHI, Laron syndrome -LS, GH Receptor deficiency -GHRD) have taken place in many locations around the globe. Results from these trials are comparable, and slight differences reported can be attributed to specific circumstances at different research sites. rhIGF-I treatment studies of GHI in Ecuador included various trials performed on children belonging to the largest and only homogeneous cohort of subjects with this condition in the world. All trials were performed by the same team of investigators and, during study periods, subjects received similar nutritional, physical activity and medical advice. Combination of these inherent conditions most likely creates less sources of variability during the research process. Indeed, diagnosis, selection and inclusion of research subjects; methodology used; transport, storage and delivery of study drug; data collection, monitoring and auditing; data analysis, discussion of results, conclusion inferences and reporting, etc., were submitted to the same sources of error. For the above-mentioned reasons, we are hereby mainly covering conclusions derived from rhIGF-I treatment studies of Ecuadorian children whit GHRD due to homozygosity of a splice site mutation occurring at GHR gene, whose unaffected parents were both heterozygous for the same mutation. We also describe studies of rhIGF-I administration in adolescent and adult subjects with GHRD, from the same cohort and with the same genetic anomaly.
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Growth Factors Release From Concentrated Growth Factors: Effect of β-Tricalcium Phosphate Addition.
Bonazza, V, Hajistilly, C, Patel, D, Patel, J, Woo, R, Cocchi, MA, Buffoli, B, Lancini, D, Gheno, E, Rezzani, R, et al
The Journal of craniofacial surgery. 2018;(8):2291-2295
Abstract
BACKGROUND Platelet concentrates represent a new approach to improve tissue regeneration and can be used alone or together with autogenous bone, recombinant human growth factors, and/or other biomaterials, to enhance tissue regeneration. Among platelet concentrates, concentrated growth factors (CGFs) exhibit an interesting clinical and biotechnological application potential. OBJECTIVE The aim of this study was to evaluate the in vitro release of 4 growth factors (bone morphogenetic proteins [BMP] -2, BMP-7, transforming growth factor [TGF] -β1, and insulin-like growth factor [IGF] -1) by the enzyme-linked immunosorbent assay (ELISA) technique, in CGFs mixed or not with β-tricalcium phosphate (β-TCP), using or not the Round-up device, at different times. METHODS CGFs were obtained from healthy volunteers, mixed or not with β-TCP, using or not the Round-up device. The release of 4 growth factors from these CGFs was then measured at 5 hours, 1, 3, 6, and 8 days, using the ELISA assay. RESULTS Comparison of the results obtained with those achieved for CGFs alone showed that BMP2 and BMP-7 release, significantly increased in CGFs mixed with Round-up and β-TCP, TGF-β1 release was similar to CGFs alone, whereas IG-1 release was lower compared with CGFs alone. CONCLUSION The present data suggest that β-TCP addition to CGF could enhance and improve tissue regeneration, especially bone regeneration, increasing the release of some growth factors that play an important role in osteogenesis.
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IGF and IGFBP as an index for discrimination between vitamin D supplementation responders and nonresponders in overweight Saudi subjects.
Al-Daghri, NM, Yakout, SM, Wani, K, Khattak, MNK, Garbis, SD, Chrousos, GP, Al-Attas, OS, Alokail, MS
Medicine. 2018;(19):e0702
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Abstract
Vitamin D deficiency is common in the Kingdom of Saudi Arabia (KSA). Therefore, it is significant to recognize which biochemical markers modulate serum 25 hydroxyvitamin D (25(OH)D) in response to vitamin D supplementation in such a population. Our aim was to study the correlation of insulin-like growth factor (IGF) and insulin growth factor binding protein (IGFBP) with serum 25(OH)D in response to vitamin D supplementation in a Saudi population. A total of 199 (89 males/110 females) vitamin D deficient subjects (25(OH)D level <50 nmol/L), aged 40.4 ± 11.4 years, were given vitamin D supplements (50,000 IU/mL every week) for the first 2 months, then twice a month for 2 months, followed by daily 1000 IU in the last 2 months. Fasting blood samples were taken at baseline and 6 months after the final dose of vitamin D. Serum 25(OH)D, IGF-1 and IGF-2, and IGFBPs 2-5 were measured. Vitamin D response was computed for all subjects as the difference in levels of serum 25(OH)D concentration at the end of 6 months compared to baseline. After intervention, serum 25(OH)D concentration significantly increased from 35.6 nmol/L (26.6-43.5) to 61.8 nmol/L (54.8-73.3) in responder subjects (P < .01) and from 35.1 nmol/L (21.2-58.2) to 38.3 nmol/L (25.5-48.3) in nonresponders (P = .13). Subjects with lower baseline serum IGF-II, IGFBP-2, and IGF-1/IGFBP-3 ratio are more sensitive to acute vitamin D status changes. IGF1 and IGF-1/IGFBP-3 ratio significantly increased in all subjects after 6 months (P = .01). Changes in 25(OH)D was significantly associated with changes in IGFBP-2 and IGF-1/IGFBP-3 ratio in responders only. This study proposes that changes in circulating IGF-I and IGFBP-3 are modulated by vitamin D supplementation and can be taken into consideration in investigations involving vitamin D correction. Moreover, increase in serum 25(OH)D and IGF-I/IGFBP-3 molar ratio are more sensitive markers for the response to vitamin D supplementation in Saudi population.
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Reduced Growth Hormone Secretion is Associated with Nonalcoholic Fatty Liver Disease in Obese Children.
Liang, S, Yu, Z, Song, X, Wang, Y, Li, M, Xue, J
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2018;(3):250-256
Abstract
The purpose of the study was to evaluate the relationship between arginine-levodopa-induced growth hormone (GH) secretion and nonalcoholic fatty liver disease (NAFLD) in obese children. This study includes a total of 84 obese and 43 normal weight children. The obese subjects are divided into two groups based on the presence or absence of NAFLD. Clinical examination, anthropometric and laboratory examinations, and liver ultrasonography are assessed for all participants. The obese group had significantly lower peak stimulated GH (p<0.001) and lower insulin-like growth factor 1 (IGF-1) (p<0.001) compared with the control group. Children with NAFLD had significantly lower peak stimulated GH (p<0.001) and lower IGF-1 (p=0.022) compared with non-NAFLD group. Results from logistic regression model showed that only peak GH after stimulation test was inversely associated with NAFLD (p=0.015), while body mass index (BMI) was positively associated with NAFLD (p=0.03). Among 84 obese children and adolescents, peak stimulated GH was negatively associated with alanine aminotransferase (r=-0.394, p<0.001), BMI (r=-0.571, p<0.001), systolic blood pressure (r=-0.223, p=0.041), diastolic blood pressure (r=-0.272, p=0.012), homeostasis model assessment of insulin resistance (r=-0.369, p=0.001), insulin (r=-0.382, p<0.001), and positively associated with high density lipoprotein cholesterol (r=0.275, p=0.011). Our study confirms a significant inverse relationship between NAFLD and GH response to standard stimulation testing in obese children without known hypothalamic/pituitary disease.
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The Influence of Maternal Obesity and Breastfeeding on Infant Appetite- and Growth-Related Hormone Concentrations: The SKOT Cohort Studies.
Larnkjær, A, Ong, KK, Carlsen, EM, Ejlerskov, KT, Mølgaard, C, Michaelsen, KF
Hormone research in paediatrics. 2018;(1):28-38
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Abstract
BACKGROUND/AIMS: Exposure to obesity during pregnancy may lead to adverse changes in the offspring's metabolic profile. We compared appetite- and growth-related hormones in a cohort of infants born to obese mothers (SKOT-II) with infants born mainly to nonobese mothers (SKOT-I). METHODS Infants from SKOT-I (n = 273) and SKOT-II (n = 132) were examined including anthropometric measurements and blood samples analyzed for glucose, insulin, insulin-like growth factor-I (IGF-I), adiponectin, and leptin. Information on breastfeeding and parental characteristics were also collected. RESULTS At 9 months of age, SKOT-II infants were 3.6% heavier and 1.2% longer than SKOT-I infants even though their mothers were shorter. There was no difference in body mass index (BMI). SKOT-II infants had higher levels of insulin, adiponectin, and leptin but lower levels of IGF-I compared to SKOT-I infants (all p ≤ 0.015). These differences remained, except for leptin, when adjusted for current weight. Breastfeeding versus nonbreastfeeding at 9 months was associated with lower concentrations of all hormones (all p ≤ 0.003). In adjusted models, maternal BMI at 9 months was positively associated with insulin and adiponectin and negatively with IGF-I. CONCLUSIONS Pre-pregnancy obesity confers symmetrically larger infant body size and higher levels of most growth- and appetite-related hormones but surprisingly lower levels of IGF-I, suggesting other possible infant growth-promoting effects through insulin.
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A novel functional crosstalk between DDR1 and the IGF axis and its relevance for breast cancer.
Belfiore, A, Malaguarnera, R, Nicolosi, ML, Lappano, R, Ragusa, M, Morrione, A, Vella, V
Cell adhesion & migration. 2018;(4):305-314
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Abstract
In the last decades increasing importance has been attributed to the Insulin/Insulin-like Growth Factor signaling (IIGFs) in cancer development, progression and resistance to therapy. In fact, IIGFs is often deregulated in cancer. In particular, the mitogenic insulin receptor isoform A (IR-A) and the insulin-like growth factor receptor (IGF-1R) are frequently overexpressed in cancer together with their cognate ligands IGF-1 and IGF-2. Recently, we identified discoidin domain receptor 1 (DDR1) as a new IR-A interacting protein. DDR1, a non-integrin collagen tyrosine kinase receptor, is overexpressed in several malignancies and plays a role in cancer progression and metastasis. Herein, we review recent findings indicating that DDR1 is as a novel modulator of IR and IGF-1R expression and function. DDR1 functionally interacts with IR and IGF-1R and enhances the biological actions of insulin, IGF-1 and IGF-2. Conversely, DDR1 is upregulated by IGF-1, IGF-2 and insulin through the PI3K/AKT/miR-199a-5p circuit. Furthermore, we discuss the role of the non-canonical estrogen receptor GPER1 in the DDR1-IIGFs crosstalk. These data suggest a wider role of DDR1 as a regulator of cell response to hormones, growth factors, and signals coming from the extracellular matrix.
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[Effects of aerobic exercise plus diet control on serum levels of total IGF-1 and IGF-1 binding protein-3 in female obese youths and adolescents].
Yang, HF, Lin, XJ, Wang, XH
Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology. 2018;(1):78-82
Abstract
OBJECTIVE To investigate the effects of 4-week moderate aerobic exercise plus diet control on serum levels of total insulin-like growth factor 1(IGF-1) and IGF-1 binding protein-3 (IGFBP-3) as well as IGF-1 activity (reflected by molar ratio of IGF-1/IGFBP-3) in female obese adolescents and youths, and their possible role on fat loss, and improvement of glucose and lipid metabolism. METHODS Nine female obese youths (age:18~19 y) and 30 female obese adolescents (age:14~16 y) were recruited and undertook 4-week aerobic exercise such as swimming and jogging (6 days/week, twice a day, 2 h/time with 5 min rest per 30 min exercise) with gradual increase of intensity from low (heart rate immediately post-exercise of 1st week:100~120 beats/min) to moderate (heart rate immediately post-exercise of 2nd-4th weeks:120~140 beats/min) level, combined with a diet intervention (total daily energy intake of 1 400 or 1 600 kcal according to basal metabolism rate) in Shanghai Dianfeng weight loss enclosed camp. Nine normal weight young women and 9 female children matched at age and nationality were recruited as the normal control. Before and after the experimental period, anthropometric index (body weight, body mass index(BMI) and waist circumference), glucose and lipid metabolism parameters including fasting blood glucose (FBG), fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR), triglyceride (TG); total cholesterol (TC), low density lipoprotein (LDL) and high density lipoprotein (HDL), and serum levels of total IGF-1 and IGFBP-3 were measured, and IGF-1 activity was calculated in the obese and normal control female adolescents. RESULTS ①Compared with normal control, the serum levels of total IGF-1 and IGFBP-3 were decreased in the female obese youths and adolescents, and IGF-1 activity was reduced only in the obese female adolescents. ②The serum level of IGFBP-3 was down-regulated and IGF-1 activity was up-regulated while no change of serum total IGF-1 was induced by 4-week moderate aerobic exercise plus diet control, accompanied with significant decreases of body weight, BMI and waist circumference as well as improvement of glucose and lipid metabolism in the female obese youths and adolescents. Except for a positive association between the increased IGF-1 activity and the decreased waist circumference was found in the female obese youths by Pearson's correlation analysis, there was no relation of the decreased IGFBP-3, the increased IGF-1 activity with the improvements of anthropometric index and glucose and lipid metabolism in female obese youths and adolescents. CONCLUSIONS The serum level of IGFBP-3 was down-regulated and the IGF-1 activity was up-regulated by 4-week moderate aerobic exercise plus diet control in female obese youths and adolescents. The increase of IGF-1 activity might be associated with the exercise-plus-diet-induced decrease of waist circumstance in female obese youths.
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Serum n-6 and n-9 Fatty Acids Correlate With Serum IGF-1 and Growth Up to 4 Months of Age in Healthy Infants.
Kjellberg, E, Roswall, J, Bergman, S, Strandvik, B, Dahlgren, J
Journal of pediatric gastroenterology and nutrition. 2018;(1):141-146
Abstract
OBJECTIVE The aim of this study was to study the relationship between insulin-like growth factor-1 (IGF-1), serum phospholipid fatty acids, and growth in healthy full-term newborns during infancy. METHODS Prospective observational study of a population-based Swedish cohort comprising 126 healthy, term infants investigating cord blood and serum at 2 days and 4 months of age for IGF-1 and phospholipid fatty acid profile and breast milk for fatty acids at 2 days and 4 months, compared with anthropometric measurements (standard deviation scores). RESULTS At all time-points arachidonic acid (AA) was negatively associated with IGF-1. IGF-1 had positive associations with linoleic acid (LA) at 2 days and 4 months and mead acid (MA) showed positive associations in cord blood. Multiple regression analyses adjusted for maternal factors (body mass index, weight gain, smoking, education), sex, birth weight and feeding modality confirmed a negative association for the ratio AA/LA to IGF-1. MA in cord blood correlated to birth size. Changes in the ratios of n-6/n-3 and AA/docosahexaenoic acid from day 2 to 4 months together with infants' weight and feeding modality determined 55% of the variability of delta-IGF-1. Breast-fed infants at 4 months had lower IGF-1 correlating with lower LA and higher AA concentrations, which in girls correlated with lower weight gain from birth to 4 months of age. CONCLUSIONS Our data showed interaction of n-6 fatty acids with IGF-1 during the first 4 months of life, and an association between MA and birth size when adjusted for confounding factors. Further follow-up may indicate whether these correlations are associated with later body composition.