Insulin-like Growth Factor-1 Response Research Articles

Short- and long-term effects of nutritional state on IGF-1 levels in nestlings of a wild passerine

Growth trajectories of young animals are intimately connected to their fitness prospects, but we have little knowledge of growth regulation mechanisms, particularly in the wild. Insulin-like growth factor 1 (IGF-1) is a central hormone in regulating resource allocation, with higher IGF-1 levels resulting in more growth. IGF-1 levels generally increase in conjunction with nutritional state, but whether IGF-1 levels are adjusted in response to current nutrient availability or to the nutrient availability integrated over a longer term is not well known. We tested for such effects by supplementary feeding the jackdaw (Corvus monedula) nestlings in experimentally reduced or enlarged broods with either water (control) or a food solution; these manipulations have long- and short-term effects on the nutritional state, respectively. Baseline plasma IGF-1 levels were higher in reduced broods. Food supplementation induced an increase in plasma IGF-1 levels measured one hour later, and this effect was significantly more substantial in nestlings in reduced broods. Changes in plasma IGF-1 levels increased with increased retention of the supplementary food, which was higher in reduced broods, explaining the stronger IGF-1 response. Thus, IGF-1 levels respond to short-term variations in the nutritional state, but this effect is amplified by longer-term variations in the nutritional state. We discuss our findings using a graphical model that integrates the results of the two treatments.

Effects of Acute Caffeine Intake on Insulin-Like Growth Factor-1 Responses to Total Sleep Deprivation: Interactions with COMT Polymorphism – A Randomized, Crossover Study

Introduction: Genes encoding catechol-O-methyl-transferase (COMT) and adenosine A2A receptor (ADORA2A) have been shown to influence cognitive performances and responses to caffeine intake during prolonged wakefulness. The rs4680 single-nucleotide polymorphism (SNP) of COMT differentiates on memory score and circulating levels of the neurotrophic factor IGF-1. This study aimed to determine the kinetics of IGF-1, testosterone, and cortisol concentrations during prolonged wakefulness under caffeine or placebo intake in 37 healthy participants, and to analyze whether the responses are dependent on COMT rs4680 or ADORA2A rs5751876 SNPs. Methods: In caffeine (2.5 mg/kg, twice over 24 h) or placebo-controlled condition, blood sampling was performed at 1 h (08:00, baseline), 11 h, 13 h, 25 h (08:00 next day), 35 h, and 37 h of prolonged wakefulness, and at 08:00 after one night of recovery sleep, to assess hormonal concentrations. Genotyping was performed on blood cells. Results: Results indicated a significant increase in IGF-1 levels after 25, 35, and 37 h of prolonged wakefulness in the placebo condition, in subjects carrying the homozygous COMT A/A genotype only (expressed in absolute values [±SEM]: 118 ± 8, 121 ± 10, and 121 ± 10 vs. 105 ± 7 ng/mL for A/A, 127 ± 11, 128 ± 12, and 129 ± 13 vs. 120 ± 11 ng/mL for G/G, and 106 ± 9, 110 ± 10, and 106 ± 10 vs. 101 ± 8 ng/mL for G/A, after 25, 35, and 37 h of wakefulness versus 1 h; p < 0.05, condition X time X SNP). Acute caffeine intake exerted a COMT genotype-dependent reducing effect on IGF-1 kinetic response (104 ± 26, 107 ± 27, and 106 ± 26 vs. 100 ± 25 ng/mL for A/A genotype, at 25, 35, and 37 h of wakefulness vs. 1 h; p < 0.05 condition X time X SNP), plus on resting levels after overnight recovery (102 ± 5 vs. 113 ± 6 ng/mL) (p < 0.05, condition X SNP). Testosterone and cortisol concentrations decreased during wakefulness, and caffeine alleviated the testosterone reduction, unrelated to the COMT polymorphism. No significant main effect of the ADORA2A SNP was shown regardless of hormonal responses. Conclusion: Our results indicated that the COMT polymorphism interaction is important in determining the IGF-1 neurotrophic response to sleep deprivation with caffeine intake (NCT03859882).

Population pharmacokinetic/pharmacodynamic analysis of PEG-rhGH enhances confidence in exploring dosing schemes with longer intervals

Background and objectivesPEG-rhGH (Jintrolong®, 0.2 mg/kg/week) is approved in China for the treatment of growth hormone deficiency (GHD) in children. Although 0.2 mg/kg/2 weeks PEG-rhGH failed the non-inferiority threshold of 20% compared with 0.2 mg/kg/week PEG-rhGH, it notably increases serum IGF-1 levels and height velocity in a phase IV trial. In the absence of investigation on the relationship between pharmacokinetics and pharmacodynamics, this analysis aimed to build a population pharmacokinetic/pharmacodynamic (PopPK/PD) model to characterize the relationship between serum PEG-rhGH concentration and serum insulin-like growth factor-1 (IGF-1) levels after subcutaneously administration of PEG-rhGH and to explore the possibility of flexible dosing schemes and improve the clinical monitor practice of IGF-1 levels. MethodsA total of 41 subjects were included for the PopPK analysis, consisting of 30 healthy adults (single dose of 0.1–0.4 mg/kg) and 11 GHD children (multiple doses of 0.2 mg/kg/2 weeks for 26 consecutive weeks). Only GHD children were included for the PopPK/PD analysis. The time courses of serum PEG-rhGH concentrations in healthy adults and GHD children and those of serum IGF-1 levels stimulated by serum PEG-rhGH were well developed with non-linear mixed-effects modeling. ResultsSerum PEG-rhGH pharmacokinetics after subcutaneous administration were adequately described by a one-compartment model with a zero-order input into the absorption compartment followed by first-order absorption dictating absorption into the central compartment, with a dual elimination process consisting of a capacity limited process and a non-capacity limited process. Body weight was a significant covariate. The drug effects on IGF-1 levels were adequately described by a turnover model with saturable effect relationship. IGF-1 responses at the various dosing scheme scenarios were simulated, and illustrated that dosing schemes with intervals longer than the approved one week could be promising, which may provide comparable peaks and average IGF-1 levels and IGF-1 SDS to dosing schemes that have been clinically proven to be tolerated and effective. An accurate prediction of the time course of the effect of various dosing schemes may assist the clinical monitoring practice. ConclusionsThis pharmacokinetic/pharmacodynamic analysis suggested that longer intervals or higher dosing strengths (e.g., 0.3 mg/kg/10 days) in children with GHD are promising compared with the approved dosing scheme (0.2 mg/kg/week). Our simulation may assist the clinical monitoring of the PEG-rhGH therapy.

Aerobic Exercise-induced Anabolic Responses After Inhibition/stimulation Of Hpa Axis In Healthy Adults

Exercise is a stress stimulus leading to endocrine changes in the human body. There are interactions between the Hypothalamo-Pituitary-Adrenal (HPA) axis components in response to exercise, depending on the characteristics of exercise (type, duration, intensity, and frequency). Anabolic responses after aerobic exercise are less predictable yet important to explore. PURPOSE: This study examined the anabolic factor insulin-like growth factor-1 (IGF-1) responses to a selected aerobic exercise protocol performed under inhibition or stimulation of the HPA axis in healthy volunteers. METHODS: Twelve healthy volunteers (8 males and 4 females, age: 30.6 ± 4.4 yrs, body mass: 77.3 ± 12.3 kg, height: 1.77 ± 0.07 m) performed a single bout of 30 min aerobic exercise at 70%VO2 max on a treadmill, on three different conditions [control (C), HPA axis inhibition (HPA-I, induced by glucocorticoid administration), HPA axis stimulation (HPA-S, induced by ACTH administration)], following standard diet. Blood samples were collected before (PRE) and at the end of the exercise bout (POST) and serum IGF-1 was measured with ELISA. Two-way ANOVA was used for statistics and data is presented as mean ± SE. RESULTS: In C condition, IGF-1 did not change post-exercise (189.4 ± 24.3; 191.6 ± 17,9 ng/mL; at PRE and POST, respectively). Under HPA-I condition, decreased levels of IGF-1 were observed at the end of exercise (212.6 ± 18.7; 155.2 ± 20.5; ng/mL; at PRE and POST, respectively), however this decrease failed to reach statistical significance (p > 0.05). Inversely, under HPA-S condition IGF-1 exhibited a trend to increase 30 min after exercise (p > 0.05) (141.8 ± 13.9; 156.1 ± 18.1 ng/mL; at PRE, and POST, respectively). Under HPA-S condition, IGF-1 levels were significantly lower compared to HPA-I condition at PRE (141.8 ± 13.9 vs 212.6 ± 18.7; p < 0.05). However, there were no significant differences in serum IGF-1 concentrations between the three conditions as a result of exercise, or between males and females. CONCLUSION: IGF-1 did not seem to change immediately after moderate aerobic exercise regardless of the inhibition or stimulation of the HPA axis. However, the modification of HPA axis found to affect IGF-1 levels at rest. Further studies are needed to characterize the IGF-1 responses during the recovery period after aerobic exercise.

Comparison of the effects of open vs. closed skill exercise on the acute and chronic BDNF, IGF-1 and IL-6 response in older healthy adults

BackgroundAccumulating evidence shows that physical exercise has a positive effect on the release of neurotrophic factors and myokines. However, evidence regarding the optimal type of physical exercise for these release is still lacking. The aim of this study was to assess the acute and chronic effects of open-skill exercise (OSE) compared to closed-skill exercise (CSE) on serum and plasma levels of brain derived neurotrophic factor (BDNFS, BDNFP), and serum levels of insulin like growth factor 1 (IGF-1), and interleukin 6 (IL-6) in healthy older adults.MethodsTo investigate acute effects, thirty-eight participants were randomly assigned to either an intervention (badminton (aOSE) and bicycling (aCSE), n = 24, 65.83 ± 5.98 years) or control group (reading (CG), n = 14, 67.07 ± 2.37 years). Blood samples were taken immediately before and 5 min after each condition. During each condition, heart rate was monitored. The mean heart rate of aOSE and aCSE were equivalent (65 ± 5% of heart rate reserve). In a subsequent 12-week training-intervention, twenty-two participants were randomly assigned to either a sport-games (cOSE, n = 6, 64.50 ± 6.32) or a strength-endurance training (cCSE, n = 9, 64.89 ± 3.51) group to assess for chronic effects. Training intensity for both groups was adjusted to a subjective perceived exertion using the CR-10 scale (value 7). Blood samples were taken within one day after the training-intervention.ResultsBDNFS, BDNFP, IGF-1, and IL-6 levels increased after a single exercise session of 30 min. After 12 weeks of training BDNFS and IL-6 levels were elevated, whereas IGF-1 levels were reduced in both groups. However, only in the cOSE group these changes were significant. We could not find any significant differences between the exercise types.ConclusionOur results indicate that both exercise types are efficient to acutely increase BDNFS, BDNFP, IGF-1 and IL-6 serum levels in healthy older adults. Additionally, our results tend to support that OSE is more effective for improving basal BDNFS levels after 12 weeks of training.

Fast Eccentric Movement Tempo Elicits Higher Physiological Responses than Medium Eccentric Tempo in Ice-Hockey Players.

Background: Resistance training is a significant part of ice-hockey players’ conditioning, where optimal loading should ensure strength development and proper recovery. Therefore, this study aimed to compare the acute physiological responses to fast and medium movement tempo resistance exercises in ice-hockey players. Methods: Fourteen ice-hockey players (26.2 ± 4.2 years; 86.4 ± 10.2 kg; squat one repetition maximum (1RM) = 130.5 ± 18.5) performed five sets of the barbell squat and barbell bench press at 80% 1RM until failure in a crossover design one week apart using either 2/0/2/0 or 6/0/2/0 (eccentric/isometric/concentric/isometric) tempo of movement. The blood samples to evaluate the concentration of cortisol, testosterone, insulin-like growth factor 1 (IGF-1), and growth hormone (hGH) were taken before exercise, 3 min after the last set of the squat exercise, 3 min after the last set of the bench press exercise, and after 30 min of recovery. Results: The 2/0/2/0 tempo resulted in a higher number of repetitions (p < 0.001) and lower time under tension (p < 0.001) in the squat and bench press exercises compared to the 6/0/2/0 movement tempo. The endocrine responses to exercise were significantly higher during the 2/0/2/0 compared to the 6/0/2/0 movement tempo protocol for IGF-1, hGH, and cortisol (p < 0.01). There were no differences in testosterone responses between exercises performed with fast and medium movement tempos. Conclusion: Fast eccentric tempo induced higher cortisol, IGF-1, and hGH responses compared to the medium tempo. Therefore, fast eccentric movement tempo seems to be more useful in eliciting training stimulus than medium eccentric tempo during resistance training in ice-hockey players. However, future studies are needed to confirm our findings.

Influence of inclusion of pigeon pea ( Cajanus cajan ) leafmeal on growth, physio‐metabolic and immune parameters, and expression of IGF‐1, IGF‐1R and IGFBP‐1 genes in Labeo rohita (Hamilton, 1822) fingerlings

A feeding trial was conducted with inclusion levels of Cajanus cajan leafmeal (CCLM) in the diet of Labeo rohita to study the growth, haematological indices, digestive enzyme, physio-metabolic changes and molecular expression of insulin-like growth factor-1 (IGF-1), insulin-like growth factor-binding protein-1 (IGFBP-1), insulin-like growth factor-1 receptor (IGF-1R) genes. Four practical diets with CCLM, control, T20 (20%), T30 (30%) and T40 (40%) were prepared. Weight gain%, SGR, FER and PER were significantly (p < 0.05) higher when 30% de-oiled rice bran (DORB) was replaced by CCLM whereas the treatment group 40% registered with lower FCR value. The protease and amylase activities were higher in the T30 group. T20 showed significantly higher (p < 0.05) hepatic and muscular lactate dehydrogenase and serum glucose was also higher, whereas, WBC content was found significantly (p < 0.05) higher in control. The hepatic IGF-1 gene expression was significantly higher (p < 0.05) in T40 followed by the T30 group but the weight gain was not significantly (p > 0.05) higher in T30 from the T40 group. Results reveal that the response of IGF-1, IGF-1R and IGFBP-1 genes was complementary to the biological growth parameters and hence were used as an indicator to evaluating growth. The study also demonstrates that CCLM can replace 100% DORB in the diet of L. rohita without any antinutritional or adverse growth effects.

IGF-1 treatment causes unique transcriptional response in neurons from individuals with idiopathic autism

BackgroundResearch evidence accumulated in the past years in both rodent and human models for autism spectrum disorders (ASD) have established insulin-like growth factor 1 (IGF-1) as one of the most promising ASD therapeutic interventions to date. ASD is phenotypically and etiologically heterogeneous, making it challenging to uncover the underlying genetic and cellular pathophysiology of the condition; and to efficiently design drugs with widespread clinical benefits. While IGF-1 effects have been comprehensively studied in the literature, how IGF-1 activity may lead to therapeutic recovery in the ASD context is still largely unknown.MethodsIn this study, we used a previously characterized neuronal population derived from induced pluripotent stem cells (iPSC) from neurotypical controls and idiopathic ASD individuals to study the transcriptional signature of acutely and chronically IGF-1-treated cells.ResultsWe present a comprehensive list of differentially regulated genes and molecular interactions resulting from IGF-1 exposure in developing neurons from controls and ASD individuals. Our results indicate that IGF-1 treatment has a different impact on neurons from ASD patients compared to controls. Response to IGF-1 treatment in neurons derived from ASD patients was heterogeneous and correlated with IGF-1 receptor expression, indicating that IGF-1 response may have responder and non-responder distinctions across cohorts of ASD patients. Our results suggest that caution should be used when predicting the effect of IGF-1 treatment on ASD patients using neurotypical controls. Instead, IGF-1 response should be studied in the context of ASD patients’ neural cells.LimitationsThe limitation of our study is that our cohort of eight sporadic ASD individuals is comorbid with macrocephaly in childhood. Future studies will address weather downstream transcriptional response of IGF-1 is comparable in non-macrocephalic ASD cohorts.ConclusionsThe results presented in this study provide an important resource for researchers in the ASD field and underscore the necessity of using ASD patient lines to explore ASD neuronal-specific responses to drugs such as IGF-1. This study further helps to identify candidate pathways and targets for effective clinical intervention and may help to inform clinical trials in the future.

SNHG7 is a lncRNA oncogene controlled by Insulin-like Growth Factor signaling through a negative feedback loop to tightly regulate proliferation

Evidence suggests Insulin-like growth factor 1 (IGF1) signaling is involved in the initiation and progression of a subset of breast cancers by inducing cell proliferation and survival. Although the signaling cascade following IGF1 receptor activation is well-studied, the key elements of the transcriptional response governing IGF1’s actions are not well understood. Recent studies reveal that the majority of the genome is transcribed and that there are more long non-coding RNAs (lncRNAs) than protein coding genes, several of which are dysregulated in human cancer. However, studies on the regulation and mechanism of action of these lncRNAs are in their infancy. Here we show that IGF1 alters the expression levels of a subset of lncRNAs. SNHG7, a member of the small nucleolar host gene family, is a highly-expressed lncRNA that is consistently and significantly down-regulated by IGF1 signaling by a post-transcriptional mechanism through the MAPK pathway. SNHG7 regulates proliferation of breast cancer cell lines in a dose-dependent manner, and silencing SNHG7 expression causes cell cycle arrest in G0/G1. Intriguingly, SNHG7 alters the expression of many IGF1 signaling intermediates and IGF1-regulated genes suggesting a feedback mechanism to tightly regulate the IGF1 response. Finally, we show in clinical data that SNHG7 is overexpressed in tumors of a subset of breast cancer patients and that these patients have lower disease-free survival than patients without elevated SNHG7 expression. We propose that SNHG7 is a lncRNA oncogene that is controlled by growth factor signaling in a feedback mechanism to prevent hyperproliferation, and that this regulation can be lost in the development or progression of breast cancer.

OR10-05 Phase 3 FliGHt Trial: Experience of Switching from Daily Growth Hormone Therapy to Once-Weekly TransCon HGH in Children with Growth Hormone Deficiency

Background: The Phase 3 fliGHt Trial evaluated children with growth hormone deficiency (GHD) of a broad range of baseline demographics and treatment durations who switched from daily growth hormone (hGH; somatropin) therapy to once-weekly TransCon hGH. TransCon hGH is an investigational long-acting prodrug consisting of 3 components: hGH, an inert carrier that protects it, and a linker that temporarily binds the two. When injected into the body, at physiologic pH and temperature, unmodified hGH is gradually released in a predictable manner. Methods: All subjects initiated open-label once-weekly TransCon hGH 0.24 mg hGH/kg/week irrespective of prior daily hGH dose. Subjects 3 to 17 years old must have been treated with daily hGH for 13 to 130 weeks; subjects 6 months to 3 years old may have been treatment-naïve or treated with daily hGH for ≤130 weeks. The primary objective was to assess safety and tolerability over this 26-week trial. Efficacy measures included annualized height velocity (AHV), height standard deviation score (SDS), and insulin-like growth factor 1 (IGF-1) SDS. Results: Of the 146 enrolled subjects, 98.6% completed the trial. Mean age at baseline was 10.6 years (range: 1, 17). The majority (97.9%) were treatment-experienced with a prior daily hGH mean dose of 0.29 mg/kg/week (range: 0.13, 0.49); 3 subjects were treatment-naïve and <3 years old. Just over half the subjects (56.8%) experienced a treatment-emergent adverse event (TEAE), with only 4.1% of subjects experiencing a TEAE considered related to study drug. No TEAE led to discontinuation of study drug. The type and frequency of TEAEs reported were similar to the published adverse event profile of daily hGH therapies. Mean hemoglobin A1c remained 5.2% at baseline and Week 26. No neutralizing antibodies were detected; low-titer anti-hGH binding antibodies were detected in 2.8% of subjects. Growth outcomes were as expected for this treatment-experienced heterogenous population, with a least-squares mean (LSM) AHV of 8.7 cm/year (95% CI: 8.2, 9.2) at Week 26 and LSM height SDS change from baseline to Week 26 of +0.25 (95% CI: 0.21, 0.29). In the age-defined subgroups, mean observed AHV at Week 26 ranged from 8.2 to 16.2 cm/year and mean observed height SDS change from baseline to Week 26 ranged from +0.23 to +0.96. Of note, the linear relationship between average IGF-1 SDS and TransCon hGH doses demonstrated in previous treatment-naïve trials was preserved in this population of treatment-experienced children who had dose titrations. Conclusions: TransCon hGH treatment outcomes, including AHV and height SDS, were as expected across a diversity of ages, disease characteristics, and treatment experiences, reflective of a real-world setting. Dose titrations of TransCon hGH demonstrated a predictable IGF-1 response. Switching to TransCon hGH resulted in a similar adverse event profile to daily hGH therapy.

Effects of Exercise Intensity on Acute Circulating Molecular Responses Poststroke

Background. Exercise intensity can influence functional recovery after stroke, but the mechanisms remain poorly understood. Objective. In chronic stroke, an intensity-dependent increase in circulating brain-derived neurotrophic factor (BDNF) was previously found during vigorous exercise. Using the same serum samples, this study tested acute effects of exercise intensity on other circulating molecules related to neuroplasticity, including vascular-endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF1), and cortisol, with some updated analyses involving BDNF. Methods. Using a repeated-measures design, 16 participants with chronic stroke performed 3 exercise protocols in random order: treadmill high-intensity interval training (HIT-treadmill), seated-stepper HIT (HIT-stepper), and treadmill moderate-intensity continuous exercise (MCT-treadmill). Serum molecular changes were compared between protocols. Mediation and effect modification analyses were also performed. Results. VEGF significantly increased during HIT-treadmill, IGF1 increased during both HIT protocols and cortisol nonsignificantly decreased during each protocol. VEGF response was significantly greater for HIT-treadmill versus MCT-treadmill when controlling for baseline. Blood lactate positively mediated the effect of HIT on BDNF and cortisol. Peak treadmill speed positively mediated effects on BDNF and VEGF. Participants with comfortable gait speed ≥0.4 m/s had significantly lower VEGF and higher IGF1 responses, with a lower cortisol response during MCT-treadmill. Conclusions. BDNF and VEGF are promising serum molecules to include in future studies testing intensity-dependent mechanisms of exercise on neurologic recovery. Fast training speed and anaerobic intensity appear to be critical ingredients for eliciting these molecular responses. Serum molecular response differences between gait speed subgroups provide a possible biologic basis for previously observed differences in training responsiveness.

Comparison of growth hormone and insulin-like growth factor-1 responses to high intensity and low intensity resistance training with and without blood flow restriction in adolescent male athletes

Comparison of growth hormone and insulin-like growth factor-1 responses to high intensity and low intensity resistance training with and without blood flow restriction in adolescent male athletes

Brain-derived neurotrophic factor, insulin like growth factor-1 and inflammatory cytokine responses to continuous and intermittent exercise in patients with type 1 diabetes

AimsType 1 diabetes mellitus (T1DM) is an important risk factor for cognitive decline and motor dysfunction due to progressive muscular atrophy. Chronic hyperglycemia may be responsible for impaired vascular function, loss of muscle mass, and morphological abnormalities in the myocytes. For the proper functioning of the neuromuscular system, two crucial growth factors are necessary: brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1), whose reduced expressions have been implicated in progressive neuropathy and muscle atrophy in patients with T1DM.The aim of the study was to compare the effects of two different exercise regimes (continuous and intermittent) on BDNF, IGF-1, blood glucose and inflammatory cytokine responses in young adults with and without Type 1 diabetes. MethodsFourteen patients (aged: 26.9 years) with T1DM and age-matched adults without diabetes participated in a 40 min continuous exercise (ExC, 50% of lactate threshold) and a high intensity intermittent exercise (ExInt, 120% of lactate threshold). During the study the patients performed self-monitoring of blood glucose levels (SMBG) under glycemic control. The effects of ExC and ExInt on BDNF, IGF-1, insulin like growth factor binding protein (IGFBP-3), insulin (INS), vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-β) and tumor necrosis factor alpha (TNF-α) were analyzed. ResultsBDNF and IGF-1 baseline serum levels were significantly lower in the T1DM patients compared to the healthy controls, but we found that ExInt and ExC significantly increase the secretion of BDNF and IGF-1 levels. Significant increases in BDNF and TGF-β levels, higher blood glucose decline, and a lower incidence of hypoglycaemia in ExInt compared to ExC were observed. Lower IGFBP-3 concentrations were revealed in T1DM patients in response to ExInt compared to ExC, suggesting a positive effect on IGF-1/IGFBP-3 ratio and the bioavailability of IGF-1. ConclusionsAccording to our results physical exercise has beneficial effects on serum BDNF and IGF-1 levels. A high-intensity intermittent exercise may be more effective at reducing the risk of exercise-induced glycaemic disorders in the T1DM patients as compared to continuous exercise.

Blunted satellite cell response is associated with dysregulated IGF-1 expression after exercise with age.

Insulin-like growth factor-1 (IGF-1) regulates protein synthesis and cell cycle kinetics. Given that aging is associated with anabolic resistance, we sought to determine if the attenuated exercise-induced satellite cell (SC) expression in older muscle is associated with a blunted IGF-1 response. SC expression (Pax7+ cells) and protein (Western blot) and mRNA (RT-PCR) expression of IGF-1 splice variants and ubiquitous (IGFBP4) and muscle-specific (IGFBP3 and -5) IGF-1 binding proteins were measured in skeletal muscle of young (Y: 22 ± 2, n = 7) and older (O: 70 ± 2, n = 7) adults up to 48h after an acute bout of resistance exercise. SC expression was greater in Y compared to O (age; P < 0.01) and increased (interaction; P < 0.05) by 24h after exercise in Y only. IGF-1Ea and IGF-1Eb mRNA tended to be greater in O (age; P < 0.06-0.09). IGF-1Eb mRNA increased at 48h (time; P < 0.05), whereas IGF-1Ec mRNA increased (interaction; P < 0.05) at 24 and 48h in O only. IGF binding protein (IGFBP)4 mRNA was greater (age; P < 0.01) in O with the increase at 24h and 48h (time; P < 0.01) primarily driven by changes in O (interaction; P < 0.01). Despite IGFBP3 mRNA being greater in O (age; P < 0.01) and increasing at 48h (time; P < 0.01), there was no effect of age or exercise on IGFBP3 protein expression. In contrast, IGFBP5 mRNA was greater (age; P < 0.01) despite IGFBP5 protein expression being lower (age; P < 0.01) in O compared to Y. The greater muscle-specific expression of IGF-1 family members with a blunted post-exercise SC expression may be a compensatory attempt to rescue age-related anabolic resistance.

Responses of dairy cows with divergent residual feed intake as calves to metabolic challenges during midlactation and the nonlactating period

Residual feed intake (RFI) is defined as the difference between the actual and expected feed intake required to support animal maintenance and growth. Thus, a cow with a low RFI can obtain nutrients for maintenance and growth from a reduced amount of feed compared with a cow with a high RFI. Variation in RFI is underpinned by a combination of factors, including genetics, metabolism, thermoregulation and body composition; hypothalamic-pituitary-adrenal (HPA) axis responsiveness is also a possible contributor. Responses to 3 metabolic challenges were measured in lactating and nonlactating dairy cattle. Sixteen Holstein Friesian cows with phenotypic RFI measurements that were obtained during the growth period (188-220 d old) were grouped as either low-calfhood RFI (n = 8) or high-calfhood RFI (n = 8). An ACTH (2 µg/kg of body weight), insulin (0.12 U/kg), and epinephrine (a low dose of 0.1 µg/kg and a high dose of 1.6 µg/kg of epinephrine) challenge were each conducted during both midlactation (122 ± 23.4 d in milk) and the nonlactating period (dry period; approximately 38 d after cessation of milking). Cows were housed in metabolism stalls for the challenges and were fed a diet of alfalfa cubes ad libitum for at least 10 d before the experiment (lactating cows also were offered a total of 6 kg of dry matter/d of crushed wheat grain plus minerals fed as 3 kg of dry matter at each milking) and were fasted for 12 h before the challenges. The efficiency of conversion of feed into milk (the ratio of feed consumed to milk produced over the 7 d before the experiment) during midlactation was better (lower) in low-calfhood RFI cows, although dry matter intake did not differ between RFI groups. Low-calfhood RFI cows exhibited a lower plasma cortisol response to the ACTH challenge than high-calfhood RFI cows, particularly in midlactation (-15%). The low-calfhood RFI cows had a greater plasma insulin-like growth factor-1 response to the insulin challenge and plasma fatty acid response to epinephrine compared with the high-calfhood RFI cows. These data suggest that high-calfhood RFI cows exhibit a more responsive HPA axis. As divergence in RFI measured during growth is retained (although reduced) during lactation, it is possible that energy is used to respond to HPA axis activation at the expense of production in high-calfhood RFI dairy cattle during lactation and contributes to a decrease in overall feed use efficiency.

IGF-1 receptor cleavage in hypertension

Increased protease activity causes receptor dysfunction due to extracellular cleavage of different membrane receptors in hypertension. The vasodilatory effects of insulin-like growth factor-1 (IGF-1) are decreased in hypertension. Therefore, in the present study the association of an enhanced protease activity and IGF-1 receptor cleavage was investigated using the spontaneously hypertensive rats (SHRs) and their normotensive Wistar Kyoto (WKY) controls (n = 4). Matrix metalloproteinase (MMP) activities were determined using gelatin zymography on plasma and different tissue samples. WKY aorta rings were incubated in WKY or SHR plasma with or without MMP inhibitors, and immunohistochemistry was used to quantify the densities of the alpha and beta IGF-1 receptor (IGF-1R) subunits and to determine receptor cleavage. The pAkt and peNOS levels in the aorta were investigated using immunoblotting as a measure of IGF-IR function. Increased MMP-2 and MMP-9 activities were detected in plasma and peripheral tissues of SHRs. IGF-1R beta labeling was similar in both groups without plasma incubation, but the fraction of immunolabeled area for IGF-1R alpha was lower in the endothelial layer of the SHR aorta (p < 0.05). A 24-h incubation of WKY aorta with SHR plasma did not affect the IGF-1R beta labeling density, but reduced the IGF-1R alpha labeling density in the endothelium (p < 0.05). MMP inhibitors prevented this decrease (p < 0.01). Western blot analyses revealed that the pAkt and peNOS levels under IGF-1-stimulated and -unstimulated conditions were lower in SHRs (p < 0.05). A reduced IGF-1 cellular response in the aorta was associated with the decrease in the IGF-1R alpha subunit in the SHR hypertension model. Our results indicate that MMP-dependent receptor cleavage contributed to the reduced IGF-1 response in SHRs.

The effects of an acute exercise bout on GH and IGF-1 in prediabetic and healthy African Americans: A pilot study investigating gene expression.

The incidence of pre-diabetes (PD) and Type-2 Diabetes Mellitus (T2D) is a worldwide epidemic. African American (AA) individuals are disproportionately more likely to become diabetic than other ethnic groups. Over the long-term, metabolic complications related to diabetes result in significant alterations in growth hormone (GH) and insulin-like growth factor-1 (IGF-1). Considering the limited exercise-related studies in the area of gene expression changes with disease progression, the objective of this study was to examine differences in exercise-induced gene expression related to the GH and IGF-1 pathways in peripheral blood mononuclear cells (PBMCs) of healthy (CON) and PD AA individuals. Design: Ten subjects [5 PD (age = 35±9.3 yr, BMI = 32.1±4.0, FBG = 101.8±1.3 mg/dl) and 5 CON (age = 31±9.4 yr, BMI = 29.4±5.2, FBG = 82.8±9.7 mg/dl)] had blood drawn for RNA isolation prior to exercise (Pre), immediately following acute moderate intensity exercise on a treadmill (Post-1), 6-hours post (Post-6), and 24-hours post (Post-24). Isolation of mRNA from PBMCs was performed using ficoll separation, while the profiling of mRNA expression was performed using Illumina beadchip arrays with standard protocols. Scan results were statistically analyzed for a specific list of genes related to GH and IGF-1. GH and IGF-1 protein levels were also assessed in each sample. To address issues of normality, all GH and IGF-1 data were log-transformed prior to analysis. Statistical significance was set at p<0.05. Results: Group differences for GH2 variant 2 (p = 0.070) and GH2 variant 3 (p = 0.059) were coupled with significant alterations in IGF-1 mRNA over time (p = 0.024). A significant interaction between group and time was observed for GHRH mRNA (p = 0.008). No group differences were observed in GH AUC (p = 0.649), ΔGH (p = 0.331), GHrec (p = 0.294), or IGF-1 AUC (p = 0.865), representing a similar exercise-induced GH and IGF-1 response for both groups. Conclusions: Analysis of GH and IGF-1 related-gene expression indicates that mild elevations in fasting blood glucose and exercise-induced alterations in gene expression are impacted by the prediabetic state.

Upregulation of IRS1 Enhances IGF1 Response in Y537S and D538G ESR1 Mutant Breast Cancer Cells.

Increased evidence suggests that somatic mutations in the ligand-binding domain of estrogen receptor [ER (ERα/ESR1)] are critical mediators of endocrine-resistant breast cancer progression. Insulinlike growth factor-1 (IGF1) is an essential regulator of breast development and tumorigenesis and also has a role in endocrine resistance. A recent study showed enhanced crosstalk between IGF1 and ERα in ESR1 mutant cells, but detailed mechanisms are incompletely understood. Using genome-edited MCF-7 and T47D cell lines harboring Y537S and D538G ESR1 mutations, we characterized altered IGF1 signaling. RNA sequencing revealed upregulation of multiple genes in the IGF1 pathway, including insulin receptor substrate-1 (IRS1), consistent in both Y537S and D538G ESR1 mutant cell line models. Higher IRS1 expression was confirmed by quantitative reverse transcription polymerase chain reaction and immunoblotting. ESR1 mutant cells also showed increased levels of IGF-regulated genes, reflected by activation of an IGF signature. IGF1 showed increased sensitivity and potency in growth stimulation of ESR1 mutant cells. Analysis of downstream signaling revealed the phosphoinositide 3-kinase (PI3K)-Akt axis as a major pathway mediating the enhanced IGF1 response in ESR1 mutant cells. Decreasing IRS1 expression by small interfering RNA diminished the increased sensitivity to IGF1. Combination treatment with inhibitors against IGF1 receptor (IGF1R; OSI-906) and ER (fulvestrant) showed synergistic growth inhibition in ESR1 mutant cells, particularly at lower effective concentrations. Our study supports a critical role of enhanced IGF1 signaling in ESR1 mutant cell lines, pointing toward a potential for cotargeting IGF1R and ERα in endocrine-resistant breast tumors with mutant ESR1.

IGF-1 Response In Middle-aged And Older Men During Continuous And Intermittent Cycling At Lactate Threshold

Insulin-like growth factor-1 (IGF-1) is a trophic factor promoting growth and survival in various types of cells including muscle cells and neurons. In our recent study, young men showed comparable IGF-1 responses in continuous and intermittent exercise at lactate threshold, whereas stress responses were smaller in the intermittent exercise. It is yet unclear if the exercise format affects the IGF-1 response in older individuals. PURPOSE: To compare changes in the circulating level of IGF-1 in middle-aged and older men during continuous and intermittent cycling at lactate threshold. METHODS: Six men, middle-aged and older (57.8±11.6 years), randomly performed two cycling tests at lactate threshold load (108.8±27.3 W) and a control test with rest on separate days. The cycling tests comprised a 20-min continuous cycling (CC) and an intermittent cycling (IC) consisting of 20 repetitions of 1-min bouts separated by 30-sec rests. The control test was administered with a schedule identical to CC. During each session, blood samples were drawn via peripheral cannulation at rest, at 25, 50, and 100% of cycling time, and 10 min after cycling. A blood concentration of IGF-1 and those of lactate, cortisol, and catecholamines were measured at each time point. Two-way analyses of variance for repeated measures with post-hoc tests, if appropriate, were performed to mainly compare changes between CC and IC. RESULTS: Significant interactions were found in all the indices (p<.05). Changes in IGF-1 concentration were comparable between CC (102.0±29.3 to 116.0±30.2 ng/ml, p<.05) and IC (104.2±33.6 to 112.0±38.6 ng/ml, p<.05). In contrast, although concentrations of lactate and norepinephrine increased in both CC and IC (p<.05), the effect was greater for CC (p<.05). Furthermore, dopamine concentration increased only in CC (p<.05) while cortisol concentration decreased in IC (p<.05) but not in CC. CONCLUSIONS: As previously shown in young men, intermittent cycling at lactate threshold evoked an IGF-1 response comparable to its continuous counterpart in men middle-aged and older, but the two cycling formats induced different stress responses. These results suggest that moderate intermittent exercise has the potential to stimulate the IGF-1 pathway without considerable stress in older individuals. Supported by JSPS 25242065.

Correlation between GH and IGF-1 during treatment for acromegaly.

OBJECTIVE The relationship between growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in patients with acromegaly as serial levels drop over time after treatment has not been examined previously. Knowledge of this relationship is important to correlate pretreatment levels that best predict response to treatment. To examine the correlation between GH and IGF-1 and IGF-1 z-scores over a wide range of GH levels, the authors examined serial GH and IGF-1 levels at intervals before and after surgery and radiosurgery for acromegaly. METHODS This retrospective analysis correlates 414 pairs of GH and IGF-1 values in 93 patients with acromegaly. RESULTS Absolute IGF-1 levels increase linearly with GH levels only up to a GH of 4 ng/ml, and with IGF-1 z-scores only to a GH level of 1 ng/ml. Between GH levels of 1 and 10 ng/ml, increases in IGF-1 z-scores relative to changes in GH diminish and then plateau at GH concentrations of about 10 ng/ml. From patient to patient there is a wide range of threshold GH levels beyond which IGF-1 increases are no longer linear, GH levels at which the IGF-1 response plateaus, IGF-1 levels at similar GH values after the IGF-1 response plateaus, and of IGF-1 levels at similar GH levels. CONCLUSIONS In acromegaly, although IGF-1 levels represent a combination of the integrated effects of GH secretion and GH action, the tumor produces GH, not IGF-1. Nonlinearity between GH and IGF-1 occurs at GH levels far below those previously recognized. To monitor tumor activity and tumor viability requires measurement of GH levels.