Plasma IGF-I Research Articles

Metabolic Status of Dairy Cows Grouped by Anabolic and Catabolic Indicators of Metabolic Stress in Early Lactation

Background: Early lactation is period followed by changed metabolism in organism of the cow. This is the consequence of negativ energy balance, metabolic stress and milk production. Early lactation is characterised by high lipide catabolism (high NEFA) and low anabolic capacity (low insulin and IGF-I concentration). The aim of this study is to examine differences in metabolic adaptation of cows in early lactation (eight weeks after calving) in accordance to anabolic (insulin, IGF-I) and catabolic (NEFA) indicators in first week after calving.Materials, Methods & Results: The experiment included 50 Holstein-Friesian cows. Blood samples were collected in first, second, fourth and eight week after calving by venepunction of v.coccigea. Based on median value of indicator, cows were significantly (P < 0.001) classified in two groups: cows under metabolic stress (indicators of anabolism below the median Me-: indicators of catabolism above the medianMe+) and cows in control group (indicators of anabolism above the median Me+: indicators of catabolism under median Me-). Following criteria for comparison were given: based on classification of cows according to one indicator of metabolic load (insulinMe-:insulinMe+; IGF-IMe-:IGF-IMe+ and NEFAMe-:NEFA Me+); based on classification of cows according to combination of two indicators (insulinMe-+NEFAMe+: insulinMe++NEFAMe- and IGF-IMe-+NEFAMe+:IGF-IMe++NEFAMe-). Cows loaded with metabolic stress showed significan difference in metabolic adaptation in relation to control group (P < 0.05 or P < 0.01): higher values of STH, BHB (criteria were insulin, IGF-I, NEFA, insulin+NEFA, IGF-I+NEFA), higher values of bilirubin, AST, ALT, GGT, AP (criteria NEFA and IGF-I+NEFA) and MDA (criteria NEFA) and lower levels of glucose, total proteins, albumin (criteria IGF-I, NEFA, IGF-I+NEFA and body condition (criteria insulin, IGF-I, NEFA, insulin+ NEFA, IGF-I+ NEFA) were noted. Differences were expressed the most in first two weeks after calving. Differences in the body condition were the most notable later in weeks. Usage of NEFA indicator in first week after calving allows the most quality recognition of cows with metabolic parameters in extreme quartiles (ROC AUC= 0.87, P < 0.01) in first eight week of lactation.Discussion: Inverse relation betwen NEFA with insulin and IGF-I is consequence of next phisiological concept: plasma insulin and IGF-I decrease in same mannure after calvig and insulin aplication increase IGF-I; low insulin concentration leads cow to lipolysis and low IGF-I leads to STH resistance with increase concentration of STH and high lipolysis. Catabolism of adipose tissue and high NEFA concentration is most important for metabolic adaptation in periparturient period. Cows with insulin resistance, ketosis and fatty liver with many problems in metabolic adaptation showed high NEFA concentration. Atenuation of NEFA by niacin or anti-inflammatory drug decreases metabolic change due to high lipide mobilisation in early lactation. Low antepartal IGF-I showed significant effect on postpartum health, but our measuremens are in first week postpartum. In addition, increase catabolism of lipide viewed in NEFA value contributes to metabolic variation and adaptation in the first eight weeks of lactation much more than decrease of anabolic indicators such as insulin and IGF-I. The combination of the indicators does not lead to better recognition of cows with extreme metabolic change in relation to classification only to the value of NEFA.

Ghrelin Receptor Agonist Rescues Excess Neonatal Mortality in a Prader-Willi Syndrome Mouse Model.

In the current study, we sought to determine the significance of the ghrelin system in Prader-Willi Syndrome (PWS). PWS is characterized by hypotonia and difficulty feeding in neonates and hyperphagia and obesity beginning later in childhood. Other features include low GH, neonatal hypoglycemia, hypogonadism, and accelerated mortality. Although the hyperphagia and obesity in PWS have been attributed to elevated levels of the orexigenic hormone ghrelin, this link has never been firmly established, nor have ghrelin's potentially protective actions to increase GH secretion, blood glucose, and survival been investigated in a PWS context. In the current study, we show that placing Snord116del mice modeling PWS on ghrelin-deficient or ghrelin receptor [GH secretagogue receptor (GHSR)]-deficient backgrounds does not impact their characteristically reduced body weight, lower plasma IGF-1, delayed sexual maturation, or increased mortality in the period prior to weaning. However, blood glucose was further reduced in male Snord116del pups on a ghrelin-deficient background, and percentage body weight gain and percentage fat mass were further reduced in male Snord116del pups on a GHSR-deficient background. Strikingly, 2 weeks of daily administration of the GHSR agonist HM01 to Snord116del neonates markedly improved survival, resulting in a nearly complete rescue of the excess mortality owing to loss of the paternal Snord116 gene. These data support further exploration of the therapeutic potential of GHSR agonist administration in limiting PWS mortality, especially during the period characterized by failure to thrive.

Effects of dietary carbohydrate levels on growth, glucose tolerance, glucose homeostasis and GLUT4 gene expression inTilapia nilotica

In this paper, the glucose tolerance tests (GTT) were performed to evaluate the effects of three dietary carbohydrate levels on growth, plasma glucose, hormones (insulin and IGF-I), glucose homeostasis and GLUT4 gene expression of Tilapia nilotica. Juvenile tilapia (av. wt.10 g) were randomly distributed into three groups with three replicates and fed for 8 weeks with three dietary carbohydrate levels: 40% (CH), 30% (CM) and 20% (CL). After 8 weeks of feeding trial, fish were injected with glucose (30 mg/100 g body weight) for GTT. The growth performance results showed the survival rate in the CH group was significantly lower than the other two groups (p < 0.05). The GTT results showed that the plasma glucose level positively correlates with the diets’ carbohydrate level initially, peaked at 1 hr and declined thereafter. The plasma IGF-1 levels were positively correlated with diets’ carbohydrate levels; first the levels increase and then decrease after injection in all the three groups. There was a direct relationship between the carbohydrate levels and the activities of liver pyruvate kinase (PK) and glucokinase (GK) enzymes. Muscle GLUT4 expression in groups changed slightly in 0–3 hr and then increased sharply during 6–12 hr. Results of this study indicated that the moderate dietary carbohydrate level may improve the glucose tolerance of T. nilotica. The carbohydrate levels can affect plasma glucose, IGF-1 and GLUT4 expression in T. nilotica. In addition, the IGF-1 may play a more important role on the glucose metabolism than insulin. The delayed gene transcription of GLUT4 may be one of the reasons for glucose intolerance in T. nilotica.

Effect of bST administration on plasma concentrations of IGF-I and follicular dynamics and ovulation during the interovulatory cycle of sheep and goats

This study used a comparative approach to gather clinical information to assess the effect of bovine somatotropin (bST) on follicular dynamics and ovulation in sheep and goats during an interovulatory cycle. The performance of general markers of ovarian function and specific features of follicular dynamics obtained by daily ultrasonography (US) were used to assess the hypothesis that bST, associated with supraphysiological levels of IGF-I, was able to disrupt the follicular dynamics and ovulation in Highlander ewes and Saanen goats. In Exp 1, 15 ewes and 14 goats were estrous-synchronized (P4-6 days + PGFα d-6) and then allocated to a bST-treated group (50 and 100 mg, Lactotropin®; n = 5 females each) and to an untreated control group (5 ewes and 4 goats) to assess the activity of bST through plasma IGF-I (RIA). In Exp 2, 12 animals from each species were synchronized. At day 6, they were divided into a bST-group (100 mg in sheep and 50 mg in goats, n = 6 each) and an untreated control group (n = 6 each). Starting at day 6 and up to 22 days after ovulation in sheep and 25 days in goats, each female was subjected to daily US (10 mHz probe) to assess follicular and luteal (CL) dynamics and ovulation. This included assessments of both general ovarian features and specific follicular wave features. Our results showed that bST increased plasma IGF-I by day 3 (p < 0.01) when compared to the control group. Moreover, these concentrations were maintained for at least 10 days in sheep and 10 days in goats before returning to pre-treatment concentrations. Increases in IGF-I after bST doses were similar in terms of a daily and total amount (P > 0.10). Results from Exp.2 indicate that in sheep, bST administration had a subtle inhibitory effect on follicular function. However, bST in goats had a stronger influence, extending the interovulatory cycle (P = 0,034), increasing the number of follicular waves during the period (P = 0.003), and reducing the functional potential of large follicles as measured by their lower follicular diameter (P = 0.02), duration of the follicle waves (P = 0.02), and persistence of follicles after reaching their maximum diameters (P = 0.04). In addition, untreated sheep and goats shared common patterns of terminal follicular development and ovulations characterized by overlapping between follicular waves and ovulations of follicles from different waves, features not seen in cattle.

Association of circular Klotho and insulin-like growth factor 1 with cardiac hypertrophy indexes in athlete and non-athlete women following acute and chronic exercise

Owing to the role of insulin-like growth factor 1 (IGF-I) in cardiac hypertrophy and the ability of Klotho in inhibiting the IGF-I action, we investigated effects of exercise on plasma Klotho and IGF-I and their association with cardiac hypertrophy. In this study, 10 non-athlete and 10 athlete women underwent a Bruce test (acute exercise) and 12-weeks water aerobics training (chronic exercise). Electrocardiographic parameters, plasma IGF-I and Klotho levels were measured in different time courses. The exercise training could significantly increase left ventricular end-diastolic diameter index (LVEDDI) in the non-athletes. Plasma levels of IGF-I significantly increased following acute and chronic exercises. The Klotho levels at the baseline were higher in athletes than non-athletes and its levels significantly increased immediately after acute exercise in both groups. The Klotho levels significantly decreased in non-athletes 24 h after chronic exercise, but its level was still higher than the baseline in the athletes. We found positive and negative correlations between cardiac hypertrophy indexes (LVEDDI and left ventricular mass index) with respectively IGF-I and Klotho. In conclusion, we found a stimulatory effect of acute and chronic exercises on plasma IGF-I and Klotho and association of IGF-I with exercise-induced cardiac hypertrophy. Moreover, Klotho could act as a negative regulator for exercise-induced cardiac hypertrophy.

Case Study: Effects of body weight gain and bovine somatotropin treatment of postpartum beef cows on concentrations of IGF-1, insulin, and glucose in blood plasma; luteal activity; and calf growth

ABSTRACT Angus × Hereford cows (2 and 3 yr of age, n = 37) were used to evaluate the effects of postpartum BW gain and treatment with bovine somatotropin (bST) on concentrations of IGF-I, glucose, and insulin in plasma during early lactation; luteal activity; and calf growth. Cows (456 ± 52 kg, BCS = 4.6 ± 0.4) were stratified based on calving date and BCS and randomly assigned to a 2 × 2 × 2 factorial: weight gain ≤0.4 kg/d (MWG) or >0.4 kg/d (HWG) during 24 to 59 d postpartum, injection with bST or saline (CON) on d 31 and 45 postpartum, and 2 or 3 yr of age. Concentrations of IGF-I in plasma before bST treatment were greater (P = 0.02) for HWG compared with MWG cows, and IGF-I was greater (P

Prolonged amino acid infusion into intrauterine growth-restricted fetal sheep increases leucine oxidation rates.

Overcoming impaired growth in an intrauterine growth-restricted (IUGR) fetus has potential to improve neonatal morbidity, long-term growth, and metabolic health outcomes. The extent to which fetal anabolic capacity persists as the IUGR condition progresses is not known. We subjected fetal sheep to chronic placental insufficiency and tested whether prolonged amino acid infusion would increase protein accretion in these IUGR fetuses. IUGR fetal sheep were infused for 10 days with either mixed amino acids providing ~2 g·kg-1·day-1 (IUGR-AA) or saline (IUGR-Sal) during late gestation. At the end of the infusion, fetal plasma leucine, isoleucine, lysine, methionine, and arginine concentrations were higher in the IUGR-AA than IUGR-Sal group ( P < 0.05). Fetal plasma glucose, oxygen, insulin, IGF-1, cortisol, and norepinephrine concentrations were similar between IUGR groups, but glucagon concentrations were fourfold higher in the IUGR-AA group ( P < 0.05). Net umbilical amino acid uptake rate did not differ between IUGR groups; thus the total amino acid delivery rate (net umbilical amino acid uptake + infusion rate) was higher in the IUGR-AA than IUGR-Sal group (30 ± 4 vs. 19 ± 1 μmol·kg-1·min-1, P < 0.05). Net umbilical glucose, lactate, and oxygen uptake rates were similar between IUGR groups. Fetal leucine oxidation rate, measured using a leucine tracer, was higher in the IUGR-AA than IUGR-Sal group (2.5 ± 0.3 vs. 1.7 ± 0.3 μmol·kg-1·min-1, P < 0.05). Fetal protein accretion rate was not statistically different between the IUGR groups (1.6 ± 0.4 and 0.8 ± 0.3 μmol·kg-1·min-1 in IUGR-AA and IUGR-Sal, respectively) due to variability in response to amino acids. Prolonged amino acid infusion into IUGR fetal sheep increased leucine oxidation rates with variable anabolic response.

Pre-diagnostic circulating insulin-like growth factor-I and bladder cancer risk in the European Prospective Investigation into Cancer and Nutrition.

Previous in vitro and case–control studies have found an association between the insulin‐like growth factor (IGF)‐axis and bladder cancer risk. Circulating concentrations of IGF‐I have also been found to be associated with an increased risk of several cancer types; however, the relationship between pre‐diagnostic circulating IGF‐I concentrations and bladder cancer has never been studied prospectively. We investigated the association of pre‐diagnostic plasma concentrations of IGF‐I with risk of overall bladder cancer and urothelial cell carcinoma (UCC) in a case–control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 843 men and women diagnosed with bladder cancer between 1992 and 2005 were matched with 843 controls by recruitment centre, sex, age at recruitment, date of blood collection, duration of follow‐up, time of day and fasting status at blood collection using an incidence density sampling protocol. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression with adjustment for smoking status. No association was found between pre‐diagnostic circulating IGF‐I concentration and overall bladder cancer risk (adjusted OR for highest versus lowest fourth: 0.91, 95% CI: 0.66–1.24, p trend = 0.40) or UCC (n of cases = 776; 0.91, 0.65–1.26, p trend = 0.40). There was no significant evidence of heterogeneity in the association of IGF‐I with bladder cancer risk by tumour aggressiveness, sex, smoking status, or by time between blood collection and diagnosis (p heterogeneity > 0.05 for all). This first prospective study indicates no evidence of an association between plasma IGF‐I concentrations and bladder cancer risk.

Effects of live yeast dietary supplementation on hormonal profile, ovarian follicular dynamics, and reproductive performance in dairy cows exposed to high ambient temperature

Two experiments were conducted to investigate the effects of dietary supplementation with live yeast culture on hormonal profile, ovarian follicular dynamics and reproductive performance of lactating dairy cows exposed to high ambient temperature. In Expt. 1, Holstein cows were fed a diet with (n = 6) or without (n = 6) 4 g yeast/h/d from 21 d before expected calving date until 8 weeks postpartum. Concentrations of glucose, insulin, insulin like growth factor-I (IGF-I), estradiol-17β (E−17β) and progesterone (P4) were determined in plasma, and transrectal ultrasonography was used to monitor ovarian follicular dynamics. In Expt. 2, 150 Holstein cows (75/dietary group) received same diets as Expt. 1 with the exception that diets were fed from d 1 to d 70 postpartum. The effect of dietary treatments on reproductive performance was examined. In Expt. 1, plasma IGF concentrations during dietary treatment were higher (P = 0.05) in cows fed diets supplemented with yeast. On d 60 postpartum, average plasma concentrations of glucose (48.3 vs. 41.0 mg/dL) and insulin (0.90 vs. 0.23 μU/mL), were also greater in cows fed diets supplemented with yeast compared to that in cow fed diets without supplementation. Similarly, plasma concentrations of E−17β at estrus (P = 0.016) and P4 on d 10 of the estrous cycle (P = 0.021) were greater in yeast-supplemented cows. Moreover, yeast supplementation resulted on average in an estrous cycle 2.6 d shorter (P = 0.05) and in the development of larger ovulatory follicles (18.4 vs. 17.2 mm in diameter; P < 0.01). In Expt. 2, days open were fewer and the proportion of pregnant cows at 120 and 150 d postpartum were greater (P < 0.01) in cows fed diets supplemented with yeast compared to those receiving diets without yeast. In summary, cows fed diets supplemented with yeast had greater plasma IGF-I, E−17β and P4 concentrations, larger ovulatory follicles, shorter estrous cycles, and improved reproductive performance. Therefore, live yeast dietary supplementation could enhance lactating dairy cow's fertility during heat stress through improvement in hormonal profile and development of larger ovulatory follicles.

Ghrelin and Its Receptors in Gilthead Sea Bream: Nutritional Regulation.

Ghrelin is involved in the regulation of growth in vertebrates through controlling different functions, such as feed intake, metabolism, intestinal activity or growth hormone (Gh) secretion. The aim of this work was to identify the sequences of preproghrelin and Ghrelin receptors (ghsrs), and to study their responses to different nutritional conditions in gilthead sea bream (Sparus aurata) juveniles. The structure and phylogeny of S. aurata preproghrelin was analyzed, and a tissue screening was performed. The effects of 21 days of fasting and 2, 5, 24 h, and 7 days of refeeding on plasma levels of Ghrelin, Gh and Igf-1, and the gene expression of preproghrelin, ghsrs and members of the Gh/Igf-1 system were determined in key tissues. preproghrelin and the receptors are well conserved, being expressed mainly in stomach, and in the pituitary and brain, respectively. Twenty-one days of fasting resulted in a decrease in growth while Ghrelin plasma levels were elevated to decrease at 5 h post-prandial when pituitary ghsrs expression was minimum. Gh in plasma increased during fasting and slowly felt upon refeeding, while plasma Igf-1 showed an inverse profile. Pituitary gh expression augmented during fasting reaching maximum levels at 1 day post-feeding while liver igf-1 expression and that of its splice variants decreased to lowest levels. Liver Gh receptors expression was down-regulated during fasting and recovered after refeeding. This study demonstrates the important role of Ghrelin during fasting, its acute down-regulation in the post-prandial stage and its interaction with pituitary Ghsrs and Gh/Igf-1 axis.

Maternal exercise in rats upregulates the placental insulin-like growth factor system with diet- and sex-specific responses: minimal effects in mothers born growth restricted.

The placental insulin-like growth factor (IGF) system is critical for normal fetoplacental growth, which is dysregulated following several pregnancy perturbations including uteroplacental insufficiency and maternal obesity. We report that the IGF system was altered in placentae of mothers born growth restricted compared to normal birth weight mothers, with maternal diet- and fetal sex-specific responses. Additionally, we report increased body weight and plasma IGF1 concentrations in fetuses from chow-fed normal birth weight mothers that exercised prior to and continued during pregnancy compared to sedentary mothers. Exercise initiated during pregnancy, on the other hand, resulted in placental morphological alterations and increased IGF1 and IGF1R protein expression, which may in part be modulated by reduced Let 7f-1 miRNA abundance. Growth restriction of mothers before birth and exercise differentially regulate the placental IGF system with diet- and sex-specific responses, probably as a means to improve fetoplacental growth and development, and hence neonatal survival. This increased neonatal survival may prevent adult disease onset. The insulin-like growth factor (IGF) system regulates fetoplacental growth and plays a role in disease programming. Dysregulation of the IGF system is implicated in several pregnancy perturbations associated with altered fetal growth, including intrauterine growth restriction and maternal obesity. Limited human studies have demonstrated that maternal exercise enhances fetoplacental growth and decreases cord IGF ligands, which may restore the placental IGF system in complicated pregnancies. This study investigated the impact maternal exercise has on the placental IGF system in placentae from mothers born growth restricted and if these outcomes are dependent on maternal diet or fetal sex. Uteroplacental insufficiency (Restricted) or sham (Control) surgery was induced on embryonic day (E) 18 in Wistar-Kyoto rats. F1 offspring were fed a chow or high-fat diet from weaning, and at 16weeks were randomly allocated an exercise protocol: Sedentary, Exercised prior to and during pregnancy (Exercise), or Exercised during pregnancy only (PregEx). Females were mated (20weeks) with placentae associated with F2 fetuses collected at E20. The placental IGF system mRNA abundance and placental morphology was altered in mothers born growth restricted. Exercise increased fetal weight and Control plasma IGF1 concentrations, and decreased female placental weight. PregEx did not influence fetoplacental growth but increased placental IGF1 and IGF1R (potentially modulated by reduced Let 7f-1 miRNA) and decreased placental IGF2 protein. Importantly, these placental IGF system changes occurred with sex-specific responses. These data highlight that exercise differently influences fetoplacental growth and the placental IGF system depending on maternal exercise initiation, which may prevent the transgenerational transmission of deficits and dysfunction.

In vivo effects of 17α-ethinylestradiol, 17β-estradiol and 4-nonylphenol on insulin-like growth-factor binding proteins (igfbps) in Atlantic salmon

Feminizing endocrine disrupting compounds (EDCs) affect the growth and development of teleost fishes. The major regulator of growth performance, the growth hormone (Gh)/insulin-like growth-factor (Igf) system, is sensitive to estrogenic compounds and mediates certain physiological and potentially behavioral consequences of EDC exposure. Igf binding proteins (Igfbps) are key modulators of Igf activity, but their alteration by EDCs has not been examined. We investigated two life-stages (fry and smolts) of Atlantic salmon (Salmo salar), and characterized how the Gh/Igf/Igfbp system responded to waterborne 17α-ethinylestradiol (EE2), 17β-estradiol (E2) and 4-nonylphenol (NP). Fry exposed to EE2 and NP for 21 days had increased hepatic vitellogenin (vtg) mRNA levels while hepatic estrogen receptor α (erα), gh receptor (ghr), igf1 and igf2 mRNA levels were decreased. NP-exposed fry had reduced body mass and total length compared to controls. EE2 and NP reduced hepatic igfbp1b1, -2a, -2b1, -4, -5b2 and -6b1, and stimulated igfbp5a. In smolts, hepatic vtg mRNA levels were induced following 4-day exposures to all three EDCs, while erα only responded to EE2 and E2. EDC exposures did not affect body mass or fork length; however, EE2 diminished plasma Gh and Igf1 levels in parallel with reductions in hepatic ghr and igf1. In smolts, EE2 and E2 diminished hepatic igfbp1b1, -4 and -6b1, and stimulated igfbp5a. There were no signs of compromised ionoregulation in smolts, as indicated by unchanged branchial ion pump/transporter mRNA levels. We conclude that hepatic igfbps respond (directly and/or indirectly) to environmental estrogens during two key life-stages of Atlantic salmon, and thus may modulate the growth and development of exposed individuals.

Time Course of Recovery From Resistance Exercise With Different Set Configurations.

Pareja-Blanco, F, Rodríguez-Rosell, D, Aagaard, P, Sánchez-Medina, L, Ribas-Serna, J, Mora-Custodio, R, Otero-Esquina, C, Yáñez-García, JM, and González-Badillo, JJ. Time course of recovery from resistance exercise with different set configurations. J Strength Cond Res 34(10): 2867-2876, 2020-This study analyzed the response to 10 resistance exercise protocols differing in the number of repetitions performed in each set (R) with respect to the maximum predicted number (P). Ten males performed 10 protocols (R(P): 6(12), 12(12), 5(10), 10(10), 4(8), 8(8), 3(6), 6(6), 2(4), and 4(4)). Three sets with 5-minute interset rests were performed in each protocol in bench press and squat. Mechanical muscle function (countermovement jump height and velocity against a 1 m·s load, V1-load) and biochemical plasma profile (testosterone, cortisol, growth hormone, prolactin, IGF-1, and creatine kinase) were assessed at several time points from 24-hour pre-exercise to 48-hour post-exercise. Protocols to failure, especially those in which the number of repetitions performed was high, resulted in larger reductions in mechanical muscle function, which remained reduced up to 48-hour post-exercise. Protocols to failure also showed greater increments in plasma growth hormone, IGF-1, prolactin, and creatine kinase concentrations. In conclusion, resistance exercise to failure resulted in greater fatigue accumulation and slower rates of neuromuscular recovery, as well as higher hormonal responses and greater muscle damage, especially when the maximal number of repetitions in the set was high.

Lack of Brain Insulin Receptor Substrate-1 (IRS1) Causes Growth Retardation via Growth Hormone Releasing Hormone

Background and Purpose: We previously revealed that systemic Irs1 deficient mice showed growth retardation, indicating that Irs1 plays an important role in growth. Irs1 is main substrate of not only insulin receptor (IR) but also IGF-1 receptor (IGF-1R) tyrosine kinase. Recently, brain specific IGF-1 receptor knockout mice were reported to become growth impairment. We hypothesized that brain Irs1 may regulate growth via IGF-1. Methods: We generated NIrs1KO mice and analyzed growth related parameter and immunohistochemistry (IHC) study. Result: The body weight of NIrs1KO mice was significantly smaller than control mice. NIrs1KO mice also showed shorter body length and bone length. On the other hand food intake and gene expression of appetite-related neuropeptides (POMC, AgRP and NPY) were not different between two groups. We next confirmed that plasma IGF-1 and growth hormone (GH) levels of NIrs1KO mice were lower than control mice. Hypothalamic GHRH mRNA expression levels of NIrs1KO mice were also lower than those of control mice although hypothalamic somatostatin mRNA expression was not different between two groups. These data strongly suggest that lack of brain Irs1 causes growth retardation via GHRH. IHC study indicated that Irs1 colocalized with GHRH neuron in hypothalamus. We next investigated the IGF-1-induced proliferation in hypothalamic neural cells by using siIrs1. Downregulation of Irs1 significantly inhibited IGF-1-induced neural cell proliferation. Conclusion: Our results suggest that IGF-1-Irs1 pathway promotes the proliferation of GHRH neurons and regulate growth. Disclosure T. Hayashi: None. N. Kubota: None. T. Kubota: None. T. Kadowaki: Consultant; Self; Novo Nordisk A/S, AstraZeneca, Merck Sharp &amp; Dohme Corp.. Research Support; Self; Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sanofi, Kyowa Hakko Kirin Co., Ltd., Novo Nordisk A/S, Astellas Pharma, Daiichi Sankyo Company, Limited, Takeda, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Merck Sharp &amp; Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Astellas Pharma, AstraZeneca, Merck Sharp &amp; Dohme Corp., Ono Pharmaceutical Co., Ltd., Takeda, Eli Lilly and Company, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk A/S.

Identification and Pharmacological Profile of an Indane Based Series of Ghrelin Receptor Full Agonists.

Cachexia and muscle wasting are very common among patients suffering from cancer, chronic obstructive pulmonary disease, and other chronic diseases. Ghrelin stimulates growth hormone secretion via the ghrelin receptor, which subsequently leads to increase of IGF-1 plasma levels. The activation of the GH/IGF-1 axis leads to an increase of muscle mass and functional capacity. Ghrelin further acts on inflammation, appetite, and adipogenesis and for this reason was considered an important target to address catabolic conditions. We report the synthesis and properties of an indane based series of ghrelin receptor full agonists; they have been shown to generate a sustained increase of IGF-1 levels in dog and have been thoroughly investigated with respect to their functional activity.

Response of the insulin-like growth factor-1 (Igf1) system to nutritional status and growth rate variation in olive rockfish (Sebastes serranoides)

Growth performance in vertebrates is regulated by environmental factors including the quality and quantity of food, which influence growth via endocrine pathways such as the growth hormone (GH)/insulin-like growth factor somatotropic axis. In several teleost fishes, circulating concentrations of insulin-like growth factor-1 (Igf1) correlate positively with growth rate, and it has been proposed that plasma Igf1 levels may serve as an indicator of growth variation for fisheries and aquaculture applications. This study tested whether plasma Igf1 concentrations might serve as an indicator of somatic growth in olive rockfish (Sebastes serranoides), one species among dozens of rockfishes important to commercial and recreational fisheries in the Northern Pacific Ocean. Juvenile olive rockfish were reared under food ration treatments of 1% or 4% wet mass per d for 98 d to experimentally generate variation in growth. Juvenile rockfish in the 4% ration grew 60% more quickly in mass and 22% faster in length than fish in the 1% ration. Plasma Igf1 levels were elevated in rockfish under the 4% ration, and individual Igf1 levels correlated positively with growth rate, as well as with individual variation in hepatic igf1 mRNA levels. Transcripts encoding the Igf binding proteins (Igfbps) igfbp1a and igfbp1b were also at higher abundance in the liver of rockfish in the 1% ration treatment, while mRNAs for igfbp5a and igfbp5b were elevated in the skeletal muscle of 4% ration fish. These findings support the use of plasma Igf1 as a physiological index of growth rate variation in rockfish.

Co-expression Analysis of Sirtuins and Related Metabolic Biomarkers in Juveniles of Gilthead Sea Bream (Sparus aurata) With Differences in Growth Performance.

Sirtuins (SIRTs) represent a conserved protein family of deacetylases that act as master regulators of metabolism, but little is known about their roles in fish and livestock animals in general. The present study aimed to assess the value of SIRTs for the metabolic phenotyping of fish by assessing their co-expression with a wide-representation of markers of energy and lipid metabolism and intestinal function and health in two genetically different gilthead sea bream strains with differences in growth performance. Fish from the fast-growing strain exhibited higher feed intake, feed efficiency and plasma IGF-I levels, along with higher hepatosomatic index and lower mesenteric fat (lean phenotype). These observations suggest differences in tissue energy partitioning with an increased flux of fatty acids from adipose tissue toward the liver. The resulting increased risk of hepatic steatosis may be counteracted in the liver by reduced lipogenesis and enhanced triglyceride catabolism, in combination with a higher and more efficient oxidative metabolism in white skeletal muscle. These effects were supported by co-regulated changes in the expression profile of SIRTs (liver, sirt1; skeletal muscle, sirt2; adipose tissue, sirt5-6) and markers of oxidative metabolism (pgc1α, cpt1a, cs, nd2, cox1), mitochondrial respiration uncoupling (ucp3) and fatty acid and triglyceride metabolism (pparα, pparγ, elovl5, scd1a, lpl, atgl) that were specific to each strain and tissue. The anterior intestine of the fast-growing strain was better suited to cope with improved growth by increased expression of markers of nutrient absorption (fabp2), epithelial barrier integrity (cdh1, cdh17) and immunity (il1β, cd8b, lgals1, lgals8, sIgT, mIgT), which were correlated with low expression levels of sirt4 and markers of fatty acid oxidation (cpt1a). In the posterior intestine, the fast-growing strain showed a consistent up-regulation of sirt2, sirt3, sirt5 and sirt7 concurrently with increased expression levels of markers of cell proliferation (pcna), oxidative metabolism (nd2) and immunity (sIgT, mIgT). Together, these findings indicate that SIRTs may play different roles in the regulation of metabolism, inflammatory tone and growth in farmed fish, arising as powerful biomarkers for a reliable metabolic phenotyping of fish at the tissue-specific level.

Randomized, phase I/II study of gemcitabine plus IGF-1R antagonist (MK-0646) versus gemcitabine plus erlotinib with and without MK-0646 for advanced pancreatic adenocarcinoma

BackgroundBinding of insulin-like growth factor-I (IGF-1) to its receptor (IGF-1R) initiates downstream signals that activate PI3K/Akt/mTOR and MEK/Erk pathways, which stimulate cancer cell proliferation and induce drug resistance. Cross talk between IGF-1R and epidermal growth factor receptor (EGFR) mediates resistance to anti-EGFR agents. We studied safety, tolerability, and outcomes of MK-0646, IGF-1 monoclonal antibody, in combination with gemcitabine (G) ± erlotinib (E) in metastatic pancreatic cancer.MethodsOur study included a phase I dose escalation and phase II randomization and expansion cohorts. A 3 + 3 dose escalation protocol was used to determine MK-0646 maximum tolerable dose (MTD) in combination with G ± E standard doses. For phase II, patients were randomized to arm A (G + MK), arm B (G + MK + E), or arm C (G + E). Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), disease control rate, toxicity, and correlation between OS and IGF-1 in patients treated with MK-0646.ResultsMK-0646 MTD was 10 mg/kg in combination with G and 5 mg/kg in combination with G + E. In randomization cohort, 15 patients were treated in each arm. Disease control rates were 50, 60, and 40% respectively. PFS was not different between the three arms. OS was significantly different between arm A (10.4 months) and C (5.7 months) (P = 0.02). However, addition of erlotinib in arm B yielded no OS benefit compared to arm A (P = 0.6). Plasma and tissue IGF-1 levels did not correlate with OS (P = 0.64, 0.87). Grade 3–4 toxicity during phase II cohorts were neutropenia (10/arm A, 14/arm B, 5/arm C), leukopenia (5/A, 5/B, 7/C), thrombocytopenia (8/A, 9/B, 2/C), hyponatremia (1/A, 3/B), and hyperglycemia (8/A, 1/B).ConclusionsMK-0646 was tolerable in combination with G and associated with improvement in OS but not PFS as compared with G + E. Tissue and serum IGF-1 did not correlate with clinical outcome.Trial registrationThis trial is registered in ClinicalTrial.gov under the Identifier NCT00769483 and registration date was October 9, 2008.

The effects of protein supplementation of fall calving beef cows on pre- and postpartum plasma insulin, glucose and IGF-I, and postnatal growth and plasma insulin and IGF-I of calves.

Fall calving (September to October) cows (n = 189 calvings in 5 replications; body weight [BW] = 626 ± 6 kg, body condition score [BCS] = 4.76 ± 0.06) grazing native dormant range were used to determine the effects of protein supplementation on performance and endocrine function of cows and calves. Cows were individually fed either a control (CON; 1.82 kg/d of 38% crude protein [CP]) or restricted (RES; 0.2 kg/d of 8% CP) protein supplement from mid-November to mid-March for 6 consecutive years. During each year, cows were reassigned dietary treatments according to calving date and BCS, and half of the CON and half of the RES cows remained on the same diets as the previous year and the other halves were assigned to the other diet. Statistical analyses were performed with the general linear model procedure utilizing a 2 × 2 factorial arrangement and a complete randomized design. Cows on CON diets lost less BW from November to January compared with RES cows (-25.9 ± 2.6 and -45.0 ± 2.6 kg, respectively; P < 0.001). Protein supplementation increased plasma concentrations of insulin of CON compared with RES cows during treatment (P < 0.05). Calf birth weight did not differ between prenatal supplemention of CON and RES (P = 0.87). A prenatal × postnatal effect was detected for BW of calves; prenatal RES and postnatal CON calves (RES-CON; 189.4 ± 4.2, P = 0.05) had greater 205-d adjusted weaning weights compared with prenatal RES and postnatal RES (RES-RES) and prenatal CON and postnatal RES (CON-RES) calves (163.0 ± 4.2 and 177.8 ± 4.2 kg, respectively). There was a prenatal × postnatal effect on gain of calves from January to weaning (P = 0.05); RES-CON gained more than RES-RES and CON-RES calves. Adjusted yearling 365-d BW was least (P = 0.02) for RES-RES calves. Prenatal protein supplementation of cows decreased (P = 0.03) final BW of calves at harvest (23 mo). Prenatal and postnatal supplementation of cows did not influence carcass characteristics of calves (P > 0.10). In conclusion, increasing protein supplementation of fall calving beef cows from November to March, during breeding and early pregnancy, reduced BW loss of cows, decreased the interval from calving to pregnancy, increased plasma concentrations of insulin in December, January, and March, and increased plasma insulin-like growth factor-I in December without alteration in pregnancy rate. Reduced protein supplementation prenatally increased BW of calves at harvest.

Endocrine and metabolic profile of peripubertal Standardbred colts

The objectives of this study were to determine the concentrations of reproductive and metabolic hormones during the peripubertal period and to assess their relationship with testicular development and body fat deposition. Blood samples were collected from 23 healthy Standardbred colts every four weeks for twelve months. Colts were weighed monthly, and percent of body fat and testicular volume estimated by ultrasound. Onset of puberty was determined as the month when testosterone was two standard deviations above the previous mean. Plasma FSH, LH, leptin, estradiol-17β, androstenedione, IGF-1, insulin, inhibin-A, and inhibin-B were analyzed for a seven month peripubertal period. Spring born Standardbred colts underwent puberty at 13 months of age; onset of puberty coincided with exponential testicular growth but did not coincide with an increase in cutaneous body fat deposition or leptin (p > 0.05). Plasma inhibin-B concentrations were significantly increased in the postpubertal period (p < 0.05), but no increase was seen in inhibin-A, androstenedione, FSH, LH, or estradiol-17β. In conclusion, the rise in testosterone and subsequent onset of puberty coincides with rapid testicular growth but is not correlated with an increase in gonadotropins, IGF-1, cutaneous body fat or leptin in the horse.