Free Insulin-like Growth Factor Research Articles

Subclinical Hyperthyroidism Enhances Gonadotropin-Lowering Effects of Metformin in Postmenopausal Women.

Metformin treatment decreases elevated concentrations of anterior pituitary hormones. The aim of this prospective, cohort study was to investigate whether hyperthyroidism modulates the impact of metformin on gonadotroph secretory function. The study population included 48 postmenopausal women with untreated type 2 diabetes or prediabetes, 24 of whom had coexisting grade 1 subclinical hyperthyroidism. Both groups were matched for age, insulin sensitivity, and gonadotropin levels. Over the entire study period, all participants were treated with metformin (2.55-3 g daily). Plasma glucose, insulin, thyroid-stimulating hormone (TSH), total and free thyroid hormones, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, prolactin, adrenocorticotropic hormone (ACTH), and insulin-like growth factor-1 (IGF-1) were assayed at entry and 6 months later. At baseline, the study groups differed in levels of TSH and thyroid hormones but not in body mass index, blood pressure, glucose homeostasis markers (fasting glucose, homeostatic model assessment 1 of insulin resistance ratio [HOMA1-IR], and glycated hemoglobin [HbA1c]), and the remaining hormones. There were no differences between both groups in the degree of reduction in plasma glucose and HbA1c in response to metformin treatment. Although metformin decreased HOMA1-IR in both groups, this effect was stronger in women with hyperthyroidism than with normal thyroid function (-50 ± 20% vs -30 ± 15%). Similar relationships were observed for FSH (-43 ± 21% vs -21 ± 12%). Only in hyperthyroid women did the drug reduce LH concentration (by 35 ± 17%). Metformin did not affect circulating levels of TSH, total and free thyroxine, total and free triiodothyronine, estradiol, prolactin, ACTH, and IGF-1. The obtained results indicate that hyperthyroidism enhances the gonadotropin-lowering effects of metformin, as well as the fact that this agent has a neutral effect on the hypothalamic-pituitary-thyroid axis in case of its overactivity.

Associations Between Hypertension, Angiotensin-Converting Enzyme Inhibitors, and Physical Performance in Very Old Adults: Results from the ilSIRENTE Study

BackgroundResults regarding the associations between hypertension-related parameters and physical performance in older adults are conflicting. A possible explanation for these divergent results is that investigations may not have adjusted their analyses according to the use of angiotensin-converting enzyme inhibitors (ACEIs).ObjectivesTo examine the associations between hypertension-related parameters, ACEI use, and a set of physical performance tests in very old adults.DesignCross-sectional study from the ilSIRENTE database.SettingMountain community of the Sirente geographic area (L’Aquila, Abruzzo, Italy).ParticipantsAll persons born in the Sirente area (13 municipalities) before 1 January 1924 and living in that region at the time of study were identified and invited to participate. The final sample included 364 older adults (mean age: 85.8 ± standard deviation [SD] 4.8).MeasurementsPhysical performance was assessed using isometric handgrip strength (IHG), walking speed (WS) at normal and fast pace, 5-time sit-to-stand test (5STS), and muscle power measures. Blood pressure (BP) was measured after 20 to 40 min of rest, while participants sat in an upright position. Drugs were coded according to the Anatomical Therapeutic and Chemical codes. ACEIs were categorized in centrally (ACEI-c) and peripherally (ACEI-p) acting. Blood inflammatory markers, free insulin-like growth factor 1 (IGF-1), and IGF-binding protein 3 (IGFBP-3) were assayed.ResultsResults indicated that 5STS test was significantly and negatively associated with diastolic BP values. However, significance was lost when results were adjusted for ACEI use. Participants on ACEIs were more likely to have greater specific muscle power and higher blood levels of IGFBP-3 than non-ACEI users. When participants were categorized according to ACEI subtypes, those on ACEI-p had higher blood IGF-1 levels compared with ACEI-c users.ConclusionsThe main findings of the present study indicate that ACEI use might influence the association between hypertension-related parameters and neuromuscular parameters in very old adults. Such results may possibly be linked to the effects of ACEI-p on the IGF-1 pathway.

Pregnancy associated plasma protein-A2 (PAPP-A2) and stanniocalcin-2 (STC2) but not PAPP-A are associated with circulating total IGF-1 in a human adult population

The pappalysins pregnancy associated plasma protein-A (PAPP-A) and -A2 (PAPP-A2) act as proteinases of insulin-like growth factor-1 (IGF-1) binding proteins, while stanniocalcin-2 (STC2) was identified as a pappalysin inhibitor. While there is some evidence from studies in children and adolescents, it is unclear whether these molecules are related to concentrations of IGF-1 and its binding proteins in adults. We investigated cross-sectionally the association of circulating PAPP-A, PAPP-A2 and STC2 with IGF-1 and its binding proteins (IGFBPs) in 394 adult pretest participants (20–69 years) of the German National Cohort Berlin North study center. Plasma PAPP-A, PAPP-A2, total and free IGF-1, IGFBP-1, IGFBP-2, IGFBP-3, IGFBP-5 and STC2 were measured by ELISAs. The associations of PAPP-A, PAPP-A2 and STC2 with IGF-1 or IGFBPs were investigated using multivariable linear regression analyses adjusting for age, sex, body mass index and pretest phase. We observed significant inverse associations of PAPP-A2 (difference in concentrations per 0.5 ng/mL higher PAPP-A2 levels) with total IGF-1 (− 4.3 ng/mL; 95% CI − 7.0; − 1.6), the IGF-1:IGFBP-3 molar ratio (− 0.34%; 95%-CI − 0.59; − 0.09), but not free IGF-1 and a positive association with IGFBP-2 (11.9 ng/mL; 95% CI 5.0; 18.8). PAPP-A was not related to total or free IGF-1, but positively associated with IGFBP-5. STC2 was inversely related to total IGF-1, IGFBP-2 and IGFBP-3 and positively to IGFBP-1. This first investigation of these associations in a general adult population supports the hypothesis that PAPP-A2 as well as STC2 play a role for IGF-1 and its binding proteins, especially for total IGF-1. The role of PAPP-A2 and STC2 for health and disease in adults warrants further investigation.

HBP1 inhibits the development of type 2 diabetes mellitus through transcriptional activation of the IGFBP1 gene.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease that is highly prevalent worldwide and characterized by glucose and lipid metabolism disorders. However, the pathogenic mechanisms have not been fully established. Here, we found that HMG-box transcription factor 1 (HBP1) is involved in T2DM and that its deficiency in mice aggravates the features of diabetes. In addition, we undertook screening by RNA sequencing and found that HBP1 activates the transcription of the insulin-like growth factor binding protein 1 (IGFBP1) gene. Moreover, Insulin and palmitic acid reduced HBP1 protein expression and inhibited its binding to the IGFBP1 promoter. Furthermore, HBP1 reduced the serum free insulin-like growth factor 1 (IGF-1) concentration through IGFBP1 and inhibited the PI3K/AKT signaling pathway. This forms an insulin/HBP1/IGFBP1 negative feedback regulatory loop to dynamically regulate blood glucose and insulin concentrations. These findings have elucidated a mechanism whereby HBP1 and its negative feedback regulatory loop influence the development of T2DM, thereby providing a new theoretical basis and potential therapeutic target for T2DM.

The Relationship between Ovarian Ultrasound Parameters and Endocrine and Metabolic Indicators in Patients with Ovarian Syndrome.

Objective The aim of this study is to investigate the relationship between the levels of endocrine and metabolic indicators and ovarian ultrasonography indicators in patients with ovarian syndrome (PCOS). Methods Three hundred and forty patients with PCOS from January 2017 to February 2022 were selected as the observation group, and 340 healthy women of the same age were selected as the control group. A retrospective analysis was performed to observe the levels of endocrine and metabolic indicators and ovarian ultrasound examination indicators in the two groups. Results The levels of testosterone, dehydroepiandrosterone (DHEA-S), luteinizing hormone (LH), LH/FSH, blood glucose, and insulin were higher in the observation group than those in the control group. The levels of low-density lipoprotein (LDL) and free insulin-like growth factor (IGF-I) were higher in the observation group than those in the control group. However, the level of high-density lipoprotein (HDL) was lower in the observation group than that in the control group. The ovarian interstitial area, total ovarian area, ovarian volume, number of follicles, uterine artery pulsatility index (PI), and resistance index (RI) were higher in the observation group than those in the control group. Pearson correlation analysis concluded that estrone (E1) levels in PCOS patients were correlated with ovarian interstitial area, total ovarian area, and ovarian volume. In addition, E1 levels correlated with LH levels, LH/FSH, testosterone, DHEA-S, and progesterone at P < 0.05. Compared with different treatment methods, the total testosterone, LH, and LH/FSH levels in the two groups were decreased compared with those before treatment, and the degree of decrease in the combined treatment group was more significant than that in the treatment alone group. Conclusion The levels of endocrine metabolism and ovarian ultrasound in PCOS patients are abnormal and there is a close relationship between the levels of endocrine metabolism and ovarian ultrasound. Attention should be paid to the monitoring and regulation of endocrine metabolism and ovarian ultrasound. Integrated traditional Chinese and western medicine can greatly improve the hormone levels in PCOS patients.

Free Insulin-like Growth Factor (IGF)-I in Children with PWS.

In children with Prader–Willi syndrome (PWS), the standard growth hormone (GH) dose often results in high immunoreactive IGF-I levels. These high immunoreactive IGF-I levels lead to concern because their long-term effects are unknown. As a result, clinicians have to lower the GH dose, which worsens body composition and quality of life. As clinical features do not seem to correspond to immunoreactive IGF-I values, it is questionable whether immunoreactive IGF-I is a suitable marker for GH dosing, or whether another parameter better reflects IGF-I bioavailability and bioactivity. We, therefore, investigate serum immunoreactive IGF-I, free IGF-I and IGFBP-3 levels in 70 GH-treated children with PWS. Our study showed that, although immunoreactive IGF-I levels were high (>2 SDS) in the vast majority of prepubertal and pubertal children, free IGF-I SDS levels were <0 SDS in most and <1 SDS in all. Free IGF-I correlated with the immunoreactive IGF-I, IGFBP-3 and IGF-I/IGFBP-3 ratio. We conclude that there is a major discrepancy between immunoreactive and free IGF-I levels. While in the majority of GH-treated children with PWS, immunoreactive IGF-I levels were high, free IGF-I levels were <0 SDS in most. Our data appear to be very reassuring and suggest that free IGF-I levels should also be taken into consideration when the immunoreactive IGF-I levels are >2 SDS in GH-treated children with PWS.

Circulating Insulin-Like Growth Factor 1-Related Biomarkers and Risk of Lethal Prostate Cancer.

BackgroundExperimental and epidemiologic evidence supports the role of circulating insulin-like growth factor-1 (IGF-1) levels with the risk of prostate cancer. Most circulating IGF-1 is bound to specific binding proteins, and only about 5% circulates in a free form. We explored the relation of free IGF-1 and other components of the IGF system with lethal prostate cancer.MethodsUsing prospectively collected samples, we undertook a nested case-only analysis among 434 men with lethal prostate cancer and 524 men with indolent, nonlethal prostate cancer in the Physicians’ Health Study and the Health Professionals Follow-up Study. Prediagnostic plasma samples were assayed for free IGF-1 and total IGF-1, acid labile subunit, pregnancy-associated plasma protein A (PAPP-A), and intact and total IGF binding protein 4. We estimated odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the associations between IGF-1–related biomarkers and lethal prostate cancer using unconditional logistic regression models adjusted for age, height, and body mass index.ResultsMen in the highest quartile of PAPP-A levels had 42% higher odds of lethal prostate cancer (pooled adjusted OR = 1.42, 95% CI = 1.04 to 1.92) compared with men in the lowest 3 quartiles. There were no statistically significant differences in the other plasma analytes. The positive association between PAPP-A and lethal prostate cancer was present among men with intact PTEN but not among those with tumor PTEN loss (2-sided Pinteraction = .001).ConclusionsOur study provides suggestive evidence that among men who later develop prostate cancer, higher plasma PAPP-A levels measured prior to diagnosis are associated with increased risk of lethal compared with indolent disease.

An Insulin-like Growth Factor-1 Conjugated Bombyx mori Silk Fibroin Film for Diabetic Wound Healing: Fabrication, Physicochemical Property Characterization, and Dosage Optimization In Vitro and In Vivo.

This study aimed to develop a silk fibroin (SF)-film for the treatment of chronic diabetic wounds. Silk fibroin was purified through a newly developed heating degumming (HD) process and casted on a hydrophobic surface to form SF-films. The process allowed the fabricated film to achieve a 42% increase in transparency and a 32% higher proliferation rate for BALB/3T3 fibroblasts compared to that obtained by conventional alkaline degumming treatment. Fourier transform infrared analysis demonstrated that secondary structure was retained in both HD- and alkaline degumming-derived SF preparations, although the crystallinity of beta-sheet in SF-film after the HD processing was slightly increased. This study also investigated whether conjugating insulin-like growth factor-1 (IGF-1) would promote diabetic wound healing and what the optimal dosage is. Using BALB/3T3 cells grown in hyperglycemic medium as a model, it was demonstrated that the optimal IGF-1 dosage to promote the cell growth was approximately 0.65 pmol. Further analysis of wound healing in a diabetic mouse model indicated that SF-film loaded with 3.25 pmol of IGF-1 showed significantly superior wound closure, a 13% increase at the 13th day after treatment relative to treatment with 65 pmol of free IGF-1. Improvement in diabetic wound healing was exerted synergistically by SF-film and IGF-1, as reflected by parameters including levels of re-epithelialization, epithelial tissue area, and angiogenesis. Finally, IGF-1 increased the epithelial tissue area and micro-vessel formation in a dose-dependent manner in a low dosage range (3.25 pmol) when loaded to SF-films. Together, these results strongly suggest that SF-film produced using HD and loaded with a low dosage of IGF-1 is a promising dressing for diabetic wound therapy.

Thrombolysis by PLAT/tPA increases serum free IGF1 leading to a decrease of deleterious autophagy following brain ischemia

ABSTRACT Cerebral ischemia is a pathology involving a cascade of cellular mechanisms, leading to the deregulation of proteostasis, including macroautophagy/autophagy, and finally to neuronal death. If it is now accepted that cerebral ischemia induces autophagy, the effect of thrombolysis/energy recovery on proteostasis remains unknown. Here, we investigated the effect of thrombolysis by PLAT/tPA (plasminogen activator, tissue) on autophagy and neuronal death. In two in vitro models of hypoxia reperfusion and an in vivo model of thromboembolic stroke with thrombolysis by PLAT/tPA, we found that ischemia enhances neuronal deleterious autophagy. Interestingly, PLAT/tPA decreases autophagy to mediate neuroprotection by modulating the PI3K-AKT-MTOR pathways both in vitro and in vivo. We identified IGF1R (insulin-like growth factor I receptor; a tyrosine kinase receptor) as the effective receptor and showed in vitro, in vivo and in human stroke patients and that PLAT/tPA is able to degrade IGFBP3 (insulin-like growth factor binding protein 3) to increase IGF1 (insulin-like growth factor 1) bioavailability and thus IGF1R activation. Abbreviations: AKT/protein kinase B: thymoma viral proto-oncogene 1; EGFR: epidermal growth factor receptor; Hx: hypoxia; IGF1: insulin-like growth factor 1; IGF1R: insulin-like growth factor I receptor; IGFBP3: insulin-like growth factor binding protein 3; Ka: Kainate; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK/ERK: mitogen-activated protein kinase; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; OGD: oxygen and glucose deprivation; OGDreox: oxygen and glucose deprivation + reoxygentation; PepA: pepstatin A1; PI3K: phosphoinositide 3-kinase; PLAT/tPA: plasminogen activator, tissue; PPP: picropodophyllin; SCH77: SCH772984; ULK1: unc-51 like kinase 1; Wort: wortmannin

Sustained Release of Insulin-Like Growth Factor-1 from Bombyx mori L. Silk Fibroin Delivery for Diabetic Wound Therapy.

The goals of this study are to develop a high purity patented silk fibroin (SF) film and test its suitability to be used as a slow-release delivery for insulin-like growth factor-1 (IGF-1). The release rate of the SF film delivering IGF-1 followed zero-order kinetics as determined via the Ritger and Peppas equation. The release rate constant was identified as 0.11, 0.23, and 0.09% h−1 at 37 °C for SF films loaded with 0.65, 6.5, and 65 pmol IGF-1, respectively. More importantly, the IGF-1 activity was preserved for more than 30 days when complexed with the SF film. We show that the IGF-1-loaded SF films significantly accelerated wound healing in vitro (BALB/3T3) and in vivo (diabetic mice), compared with wounds treated with free IGF-1 and an IGF-1-loaded hydrocolloid dressing. This was evidenced by a six-fold increase in the granulation tissue area in the IGF-1-loaded SF film treatment group compared to that of the PBS control group. Western blotting analysis also demonstrated that IGF-1 receptor (IGF1R) phosphorylation in diabetic wounds increased more significantly in the IGF-1-loaded SF films group than in other experimental groups. Our results suggest that IGF-1 sustained release from SF films promotes wound healing through continuously activating the IGF1R pathway, leading to the enhancement of both wound re-epithelialization and granulation tissue formation in diabetic mice. Collectively, these data indicate that SF films have considerable potential to be used as a wound dressing material for long-term IGF-1 delivery for diabetic wound therapy.

Association Between Serum Insulin-Like Growth Factor 1 Levels and the Clinical Symptoms of Chronic Schizophrenia: Preliminary Findings.

Purpose: Insulin-like growth factor 1 (IGF-1) is a trophic mediator that is regulated by growth hormone and associated with the proliferation, development, and growth of neural cells. IGF-1 may be associated with the pathophysiology of schizophrenia, but this association remains controversial. This study aimed to investigate the relationship between serum IGF-1 levels and psychiatric symptoms in patients with chronic schizophrenia.Patients and Methods: A total of 65 patients were recruited from the University of Occupational and Environmental Health, Komine Eto Hospital, Moji Matsugae Hospital, Shin-Moji Hospital, and Tsutsumi Hospital in Kitakyushu between September 2019 and June 2020. Further, 20 healthy age- and sex-matched control participants were recruited from the Komine Eto Hospital and the University of Occupational and Environmental Health. Patients with schizophrenia were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Drug-Induced Extrapyramidal Symptoms Scale. Serum levels of free plus albumin-bound IGF-1 (IGF-1) were measured by immunoradiometric assay. The measurements were performed using antibody beads for bound/free separation. Associations between serum IGF-1 levels and the PANSS scores were determined. We also examined the associations between serum IGF-1 levels and diabetes, antipsychotic drug use, and disease duration.Results: No significant difference was found in the serum IGF-1 level between patients with schizophrenia and healthy controls. Serum IGF-1 levels were significantly negatively correlated with the PANSS total score (R2 = 0.06, p = 0.015) and PANSS general score (R2 = 0.088, p = 0.008), but not with the PANSS positive scores and PANSS negative scores. Serum IGF-1 levels were not related to the prevalence of diabetes (p = 0.64). However, a significant correlation was observed between serum IGF-1 levels and age (B = −1.88, p < 0.0001). Serum IGF-1 levels could not distinguish patients with schizophrenia and healthy controls.Conclusion: The association between serum IGF-1 levels and psychiatric symptoms may be complicated in patients with chronic schizophrenia.

Cathepsin G-Induced Insulin-Like Growth Factor (IGF) Elevation in MCF-7 Medium Is Caused by Proteolysis of IGF Binding Protein (IGFBP)-2 but Not of IGF-1.

Cathepsin G (CG), a neutrophil serine protease, induces cell migration and multicellular aggregation of human breast cancer MCF-7 cells. It has been suggested that tumor cell aggregates are associated with tumor embolism, thus CG-induced cell aggregation may promote tumor metastasis. We have revealed that cell aggregation is caused by elevated free insulin-like growth factor (IGF)-1 in the medium, followed by activation of IGF-1 receptor (IGF-1R). However, the molecular mechanism underlying IGF-1 elevation induced by CG remains unclear. Here, we aimed to elucidate the mechanism by examining the degradative effects of CG on IGF-1, and the IGF binding proteins (IGFBPs), which interfere with the binding of IGF-1 to its receptor. CG specifically evoked MCF-7 cell aggregation at less than 1 nM in a dose-dependent manner, however, neutrophil elastase (NE), chymotrypsin, and trypsin did not. Free IGF-1 concentration was continuously elevated in the medium of cells treated with CG, whereas treatments with other serine proteases resulted in only a transient or slight increase. IGFBP-2, the predominant IGFBP in MCF-7 cells, was gradually digested by CG. CG did not cleave IGF-1 for at least 48 h, whereas other proteases completely digested it. Moreover, CG induced continuous phosphorylation of IGF-1R and Akt, whereas NE-induced phosphorylation was transient, possibly due to insulin receptor substrate (IRS)-1 digestion. These results indicated that CG-specific IGF-1 elevation in the medium is caused by digestion of IGFBP-2, not IGF-1. Hence, this study clarifies the molecular mechanism of CG-specific cell aggregation.

The Multi-Faced Role of PAPP-A in Post-Partum Breast Cancer: IGF-Signaling is Only the Beginning.

Insulin-like growth factor (IGF) signaling and control of local bioavailability of free IGF by the IGF binding proteins (IGFBP) are important regulators of both mammary development and breast cancer. A recent genome-wide association study (GWAS) identified small nucleotide polymorphisms that reduce the expression of IGFBP-5 as a risk factor of developing breast cancer. This observation suggests that genetic alterations leading to a decreased level of IGFBP-5 may also contribute to breast cancer. In the current review, we focus on Pregnancy-Associated Plasma Protein A (PAPP-A), a protease involved in the degradation of IGFBP-5. PAPP-A is overexpressed in the majority of breast cancers but its role in cancer has only begun to be explored. More specifically, this review aims at highlighting the role of post-partum involution in the oncogenic function of PAPP-A. Notably, we summarize recent studies indicating that PAPP-A plays a role not only in the degradation of IGFBP-5 but also in the deposition of collagen and activation of the collagen receptor discoidin 2 (DDR2) during post-partum involution. Finally, considering the immunosuppressive microenvironment of post-partum involution, we also discuss the unexpected finding made in Ewing Sarcoma that PAPP-A plays a role in immune evasion. While the immunosuppressive role of PAPP-A in breast cancer remains to be determined, collectively these studies highlight the multifaced role of PAPP-A in cancer that extends well beyond its effect on IGF-signaling.

Insulin-Like Growth Factor 1 Related to Chronic Low-Grade Inflammation in Patients with Obesity and Early Change of its Levels After Laparoscopic Sleeve Gastrectomy.

Insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein (IGFBP) have an influence on metabolism. However, changes in metabolism after sleeve gastrectomy (SG) are not clearly known. This study investigated the change in IGFBP3 levels in obesity after bariatric surgery. We evaluated 36 patients with obesity (14 males, aged 31.36 ± 7.06years and 22 females, aged 32.55 ± 11.40years) at baseline and 3months after SG. Changes in their IGF1, IGFBP3, and IGF1/IGFBP3 ratios and glucose-lipid metabolic, inflammation, and oxidative stress parameters were measured. Enzyme-linked immunosorbent assay was used to measure their IGF1 and IGFBP3 levels. (1) IGFBP3 levels were negatively associated with waist circumference (WC) and waist-to-hip ratio (r = - 0.482, P = 0.043; r = - 0.503, P = 0.033); total IGF1 levels were negatively associated with body mass index and WC (r = - 0.569, P = 0.014; r = - 0.470, P = 0.048); and free IGF1 levels were negatively related to tumor necrosis factor (TNF)-α level independent of age (r = - 0.544, P = 0.020). Free IGF1 levels were negatively associated with uric acid, interleukin-6 (IL-6), IL-8, and TNF-α levels (r = - 0.646, P = 0.032; r = - 0.667, P = 0.025; r = - 0.641, P = 0.033; r = - 0.733, P = 0.010) and positively associated with superoxide dismutase activity (r = 0.635, P = 0.036) in females; this relation was not significant in males (all P > 0.05). Total IGF1 was also negatively associated with C-reactive protein (CRP) level in females (r = - 0.671, P = 0.024). (2) IGFBP3 level significantly decreased at 3months after bariatric surgery in females (P < 0.001) but not in males (P = 0.815). Total IGF1 level significantly decreased after bariatric surgery (P = 0.048); the change was also significant in females (P = 0.014) but not in males (P = 0.626). Free IGF1 level after bariatric surgery was not statistically different between males (P = 0.605) and females (P = 0.628). (3) In females, the change in IGFBP3 level was associated with a change in high-density lipoprotein cholesterol and free fatty acid levels (r = 0.607, P = 0.003; r = 0.546, P =0.016), and a change in total IGF1 level was associated with a change in CRP level (r = 0.664, P = 0.009). IGF1 level was related to chronic low-grade inflammation and oxidative stress in obesity, especially in females. IGFBP3 and IGF1 levels decreased in obesity after SG, especially in females. Changes in IGF/IGFBP3 levels were associated with a change in the inflammatory state after surgery.

Role of Tumor and Stroma-Derived IGF/IGFBPs in Pancreatic Cancer.

Pancreatic cancer (PC) is the utmost stroma-rich cancer, which is accompanied by fibrotic reactions that stimulate interactions between tumor cells and stroma to promote tumor progression. Considerable research evidence denotes that insulin-like growth factor (IGF)/IGF binding proteins (IGFBP) signaling axis facilitate tumor growth, metastasis, drug resistance, and thereby facilitate PC into an advanced stage. The six members of IGFBPs were initially considered as passive carriers of free IGFs; however, current evidence revealed their functions beyond the endocrine role in IGF transport. Though numerous efforts have been made in blocking IGF/IGFBPs, the targeted therapies remain unsuccessful due to the complexity of tumor-stromal interactions in the pancreas. In this review, we explore the emerging evidence of the various roles of the tumor as well as stroma derived IGF/IGFBPs and highlight as a novel therapeutic target against PC progression.

Can IGF-1 Serum Levels Really be Changed by Acute Physical Exercise? A Systematic Review and Meta-Analysis.

Physical exercise plays an important role in metabolic health, especially in the insulin-like growth factor-1 (IGF-1) system. The objective of this study was to perform a systematic review and meta-analysis to evaluate the effects of a single endurance and resistance exercise session on IGF-1 serum. The systematic review was performed in SPORTDiscus, MEDLINE, PubMed, and Google Scholar databases. All analyses are based on random-effect models. The study identified 249 records of which 21 were included. There was an effect of endurance exercise on total IGF-1 (P = .01), but not for free IGF-1 (P = .36). Resistance exercise similarly only affected total IGF-1 (P = .003) and not free IGF-1 (P = .37). The effect size indicated that total IGF-1 is more affected (ES = 0.81) by endurance than by resistance exercise (ES = 0.46). The present study showed that IGF-1 serum concentrations are altered by exercise type, but in conditions which are not well-defined. The systematic review and meta-analysis suggest that there is no determinant in serum IGF-1 changes for the exercise load characteristic. Therefore, physical exercise may be an alternative treatment to control changes in IGF-1 metabolism and blood concentration.

Moderate intensity exercise in hypoxia increases IGF-1 bioavailability and serum irisin in individuals with type 1 diabetes.

Aim:This study aimed to determine the effect of moderate intensity continuous exercise (Ex) and hypoxia (Hyp) on serum brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1) and its binding protein-3 (IGFBP-3), irisin and cytokines levels in patients with type 1 diabetes (T1D).Methods:A total of 14 individuals with T1D (age: 28.7 ± 7.3 years) and 14 healthy adults (age: 27.1 ± 3.9 years) performed 40-min continuous Ex at moderate intensity (50% lactate threshold) on a cycle ergometer in normoxia (Nor) and Hyp (FiO2 = 15.1%) Biochemical factors, glucose concentrations and physiological variables were measured at rest, immediately and up to 24 h after both Ex protocols.Results:Patients with T1D had significantly lower pre-Ex serum concentrations of BDNF (p < 0.05, p < 0.01), and total IGF-1 (p < 0.001, p < 0.05) and significantly higher irisin levels (p < 0.05, p < 0.01) in Nor and Hyp, compared with healthy subjects. Ex significantly increased in T1D group serum BDNF (in Nor only p < 0.05) and total IGF-1 levels in Nor and Hyp (p < 0.001 and p < 0.01, respectively). Immediately after Ex in Hyp, freeIGF-1 (p < 0.05) and irisin levels (p < 0.001) were significantly higher compared with the levels induced by Ex alone. Free IGF-1 and irisin serum levels remained elevated in 24 h post-Ex in Hyp. In T1D, significant blood glucose (BG) decrease was observed immediately after Ex in Hyp (p < 0.001) and in 24 h recovery (p < 0.001) compared with pre-Ex level.Conclusion:The study results suggest that moderate intensity continuous Ex has beneficial effect on BDNF and IGF-1 levels. Ex in hypoxic conditions may be more effective in increasing availability of IGF-1. The alterations in the post-Ex irisin levels and IGF-1 system may be contributing to more effective glycaemia control in patients with T1D.

Effects of IGF-1 on the Cardiovascular System.

Cardiovascular (CV) diseases are the most common health problems worldwide, with a permanent increase in incidence. Growing evidence underlines that insulin-like growth factor 1 (IGF-1) is a very important hormone responsible for normal CV system physiology. IGF-1 is an anabolic growth hormone, responsible for cell growth, differentiation, proliferation, and survival. Despite systemic effects, IGF-1 exerts a wide array of influences in the CV system affecting metabolic homeostasis, vasorelaxation, cardiac contractility and hypertrophy, autophagy, apoptosis, and antioxidative processes. The vasodilatory effect of IGF-1, is achieved through the regulation of the activity of endothelial nitric oxide synthase (eNOS) and, at least partly, through enhancing inducible NOS (iNOS) activity. Also, IGF-1 stimulates vascular relaxation through regulation of sodium/potassiumadenosine- triphosphatase. Numerous animal studies provided evidence of diverse influences of IGF-1 in the CV system such as vasorelaxation, anti-apoptotic and prosurvival effects. Human studies indicate that low serum levels of free or total IGF-1 contribute to an increased risk of CV and cerebrovascular disease. Large human trials aiming at finding clinical efficacy and outcome of IGF-1-related therapy are of great interest. We look forward to the development of new IGF 1 therapies with minor side effects. In this review, we discuss the latest literature data regarding the function of IGF-1 in the CV system in the physiological and pathophysiological conditions.

P.672 Physical, physiological and biochemical parameters of adults with schizophrenia: Data from cognitive rehabilitation and training with exercise for schizophrenia study

Exercise training has been shown to improve learning and memory, and to protect against the negative impact of sleep deprivation. The aim of this study was to investigate the effects of seven weeks of moderate- and high-intensity interval exercise training on vigilance/sustained attention, inhibition processes and working memory during 40-h total sleep deprivation (TSD) in 16 healthy young men.The subjects were evaluated before (Baseline, BAS) and during TSD, and the day after a night of recovery sleep (Recovery, REC).Exercise training significantly decreased errors and increased speed assessed by the psychomotor vigilance task (PVT) during TSD and REC while no difference was found in executive inhibition (Go–noGo task) and working memory (2-Back task) performances. The multiple sleep latency test results were higher during BAS and REC at Post-exercise training, and no difference occurred in subjective sleepiness and daytime microsleeps over the 40-h TSD. The PVT speed was positively correlated with maximal oxygen consumption and maximal aerobic power measured before entry in the in-laboratory TSD protocol, and stage 3 sleep duration measured during the first night in the in-laboratory TSD protocol (N-1). Exercise training effects on sleep were found during the night recovery with lower stage-3 sleep and higher rapid eye movement (REM) sleep durations. An exercise training effect was also found on free insulin-like growth factor I levels with lower levels during TSD at Post-exercise training.In healthy young men, exercise training reduced sleep pressure at baseline and protected against sustained attention deficits induced by TSD with persistent effect after one night of recovery sleep. Nevertheless, exercise training was not effective in reducing deficits in executive inhibition and working memory induced by TSD.

Model-Informed Dose Selection for Xentuzumab, a Dual Insulin-Like Growth Factor-I/II-Neutralizing Antibody.

Over the past decade, the insulin-like growth factor (IGF)-signaling pathway has gained substantial interest as potential therapeutic target in oncology. Xentuzumab, a humanized IgG1 monoclonal antibody, binds to IGF-I and IGF-II thereby inhibiting the downstream signaling essential for survival and tumor growth. This pathway is further regulated by circulating IGF binding proteins (IGFBPs). In this work, a mechanistic model characterizing the dynamics and interactions of IGFs, IGFBPs, and Xentuzumab has been developed to guide dose selection. Therefore, in vitro and in vivo literature information was combined with temporal IGF-I, IGF-II, and IGFBP-3 total plasma concentrations from two phase I studies. Based on the established quantitative framework, the time-course of free IGFs as ultimate drug targets not measured in clinics was predicted. Finally, a dose of 1000mg/week-predicted to reduce free IGF-I and free IGF-II at steady-state by at least 90% and 64%, respectively-was suggested for phase II.