Plasma Insulin-like Growth factor-I Research Articles

Preoperative Plasma Insulin-Like Growth Factor-I and Its Binding Proteins-Based Risk Stratification of Patients Treated With Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma

IntroductionWe evaluate the predictive and prognostic value of insulin-like growth factor-I (IGF-1), IGF binding protein-2 (IGFBP-2) and -3 (IGFBP-3) in patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). MethodsThis is a retrospective analysis of a multi-institutional database comprising 753 patients who underwent RNU for UTUC and had a preoperative plasma available. Logistic and Cox regression analyses were performed. The discriminative ability and clinical utility of the models was calculated using the lasso regression test, area under receiver operating characteristics curves, C-index, and decision curve analysis (DCA). ResultsLower preoperative plasma levels of IGFBP-2 and -3 independently correlated with increased risks of lymph node metastasis, pT3/4 disease, nonorgan confined disease, and worse recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) (all P ≤ .004). The addition of both IGFBP-2 and -3 to a postoperative multivariable model, that included standard clinicopathologic characteristics, improved the model's concordance index by 10%, 9%, and 8% for RFS, CSS, and OS, respectively. On DCA, addition of both IGFBP-2 and -3 to base models improved their performance for RFS, CSS, and OS by a statistically and clinically significant margin. Plasma IGF-1 was not associated with any of outcomes. ConclusionsWe confirmed that a lower plasma levels of IGFBP-2 and -3 both are independent and clinically significant predictors of adverse pathological features and survival outcomes in UTUC patients treated with RNU. These findings might help guide the clinical decision-making regarding perioperative systemic therapy and follow-up scheduling.

Association of an impaired GH-IGF-I axis with cardiac wasting in patients with advanced cancer.

Growth hormone (GH) resistance is characterized by high GH levels but low levels of insulin-like growth factor-I (IGF-I) and growth hormone binding protein (GHBP) and, for patients with chronic disease, is associated with the development of cachexia. We investigated whether GH resistance is associated with changes in left ventricular (LV) mass (cardiac wasting) in patients with cancer. We measured plasma IGF-I, GH, and GHBP in 159 women and 148 men with cancer (83% stage III/IV). Patients were grouped by tertile of echocardiographic LVmass/height2 (women, < 50, 50-61, > 61g/m2; men, < 60, 60-74, > 74g/m2) and by presence of wasting syndrome with unintentional weight loss (BMI < 24kg/m2 and weight loss ≥ 5% in the prior 12months). Repeat echocardiograms were obtained usually within 3-6months for 85 patients. Patients in the lowest LVmass/height2 tertile had higher plasma GH (median (IQR) for 1st, 2nd, and 3rd tertile women, 1.8 (0.9-4.2), 0.8 (0.2-2.2), 0.5 (0.3-1.6) ng/mL, p = 0.029; men, 2.1 (0.8-3.2), 0.6 (0.1-1.7), 0.7 (0.2-1.9) ng/mL, p = 0.003). Among women, lower LVmass was associated with higher plasma IGF-I (68 (48-116), 72 (48-95), 49 (35-76) ng/mL, p = 0.007), whereas such association did not exist for men. Patients with lower LVmass had lower log IGF-I/GH ratio (women, 1.60 ± 0.09, 2.02 ± 0.09, 1.88 ± 0.09, p = 0.004; men, 1.64 ± 0.09, 2.14 ± 0.11, 2.04 ± 0.11, p = 0.002). GHBP was not associated with LVmass. Patients with wasting syndrome with unintentional weight loss had higher plasma GH and GHBP, lower log IGF-I/GH ratio, and similar IGF-I. Overall, GHBP correlated inversely with log IGF-I/GH ratio (women, r = - 0.591, p < 0.001; men, r = - 0.575, p < 0.001). Additionally, higher baseline IGF-I was associated with a decline in LVmass during follow-up (r = - 0.318, p = 0.003). In advanced cancer, reduced LVmass is associated with increased plasma GH and reduced IGF-I/GH ratio, suggesting increasing GH resistance, especially for patients with wasting syndrome with unintentional weight loss. Higher baseline IGF-I was associatedwith a decrease in relative LVmass during follow-up.

Ration Size and Protein Intake affect Circulating Growth Hormone Concentration, Hepatic Growth Hormone Binding and Plasma Insulin-Like Growth Factor-I Immunoreactivity in a Marine Teleost, the Gilthead Sea Bream (Sparus aurata)

The nutritional regulation of the growth hormone liver axis has been studied in gilthead sea bream (Sparus aurata). In a first study, fingerling fish were fed three experimental diets with varying proportions of protein (34, 45 and 55%). A 60% decrease in plasma growth hormone concentration was observed with the increase of specific growth rates and dietary protein levels. An opposite response was observed in hepatic growth hormone-binding sites and plasma insulin-like growth factor-I immunoreactivity that would reflect the insensitivity of liver to growth hormone action during relatively low protein intake. In a second study, fish were fed a commercial diet (55% protein) at different feeding levels (0, 1.2, 2.7 and 5.5 g/(100 g body wt·d). An 84% decrease in plasma growth hormone concentration was observed with the increase of specific growth rates and feeding levels from 0 to 2.7 g/(100 g body wt·d). However, significantly greater growth hormone concentration was found in fish fed 5.5 g/(100 g body wt·d) when compared with fish fed 2.7 g/(100 g body wt·d). Hepatic growth hormone-binding sites and plasma insulin-like growth factor-I immunoreactivity increased with the increase of feeding levels from 0 to 2.7 g/(100 g body wt·d), but these values were lower in fish-fed 5.5 g/(100 g body wt·d) than in those fed 2.7 g/(100 g body wt·d). The physiological importance of these results remains to be clarified, though probably it is a part of the mechanism that diminishes feed utilization for growth at high feeding levels. In any case, for fish of the same age, the increase of circulating growth hormone can be used as a reliable marker of impaired growth in marine fish such as gilthead sea bream.

Dietary Crude Protein Changes Rapidly Alter Metabolism and Plasma Insulin-Like Growth Factor I Concentrations in Broiler Chickens

Although changes in dietary crude protein levels change metabolism in broiler chickens, there is little information concerning the time course of the process of adaptation. Therefore, male Indian River broiler chickens were fed diets containing either 120 or 210 g protein/kg from 7 to 28 d of age and then were fed the other level for an additional 12 d. Birds were bled and killed at 0, 2, 5, 7, 9 and 12 d following the reversals. Measurements taken at these intervals included in vitro lipogenesis, growth and feed consumption, hepatic enzyme activities and plasma metabolites and metabolites. Birds fed the lower level of crude protein were smaller and less efficient in growth from 7 to 28 d. Feeding these birds a higher protein diet from 28 to 40 d improved both growth and feed efficiency. Lipogenesis was also greater and plasma insulin-like growth factor-I (IGF-I) less in birds fed the lower protein diet. Switching dietary treatments increased and decreased lipogenesis as birds were switched from high to low protein and from low to high protein diets, respectively. Half-maximal changes were observed 4 d after the reversal and maximal changes 7 d after the reversal. In contrast, switching dietary treatments decreased and increased plasma IGF-I as birds were switched from high to low protein and from low to high protein diets, respectively. Half-maximal changes were observed 2 d after the reversal. Of the three hepatic enzymes monitored, malic enzyme activity most closely followed the rapid changes in in vitro lipogenesis. Plasma IGF-I may be a more sensitive indicator of changes in dietary protein than changes in intermediary metabolism.

Metabolic and production parameters of dairy cows with different dry period lengths and parities.

To assess the effects of dry period (DP) length on metabolic, reproductive, and productive parameters, second- (SP) and third- (TP) parity cows were assigned to a traditional (9 weeks, T) or short (5 weeks, S) DP, obtaining four subgroups: second-parity cows with traditional (SPT = 8) and short (SPS = 8) DP, third-parity cows with traditional (TPT = 8) and short (TPS = 10) DP. Plasma insulin-like growth factor-I (IGF-I) and non-esterified fatty acid (NEFA) levels were assessed from 5 weeks before to 14 weeks after parturition. IGF-I concentrations were affected by parity (P < 0.05) and by the interaction of time and DP length (P < 0.01). NEFA levels were affected only by time (P < 0.01). S DP cows showed a shorter interval between calving and ovarian cyclicity resumption (P < 0.01) and a higher milk yield (P < 0.01) and fat and protein corrected milk (P < 0.01) compared with T DP cows. Decreased milk protein content was found in the SPS group compared to the SPT (P < 0.05) and the TPS (P < 0.05) group. In conclusion, a short DP length does not affect reproductive performances, except for hastening the resumption of ovarian cyclicity. A short DP appears to increase milk production and is associated with higher IGF-I levels both in the prepartum and the postpartum period.

Effects of early high nutrition related to metabolic imprinting events on growth, carcass characteristics, and meat quality of grass-fed Wagyu (Japanese Black cattle).

The study was conducted to clarify how early high plane of nutrition related to metabolic imprinting affected growth, carcass characteristics, and meat quality of grass-fed Wagyu (Japanese Black cattle). Wagyu steers were allocated randomly into 2 dietary groups: (1) steers fed milk replacer (crude protein 26.0%, crude fat 25.5%; maximum intake 0.6 kg/d) until 3 mo of age and then fed roughage (orchard grass hay) ad libitum from 4 to 10 mo of age (roughage group, RG; n = 11); (2) steers fed milk replacer (maximum intake of 1.8 kg/d) until 3 mo of age and then fed a high-concentrate diet from 4 to 10 mo of age (early high nutrition, EHN; n = 12). After 11 mo of age, all steers were fed roughage ad libitum until 31 mo of age and then slaughtered. Growth performance, carcass traits, longissimus muscle (LM) meat quality and intramuscular fat (IMF) content, plasma insulin-like growth factor I (IGF-I) concentration, and bone mineral density were measured. Body weight was greater in EHN steers (571 kg) than RG steers (520 kg; P < 0.01). Plasma IGF-I levels were higher in EHN steers than in RG steers at 3, 10, and 14 mo of age (P < 0.01, P < 0.005, P < 0.001, respectively); however, plasma IGF-I levels were lower in EHN steers compared with RG steers at 30 mo of age (P < 0.01). The total weight of the muscles and bones of the left half of the carcass was not different between the 2 groups (P = 0.065). Five of the 19 muscles investigated (semimembranosus, P = 0.036; infraspinatus, P = 0.024; supraspinatus, P = 0.0019; serratus ventralis cervicis, P = 0.032; serratus ventralis thoracis, P = 0.027) were heavier in EHN steers. Total fat weight in the left half of the carcass was 30% greater (P = 0.025) in HNE carcasses. Subcutaneous and perirenal fat weights were 53% and 84% greater (P = 0.008, P = 0.002, respectively) in EHN carcasses. The LM IMF content was greater in EHN loins (13.2%) compared with RG loins (9.4%) at 31 mo of age (P = 0.038); however, no differences were found for shear force, tenderness, and cook loss. These results suggested early high-nutrition affected the growth and meat quality of livestock.

Postpartum nutrition affects the insulin-like growth factor system in dominant follicles and plasma of anestrous beef cows

Effects of nutrition on insulin-like growth factor-I (IGF-I), IGF binding proteins (IGFBP), and insulin in plasma and dominant follicles were evaluated at day 72 and 56 (Exp. 1, n = 12 and Exp. 2, n = 28, respectively) postpartum in anovulatory primiparous beef cows. Cows were stratified based on body condition score at calving and randomly assigned to nutritional treatments: maintain (M), 2.27 kg of a 40 % CP supplement per day and ad libitum hay; or gain (G), ad libitum access to a 50 % concentrate diet and ad libitum hay. Blood samples were collected twice weekly starting 30 days postpartum. Ovarian follicles were evaluated using ultrasonography commencing 42 (Exp. 1) or 30 (Exp. 2) days postpartum. Body weight and condition score were greater (P < 0.05) for cows of G than M groups and postpartum interval to luteal function was longer for cows of the M than G group. Insulin and IGF-I concentrations in follicular fluid (FF) and plasma were greater (P < 0.05) for cows of the G than M group at follicular aspiration. Plasma and FF IGFBP4 and IGFBP5 concentrations were greater (P < 0.05) in Exp. 2, and IGFBP5 was greater in Exp. 1 for cows of the G than M group. Treatment did not affect FF steroid concentrations or granulosal cell CYP19A1, PAPPA, IGFBP4, and IGFBP5 mRNA abundance. These results indicate concentrations of IGF-I, insulin, IGFBP4, and IGFBP5 in FF and plasma are affected by nutritional intake and may be related to follicular function.

α7 Nicotinic Acetylcholine Receptor Agonists Regulate Inflammation and Growth Hormone Resistance in Sepsis.

During sepsis the normal induction of circulating insulin-like growth factor-I (IGF-I) by growth hormone (GH) action on liver is attenuated, a phenomenon called hepatic GH resistance. Hepatic GH resistance can be caused by cytokine-mediated activation of the NF-κB pathway which interferes with normal GH-signaling. The afferent and efferent fibers of the vagus nerve are integral to the cholinergic anti-inflammatory pathway (CAP) which attenuates hepatic TNFα production by activating the α7 nicotinic acetylcholine receptor (α7nAChR). We examined the effects of selective afferent vagotomy (SAV) and α7nAChR activation on sepsis-induced mortality, hepatic and systemic inflammation, the GH/IGF system and hepatic GH resistance using Sprague Dawley (SD) rats, C57BL/6 wild type (WT) mice, and α7nAChR knockout (KO) mice. Capsaicin was used to perform SAV and GTS-21 (α7nAChR agonist) was used to activate the α7nAChR. Sepsis-induced mortality, hepatic NF-κB activation, and plasma cytokine levels were increased in SAV rats and reduced in GTS-21-treated mice. The effects of sepsis on the GH/IGF-I system plasma IGF-I, IGF binding protein-1 (IGFBP-1), hepatic IGF-I, IGFBP-1, and GH receptor (GHR) mRNA and rhGH-responsiveness in mice were improved by GTS-21. Collectively these results confirm the protective effects of the anti-inflammatory CAP and α7nAChR activation in sepsis. They also provide evidence the CAP and α7nAChR activation could be used to attenuate hepatic GH resistance and anabolic failure in sepsis.

Cord Blood IGF-I, Proinsulin, Leptin, HMW Adiponectin, and Ghrelin in Short or Skinny Small-for-Gestational-Age Infants.

Small-for-gestational-age (SGA) is an indicator of poor fetal growth "programming" an elevated risk of type 2 diabetes in adulthood. Little is known about early-life endocrine characteristics in SGA subtypes. Stunting (short) and wasting (skinny) are considered distinct SGA phenotypes in neonatal prognosis. This work aimed to assess whether SGA infants with stunting or wasting have similar alterations in neonatal endocrine metabolic health biomarkers. This was a nested case-control study based on the 3D (Design, Develop, and Discover) birth cohort in Canada. The study subjects were 146 SGA (birth weight < 10th percentile) and 155 optimal-for-gestational age (OGA, 25th-75th percentiles) infants. Stunting was defined as birth length less than the 10th percentile, and wasting as body mass index less than the 10th percentile for sex and gestational age, respectively. Main outcome measures included cord plasma concentrations of insulin-like growth factor I (IGF-I), proinsulin, leptin, high-molecular-weight (HMW) adiponectin, and ghrelin. Comparing to OGA infants adjusted for maternal and neonatal characteristics, SGA infants with either stunting only or wasting only had lower cord plasma IGF-I and leptin concentrations. HMW adiponectin concentrations were lower in SGA infants with wasting only (P = .004), but similar in SGA infants with stunting only (P = .816). Only SGA infants with both stunting and wasting had substantially lower proinsulin (P < .001) and higher ghrelin concentrations (P < .001) than OGA infants. This study is the first to demonstrate that SGA infants with wasting only are characterized by low HMW adiponectin concentrations, whereas those with stunting only are not. SGA with both stunting and wasting are characterized by low proinsulin and high ghrelin concentrations.

Effects of Dietary Supplementation of Conjugated Linoleic Acids and Their Inclusion in Semen Extenders on Bovine Sperm Quality.

Simple SummarySuboptimal fertility in males accounts for about two-thirds of infertility cases, thus being of serious concern for the dairy industry, where optimal fertility is fundamental for farm profitability. Although genetic defects responsible for subfertility have been identified, the role of seminal compounds on fertility remain unclear. Feeding rumen-protected isomers of conjugated linoleic acid (CLA) to dairy cows reportedly enhances circulating insulin-like growth factor I (IGF-I) levels. In breeding bulls, the IGF-I concentration in seminal plasma has been positively correlated with fertility rates. Therefore, the objective of the study was to evaluate the effect of dietary CLA supplementation and of their inclusion to the semen extender on bovine semen quality and freezability.Isomers of conjugated linoleic acid (CLA) enhances circulating insulin-like growth factor I (IGF-I) levels. Furthermore, fertility rate of breeding bulls is positively correlated to seminal plasma IGF-I concentration. Our objective was to evaluate the effect of dietary CLA supplementation and inclusion to the semen extender on bovine semen quality and freezability. Fourteen bulls, randomly assigned to control (CTL) and CLA (50 g/day) groups, were supplemented for 10 weeks. Samples were collected at Weeks −2 (before supplementation), 0, 4, 6 (during supplementation), 10, and 11 (after supplementation). Blood and seminal plasma were analyzed for IGF-I; the ejaculates were frozen in the following subgroups: CTL (no addition to semen extender), CLA c9, t11 (50 µM), CLA c9, t11 (100 µM), CLA t10, c12 (50 µM), CLA t10, c12 (100 µM), and CLA mix (50 µM each of CLA c9, t11 and CLA t10, c12). Sperm motility, morphology, viability, mitochondrial membrane potential, and reactive oxidative species were assessed. CLA supplementation decreased ejaculates’ total volume, increased sperm concentration, beat cross frequency, and decreased oxidative stress; it also increased plasma and seminal plasma IGF-I levels compared to the CTL. The inclusion of CLA c9, t11 100 µM and CLA mixture in the extender increased live spermatozoa percentage post-thawing compared to other groups. Our results show a beneficial effect of CLA supplementation on semen quality; however, further studies evaluating fertilization rates are necessary to corroborate the results.

Photoperiodic changes in hippocampal neurogenesis and plasma metabolomic profiles in relation to depression-like behavior in mice

Photoperiod alters affective behaviors and brain neuroplasticity in several mammalian species. We addressed whether neurogenesis and signaling pathways of insulin-like growth factor-I (IGF-I), a key modulator of neuroplasticity, are regulated by photoperiod in C57BL/6 J mice, a putative model of seasonal affective disorder. We also examined the effects of photoperiod on plasma metabolomic profiles in relation to depression-like behavior to understand a possible linkage between peripheral metabolism and behavior. Mice that were maintained under long-day conditions (LD) exhibited a higher number of 5-bromo-2′-deoxyuridine-positive cells and higher levels of astrocyte marker in the dentate gyrus of the hippocampus compared to that of mice under short-day conditions (SD). Plasma IGF-I levels and levels/expression of IGF-I signaling molecules in the hippocampus (Brn-4, NeuroD1, and phospho-Akt) involved in neuronal proliferation and differentiation were higher in the mice under LD. Metabolome analysis using plasma of the mice under LD and SD identified several metabolites that were highly correlated with immobility in the forced swim test, a depression-like behavior. Negative correlations with behavior occurred in the levels of 23 metabolites, including metabolites related to neurogenesis and antidepressant-like effects of exercise, metabolites in the biosynthesis of arginine, and the occurrence of branched chain amino acids. Three metabolites had positive correlations with the behavior, including guanidinosuccinic acid, a neurotoxin. Taken together, photoperiodic responses of neurogenesis and neuro-glial organization in the hippocampus may be involved in photoperiodic alteration of depression-like behavior, mediated through multiple pathways, including IGF-I and peripheral metabolites.

Metabolic and hormonal control of energy utilization and partitioning from early to mid lactation in Sarda ewes and Saanen goats

In a recent study, we observed that starch-rich diets used in mid lactation induced lower milk production persistency and higher body fat accumulation in dairy ewes compared with dairy goats. Because these species differences could be linked to hormonal mechanisms that drive energy partitioning, in the same experiment, we explored the evolution of metabolic and hormonal status during lactation to test this hypothesis. Twenty mature Sarda dairy ewes and 20 mature Saanen goats [15-134 ± 11 d in milk (DIM), mean ± SD] were compared simultaneously. In early lactation, each species was allocated to one dietary treatment: high-starch diet [HS: 20.4% starch, on dry matter (DM) basis], whereas from 92 ± 11 DIM, each species was allocated to 1 of 2 dietary treatments: HS (20.0% starch, on DM basis) and low-starch (LS: 7.8% starch, on DM basis) diets. Blood samples were collected in the morning to analyze glucose, nonesterified fatty acids (NEFA), growth hormone (GH), insulin, and insulin-like growth factor I (IGF-I). Data were analyzed using the PROC MIXED procedure of SAS with repeated measurements (SAS Version 9.0). The HS and LS diets applied in mid lactation did not affect metabolic status of the animal within species; thus, only a comparison between species was carried out. From early to mid lactation, plasma glucose concentration was higher in ewes than in goats (54.57 vs. 48.35 ± 1.18 mg/dL), whereas plasma NEFA concentration was greater in goats than in ewes (0.31 vs. 0.25 ± 0.03 mmol/L). Goats had higher plasma GH concentration and lower plasma insulin content than ewes (4.78 vs. 1.31 ng/mL ± 0.47; 0.11 vs. 0.26 μg/L ± 0.02). Plasma IGF-I concentration did not vary between species. The comparison of metabolic and hormonal status of lactating Sarda dairy ewes and Saanen goats, carried out by studying simultaneously the 2 species in the same stage of lactation and experimental conditions, suggests that the higher insulin and glucose concentration observed in Sarda ewes explains why they partitioned more energy toward body reserves than to the mammary gland, especially in mid lactation. This can justify the negative effect of high-starch diets in mid-lactating Sarda ewes. Conversely, the highest GH and NEFA concentration observed in Saanen goats explain why they partitioned more energy of starch diets toward the mammary gland than to body reserves and justify the positive effect of high-starch diet in mid lactation. Together, these different responses contribute to explain why specialized dairy goats, such as the Saanen breed, have a higher milk production persistency than specialized dairy sheep breeds, such as the Sarda.

Relationship between plasma concentrations of IGF-I and clinical endometritis, and response to progesterone synchrony in dairy cows during early lactation

The first aim of this study was to evaluate the relationship between the concentrations of plasma insulin-like growth factor-I (IGF-I) in the transition period and the incidence of clinical endometritis postpartum. The second aim was to evaluate the relationship between the concentration of plasma IGF-I in the transition period and the estrous synchrony response and pregnancy rate to a controlled internal drug release (CIDR) protocol. A total of 402 dairy cows, 250 multiparous and 152 primiparous, were enrolled. A blood sample was taken from all cows 2 and 1 wk precalving and wk 1, 3, 4, and 5 postcalving for subsequent analysis of IGF-I. Vaginal discharge score as a measurement of uterine health was recorded in wk 3, 4, and 5 postcalving. Estrous cycles of all cows were synchronized on ≥37 d in milk (mean = 59; range 37-93) using an 8-d CIDR protocol. All cows were scanned at 32 to 35 d after insemination to confirm pregnancy. Data were analyzed using Proc Mixed and Proc Logistic models in SAS (version 9.3; SAS Institute Inc., Cary, NC). Plasma IGF-I concentrations were significantly greater in the primiparous cows than in the multiparous cows, both before and after calving, and were therefore analyzed separately. In multiparous cows plasma IGF-I concentrations postcalving were significantly lower among cows with uterine infection than in those without infection, and multiparous cows with a plasma IGF-I concentration less than 40 ng/mL 1 wk after calving were 3 times more likely to suffer from a uterine infection 4 to 5 weeks postcalving (odds ratio 2.8; 95% confidence interval 1.0-7.6). Plasma IGF-I concentrations were significantly greater after calving in the 121 primiparous cows that exhibited estrus post-CIDR protocol (mean 125 ng/mL) than in the 25 primiparous cows that did not respond (mean 95 ng/mL). Multiparous cows with greater plasma IGF-I concentrations postcalving had a significantly greater chance of conceiving (mean plasma IGF-I concentration of conceiving cows = 86 ng/mL; nonconceiving = 70 ng/mL). These results show an association between greater concentrations of plasma IGF-I postcalving and response to CIDR protocol in primiparous animals (mean plasma IGF-I concentration of responders = 116 ng/mL; nonresponders = 95 ng/mL). In contrast no association was detected between concentrations of plasma IGF-I in relation to the response to the CIDR protocol in multiparous cows. In conclusion, changes in circulating concentrations of plasma IGF-I early postpartum may help predict reproductive status of dairy cows.

Effects of preoperative oral administration of glucose solution combined with postoperative probiotics on inflammation and intestinal barrier function in patients after colorectal cancer surgery.

The effects of preoperative oral administration of glucose solution combined with postoperative probiotics on inflammation and intestinal barrier function in patients after colorectal cancer surgery were observed. Sixty patients treated and scheduled to undergo radical resection of colorectal cancer in The Second Affiliated Hospital of Kunming Medical University from March 2017 to December 2017 were selected and randomly divided into the glucose solution group (n=30) and combined probiotics group (n=30). Patients in both groups took orally 12.5% glucose solution before surgery, and those in the combined probiotics group received bifidus-triple viable preparation every day for 7 consecutive days. Changes in endotoxin, insulin-like growth factor-I (IGF-I) concentration, white blood cell count (WBC), C-reactive protein (CRP), D-lactic acid and urinary lactulose/mannitol (L/M) were detected before surgery and at 1, 3 and 7 days after surgery. The general condition was observed and changes in intestinal florae were compared between the two groups. The body temperature was measured every 4 h with an electronic thermometer, and the duration of fever was recorded (from the first day after operation to the time with normal body temperature after operation, axillary temperature <37.4°C), and the average heart rate was recorded by the ECG monitor. In addition, the time of the first anal exsufflation (the time from the beginning of the operation to the first anal exsufflation) was recorded. In the combined probiotics group, the plasma endotoxin, IGF-I concentration, D-lactic acid and urinary L/M levels were significantly lower than those in the glucose solution group (P<0.05). Moreover, the duration of postoperative fever, average heart rate at 7 days after surgery as well as WBC and CRP clinical indexes were obviously shorter and lower in the combined probiotics group than those in the glucose solution group (P<0.05). Therefore, the combined application of probiotics after surgery can effectively improve the imbalance of intestinal flora. In conclusion, preoperative oral administration of glucose solution combined with postoperative probiotics can improve the intestinal barrier function after colorectal cancer surgery, and benefit the recovery of early inflammatory response after surgery.

Idiopathic short stature and growth hormone sensitivity in prepubertal children.

We compared growth hormone sensitivity to an insulin-like growth factor I (IGF-I) generation test in children with idiopathic short stature (ISS) and of normal stature (NS) across the birthweight range. Forty-six prepubertal children (~7.1years) born at term were studied: ISS (n=23; 74% boys) and NS (n=23; 57% boys). Children underwent a modified IGF-I generation test with recombinant human growth hormone (rhGH; 0.05mg/kg/d) over four consecutive days. Hormonal concentrations were measured at baseline and day 5. Children with idiopathic short stature were 1.90 SDS lighter (P<0.0001) but had 4.5% more body fat (P=0.0007) than NS children. Overall, decreasing birthweight SDS across the normal range (-1.9 to +1.5 SDS) was associated with lower percentageIGF-I response to rhGH stimulation in univariable (r=0.45; P=0.002) and multivariable models (β=24.6; P=0.006). Plasma IGF-I concentrations rose in both groups with rhGH stimulation (P<0.0001). GHBP levels (P=0.002) were suppressed in ISS children (-19%; P=0.029) but increased among NS children (+18%; P=0.028), with contrasting responses also observed for leptin and IGFBP-1. Further, the increase in insulin concentrations in response to rhGH stimulation was ~3-fold greater in NS children (142% vs 50%; P=0.006). A progressive decrease in birthweight SDS was associated with a reduction in GH sensitivity in both NS and ISS children. Thus, the lower IGF-I response to rhGH stimulation in association with decreasing birthweight indicates that the ISS children at the lower end of the birthweight spectrum may have partial GH resistance, which may contribute to their poorer growth.

Editing the duplicated insulin-like growth factor binding protein-2b gene in rainbow trout (Oncorhynchus mykiss)

In salmonids, the majority of circulating insulin-like growth factor-I (IGF-I) is bound to IGF binding proteins (IGFBP), with IGFBP-2b being the most abundant in circulation. We used CRISPR/Cas9 methodology to disrupt expression of a functional IGFBP-2b protein by co-targeting for gene editing IGFBP-2b1 and IGFBP-2b2 subtypes, which represent salmonid-specific gene duplicates. Twenty-four rainbow trout were produced with mutations in the IGFBP-2b1 and IGFBP-2b2 genes. Mutant fish exhibited between 8–100% and 2–83% gene disruption for IGFBP-2b1 and IGFBP-2b2, respectively, with a positive correlation (P < 0.001) in gene mutation rate between individual fish. Analysis of IGFBP-2b protein indicated reductions in plasma IGFBP-2b abundance to between 0.04–0.96-fold of control levels. Plasma IGF-I, body weight, and fork length were reduced in mutants at 8 and 10 months post-hatch, which supports that IGFBP-2b is significant for carrying IGF-I. Despite reduced plasma IGF-I and IGFBP-2b in mutants, growth retardation in mutants was less severe between 10 and 12 months post-hatch (P < 0.05), suggesting a compensatory growth response occurred. These findings indicate that gene editing using CRISPR/Cas9 and ligand blotting is a feasible approach for characterizing protein-level functions of duplicated IGFBP genes in salmonids and is useful to unravel IGF-related endocrine mechanisms.

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.

Circulating insulin-like growth factor I modulates mood and is a biomarker of vulnerability to stress: from mouse to man

Individual susceptibility to anxiety disorders after maladaptive responses to stress is not well understood. We now report that while exploring stress responses in mice after traumatic brain injury (TBI), a condition associated to stress susceptibility, we observed that the anxiogenic effects of either TBI or exposure to life-threatening experiences (predator) were blocked when both stressors were combined. Because TBI increases the entrance into the brain of serum insulin-like growth factor I (IGF-I), a known modulator of anxiety with a wide range of concentrations in the human population, we then determined whether circulating IGF-I is related to anxiety measures. In mice, anxiety-like responses to predator were inversely related to circulating IGF-I levels. Other indicators of mood regulation such as sensitivity to dexamethasone suppression and expression levels of blood and brain FK506 binding protein 5 (FKBP5), a co-chaperone of the glucocorticoid receptor that regulates its activity, were also associated to circulating IGF-I. Indeed, brain FKBP5 expression in mice was stimulated by IGF-I. In addition, we observed in a large human cohort (n = 2686) a significant relationship between plasma IGF-I and exposure to recent stressful life events, while FKBP5 expression in blood cells was significantly associated to plasma IGF-I levels. Collectively, these data indicate that circulating IGF-I appears to be involved in mood homeostasis across different species. Furthermore, the data in mice allow us to indicate that IGF-I may be acting at least in part by modulating FKBP5 expression.

Hyperammonemia in a Child Presenting with Growth Delay, Short Stature, and Diarrhea

A 5-year-old male child was referred to the metabolism clinic with a history of failure to thrive, chronic intermittent emesis, diarrhea, seizures, hypotonia, and growth hormone deficiency. He was also noted to experience frequent falling episodes. Routine biochemistry testing revealed increased plasma ammonia concentration at 184 μmol/L (reference interval, 16–47) and lactate dehydrogenase concentration at 445 U/L (reference interval, 110–295). Plasma free and total carnitine concentrations were decreased at 5 μmol/L (reference interval, 26–60) and 17.1 μmol/L (reference interval, 32–84), respectively. Orotic acid excretion in urine was also markedly increased at >80 mmol/mol creatinine (reference interval, 0.2–1.5). Plasma insulin-like growth factor-I (IGF-I)4 concentration was also decreased at <25 ng/mL (reference interval, 50–286). Paired plasma and urine specimens were collected for amino acid analysis using ultraperformance liquid chromatography. The results are shown in Table 1. View this table: Table 1. Amino acid analysis of paired plasma and urine. This patient has lysinuric protein intolerance (LPI), an autosomal recessive disorder of amino acid transport, caused by mutations in the solute carrier family 7, member 7 ( SLC7A7 ) gene (1, 2, 3). Although the worldwide incidence is not known, LPI is estimated to occur in approximately 1 in 60000 newborns in Finland and Japan (2). The SLC7A7 gene product is the …

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.