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Microgravity has been shown to lead to both muscle atrophy and impaired muscle regeneration. The purpose was to study the efficacy of microgravity to model impaired muscle regeneration in an engineered muscle platform and then to demonstrate the feasibility of performing drug screening in this model. Engineered human muscle was launched to the International Space Station National Laboratory, where the effect of microgravity exposure for 7 days was examined by transcriptomics and proteomics approaches. Gene set enrichment analysis of engineered muscle cultured in microgravity, compared to normal gravity conditions, highlighted a metabolic shift toward lipid and fatty acid metabolism, along with increased apoptotic gene expression. The addition of pro-regenerative drugs, insulin-like growth factor-1 (IGF-1) and a 15-hydroxyprostaglandin dehydrogenase inhibitor (15-PGDH-i), partially inhibited the effects of microgravity. In summary, microgravity mimics aspects of impaired myogenesis, and the addition of these drugs could partially inhibit the effects induced by microgravity.

AbstractBackgroundObjectivesDesign/MethodsResultsConclusionCongenital cyanotic heart disease (CHD) in children is associated with several complications, amongst these complications is growth retardation which is believed to be multifactorial.The objective of this study is to find out the role of leptin and Insulin-Like Growth Factor-1 (IGF-1) in the growth of paediatric patients with cyanotic CHD of different anatomical defects.This is a cross-sectional study involving thirty-nine children known to suffer from congenital cyanotic heart disease followed by the cardiology outpatient department, and forty-seven matched controls. Serum leptin and IGF-1 were evaluated in all the enrolled subjects besides anthropometric measurement and assessment of average oxygen saturation.The patients’ group showed statistically significant lower height, weight, Body mass index (BMI), leptin levels, and IGF-1. In addition, the patient group had a significant positive correlation between serum leptin and BMI, as well as a positive correlation of IGF-1 with average oxygen saturation.Children suffering from congenital cyanotic heart disease have a higher probability of developing poor growth. Serum leptin and IGF-1 are lower in affected children with congenital cyanotic cardiac defects suggesting that they may play a role in their poor growth. [ABSTRACT FROM AUTHOR]

Introduction The neurobehavioral significance of white matter hyperintensities (WMHs) seen on magnetic resonance imaging after traumatic brain injury (TBI) remains unclear, especially in Veterans and Service Members with a history of mild TBI (mTBI). In this study, we investigate the relation between WMH, mTBI, age, and cognitive performance in a large multisite cohort from the Long-term Impact of Military-relevant Brain Injury Consortium—Chronic Effects of Neurotrauma Consortium. Materials and Methods The neuroimaging and neurobehavioral assessments for 1,011 combat-exposed, post-9/11 Veterans and Service Members (age range 22-69 years), including those with a history of at least 1 mTBI (n  = 813; median postinjury interval of 8 years) or negative mTBI history (n  = 198), were examined. Results White matter hyperintensities were present in both mTBI and comparison groups at similar rates (39% and 37%, respectively). There was an age-by-diagnostic group interaction, such that older Veterans and Service Members with a history of mTBI demonstrated a significant increase in the number of WMHs present compared to those without a history of mTBI. Additional associations between an increase in the number of WMHs and service-connected disability, insulin-like growth factor-1 levels, and worse performance on tests of episodic memory and executive functioning-processing speed were found. Conclusions Subtle but important clinical relationships are identified when larger samples of mTBI participants are used to examine the relationship between history of head injury and radiological findings. Future studies should use follow-up magnetic resonance imaging and longitudinal neurobehavioral assessments to evaluate the long-term implications of WMHs following mTBI. [ABSTRACT FROM AUTHOR]

Introduction Winter warfare training (WWT) is a critical component of military training that trains warfighters to operate effectively in extreme environments impacted by snow and mountainous terrain. These environmental factors can exacerbate the disruption to the hormone milieu associated with operating in multi-stressor settings. To date, there is limited research on the physiological responses and adaptations that occur in elite military populations training in arduous environments. The purpose of this study was to quantify hormone responses and adaptations in operators throughout WWT. Materials and Methods Participants engaged in baseline laboratory metrics at their home station, Fort Carson, located in Colorado (CO) prior to WWT, for one week in Montana (MT) and one week in Alaska (AK). WWT periods were separated by approximately one month. Blood was collected upon wake at baseline (CO) and on the first and last day of WWT at each location (MT and AK). Plasma was analyzed for stress, metabolic, and growth-related hormones via enzyme-linked immunoassay (ELISA). Sleep quality was assessed via the Pittsburg Sleep Quality Index (PSQI) at baseline (CO) and on the first day of training in MT and AK. Cognitive function was evaluated using the Defense Automated Neurobehavioral Assessment (DANA) at baseline (CO) and on the first and last day of WWT in both MT and AK. Results Fourteen US Army operators in 10th Special Forces Group (SFG) Operational Detachment participated in winter warfare training (WWT; age: 31.5 years; 95%CI[28.1, 34.3]; height: 180.6 cm; 95%CI[177.3, 183.4]; weight: 87.4 kg.; 95%CI[80.6, 97.7]; body fat: 18.9%; 95%CI[13.7, 23.1]; male: n=13; female: n=1). Plasma adrenocorticotropic hormone (ACTH) levels increased from baseline (19.9 pg/mL; 95%CI[8.6, 24.2])  to pre-WWT (26.9 pg/mL; 95%CI [16.2, 37]; p=0.004), decreased from pre-  (26.9 pg/mL; 95%CI [16.2, 37]) to post-WWT in MT (22.3 pg/mL; 95% CI [8, 23.7]; p=0.004;), and increased from pre-  (25 pg/mL; 95%CI[ 28.4) to post-WWT (36.6 pg/mL; 95%CI [17.9, 48.9]) in AK (p=0.005). Plasma cortisol levels decreased from pre- (174 ng/mL; 95%CI[106.2, 233.6])  to post-WWT (94.5 ng/mL; 95%CI[54.8, 101.7]) in MT (p=0.001) and, conversely, increased from pre- (123.1 ng/mL; 95%CI[97.5, 143.9]) to post-WWT  (162.8 ng/mL; 95%CI[128, 216.7]) in AK (p<0.001). Alterations in growth-related hormones (insulin-like growth factor 1 [IGF-1], insulin-like growth factor binding protein 3 [IGFBP-3], and sex hormone binding globulin [SHBG]) were observed throughout WWT (p<0.05). The Total Testosterone / Cortisol ratio (TT / CORT; molar ratio) was lower pre-WWT in MT (0.04; 95%CI[0.01,0.04) compared to baseline in CO (0.07; 95%CI[0.04, 0.07]; p=0.042). Triiodothyronine (T3) levels increased from pre-  (101.7 ng/dL; 95%CI[93.7, 110.4]) to post-WWT  (117.8 ng/dL; 95%CI[105.1, 129.4]) in MT (p=0.042). No differences in sleep quality were reported between locations (CO, MT, and AK). Alterations in cognitive function were exhibited between locations and during WWT in both MT and AK (p<0.05). Conclusions Over the course of WWT, elite operators experienced alterations in stress, metabolic, and growth-related hormones, as well as cognitive performance. The increase in stress hormones (i.e. ACTH and cortisol) and reduction in cognitive performance following training in AK are suggestive of heightened physiological strain, despite similarities in physical workload, self-reported sleep quality, and access to nutrition. The variation in hormone levels documented between MT and AK may stem from differences in environmental factors, such as lower temperatures and harsh terrain. Further research is warranted to provide more information on the combined effects of military training in extreme environments on operator health and performance. [ABSTRACT FROM AUTHOR]

Objective: Acromegaly is associated with increased morbidity and mortality if left untreated. The therapeutic options include surgery, medical treatment, and radiotherapy. Several guidelines and recommendations on treatment algorithms and follow‐up exist. However, not all recommendations are strictly evidence‐based. To evaluate consensus on the treatment and follow‐up of patients with acromegaly in the Nordic countries. Methods: A Delphi process was used to map the landscape of acromegaly management in Denmark, Sweden, Norway, Finland, and Iceland. An expert panel developed 37 statements on the treatment and follow‐up of patients with acromegaly. Dedicated endocrinologists (n = 47) from the Nordic countries were invited to rate their extent of agreement with the statements, using a Likert‐type scale (1−7). Consensus was defined as ≥80% of panelists rating their agreement as ≥5 or ≤3 on the Likert‐type scale. Results: Consensus was reached in 41% (15/37) of the statements. Panelists agreed that pituitary surgery remains first line treatment. There was general agreement to recommend first‐generation somatostatin analog (SSA) treatment after failed surgery and to consider repeat surgery. In addition, there was agreement to recommend combination therapy with first‐generation SSA and pegvisomant as second‐ or third‐line treatment. In more than 50% of the statements, consensus was not achieved. Considerable disagreement existed regarding pegvisomant monotherapy, and treatment with pasireotide and dopamine agonists. Conclusion: This consensus exploration study on the management of patients with acromegaly in the Nordic countries revealed a relatively large degree of disagreement among experts, which mirrors the complexity of the disease and the shortage of evidence‐based data. [ABSTRACT FROM AUTHOR]

PURPOSE: Graves orbitopathy (GO) is an orbital manifestation of autoimmune Graves disease, and orbital fibroblast is considered a target cell, producing pro-inflammatory cytokines and/or differentiating into adipocytes. Adipose tissue has been focused on as an endocrine and inflammatory organ secreting adipokines. We investigated the pathogenic role of a specific adipokine, adipsin, known as complement factor D in Graves orbital fibroblasts. METHODS: The messenger RNA (mRNA) expression of multiple adipokines was investigated in adipose tissues harvested from GO and healthy subjects. Adipsin protein production was analyzed in primary cultured orbital fibroblasts under insulin growth factor (IGF)-1, CD40 ligand (CD40L) stimulation, and adipogenesis. The effect of blocking adipsin with small interfering RNA (siRNA) on pro-inflammatory cytokine production and adipogenesis was evaluated using quantitative real-time PCR, Western blot, and ELISA. Adipogenic differentiation was identified using Oil Red O staining. RESULTS: Adipsin gene expression was significantly elevated in GO tissue and increased after the stimulation of IGF-1 and CD40L, as well as adipocyte differentiation in GO cells. Silencing of adipsin suppressed IGF-1-induced IL-6, IL-8, COX2, ICAM-1, CCL2 gene expression, and IL-6 protein secretion. Adipsin suppression also attenuated adipocyte differentiation. Exogenous treatment of recombinant adipsin resulted in the activation of the Akt, ERK, p-38, and JNK signaling pathways. CONCLUSIONS: Adipsin, secreted by orbital fibroblasts, may play a distinct role in the pathogenesis of GO. Inhibition of adipsin ameliorated the production of pro-inflammatory cytokines and adipogenesis in orbital fibroblasts. Our study provides an in vitro basis suggesting adipsin as a potential therapeutic target for GO treatment.

ObjectivesTo assess (a) the impact of daily preventive zinc tablets (7 mg; PZ), zinc-containing multiple micronutrient powder (10 mg zinc, and 13 other micronutrients; MNP) or placebo, delivered for 9 months, on Insulin-like Growth Factor 1 (IGF1) and IGF Binding Protein 3 (IGFBP3) among Laotian children 6-23 months, and (b) whether the effects of PZ and MNP on length-for-age z-scores (LAZ) and weight-for-age z-scores (WAZ) are modified by baseline IGF1 and IGFBP3.DesignA double-blind, placebo-controlled trial (N = 419).MethodsPlasma IGF1 and IGFBP3 concentrations at baseline and 36 weeks were analyzed by automated chemiluminescent assay. Anthropometry was assessed at baseline, at 18 and 36 weeks. Intervention effects were estimated using ANCOVA.ResultsAt 36 weeks, geometric mean IGF1 (~39.0-39.2 ng/mL; p = 0.99) and IGFBP3 (2038-2076 ng/mL; p = 0.83) did not differ by group. At 18 weeks (but not at 36 weeks), LAZ in the PZ group (-1.45) was higher than the MNP (-1.70) and control (-1.55) groups (p = 0.01) among children in the highest baseline IGF1 tertile (p for interaction = 0.006). At 36 weeks (but not at 18 weeks), WAZ in the PZ group (-1.55) was significantly higher than the MNP (-1.75) and control (-1.65) groups (p = 0.03), among children in the lowest baseline IGFBP3 tertile (p for interactions = 0.06).ConclusionsAlthough IGF1 and IGFBP3 did not respond to PZ and MNP, baseline IGF1 and IGFBP3 significantly modified the impact of PZ on linear and ponderal growth, suggesting that IGF1 bioavailability may drive catch-up growth in zinc-supplemented children.

Volumetric muscle loss (VML), which refers to a composite skeletal muscle defect, most commonly heals by scarring and minimal muscle regeneration but substantial fibrosis. Current surgical interventions and physical therapy techniques are limited in restoring muscle function following VML. Novel tissue engineering strategies may offer an option to promote functional muscle recovery. The present study evaluates a colloidal scaffold with hierarchical porosity and controlled mechanical properties for the treatment of VML. In addition, as VML results in an acute decrease in insulin-like growth factor 1 (IGF-1), a myogenic factor, the scaffold was designed to slowly release IGF-1 following implantation. The foam-like scaffold is directly crosslinked onto remnant muscle without the need for suturing. In situ 3D printing of IGF-1-releasing porous muscle scaffold onto VML injuries resulted in robust tissue ingrowth, improved muscle repair, and increased muscle strength in a murine VML model. Histological analysis confirmed regeneration of new muscle in the engineered scaffolds. In addition, the scaffolds significantly reduced fibrosis and increased the expression of neuromuscular junctions in the newly regenerated tissue. Exercise training, when combined with the engineered scaffolds, augmented the treatment outcome in a synergistic fashion. These data suggest highly porous scaffolds and exercise therapy, in combination, may be a treatment option following VML.

Abstract Childhood stunting and wasting, or decreased linear and ponderal growth associated with undernutrition, continue to be a major global public health challenge. Although many of the current therapeutic and dietary interventions have significantly reduced childhood mortality caused by undernutrition, there remain great inefficacies in improving childhood stunting. Longitudinal bone growth in children is governed by different genetic, nutritional and other environmental factors acting systemically on the endocrine system and locally at the growth plate. Recent studies have shown that this intricate interplay between nutritional and hormonal regulation of the growth plate could involve the gut microbiota, highlighting the importance of a holistic approach in tackling childhood undernutrition. In this review, I focus on the mechanistic insights provided by these recent advances in gut microbiota research and discuss ongoing development of microbiota‐based therapeutics in humans, which could be the missing link in solving undernutrition and childhood stunting.

Inadequate diet and frequent symptomatic infections are considered major causes of growth stunting in low-income countries, but interventions targeting these risk factors have achieved limited success. Asymptomatic infections can restrict growth, but little is known about their role in global stunting prevalence. We investigated factors related to length-for-age Z-score (LAZ) at 24 months by constructing an interconnected network of various infections, biomarkers of inflammation (as assessed by alpha-1-acid glycoprotein [AGP]), and growth (insulin-like growth factor 1 [IGF-1] and collagen X biomarker [CXM]) at 18 months, as well as other children, maternal, and household level factors. Among 604 children, there was a continuous decline in mean LAZ and increased mean length deficit from birth to 24 months. At 18 months of age, the percentage of asymptomatic children who carried each pathogen was: 84.5% enterovirus, 15.5% parechovirus, 7.7% norovirus, 4.6% rhinovirus, 0.6% rotavirus, 69.6% Campylobacter, 53.8% Giardia lamblia, 11.9% malaria parasites, 10.2% Shigella, and 2.7% Cryptosporidium. The mean plasma IGF-1 concentration was 12.5 ng/ml and 68% of the children had systemic inflammation (plasma AGP concentration >1 g/L). Shigella infection was associated with lower LAZ at 24 months through both direct and indirect pathways, whereas enterovirus, norovirus, Campylobacter, Cryptosporidium, and malaria infections were associated with lower LAZ at 24 months indirectly, predominantly through increased systemic inflammation and reduced plasma IGF-1 and CXM concentration at 18 months.

Insulin, insulin-like growth factors (IGF) and their receptors are highly expressed in the adult hippocampus. Thus, disturbances in the insulin-IGF signalling pathway may account for the selective vulnerability of the hippocampus to nascent Alzheimer's disease (AD) pathology. In the present study, we examined the predominant IGF-binding protein in the CSF, IGFBP2. CSF was collected from 109 asymptomatic members of the parental history-positive PREVENT-AD cohort. CSF levels of IGFBP2, core AD and synaptic biomarkers were measured using proximity extension assay, ELISA and mass spectrometry. Cortical amyloid-beta (Aβ) and tau deposition were examined using 18F-NAV4694 and flortaucipir. Cognitive assessments were performed during up to 8 years of follow-up, using the Repeatable Battery for the Assessment of Neuropsychological Status. T1-weighted structural MRI scans were acquired, and neuroimaging analyses were performed on pre-specified temporal and parietal brain regions. Next, in an independent cohort, we allocated 241 dementia-free ADNI-1 participants into four stages of AD progression based on the biomarkers CSF Aβ42 and total-tau (t-tau). In this analysis, differences in CSF and plasma IGFBP2 levels were examined across the pathological stages. Finally, IGFBP2 mRNA and protein levels were examined in the frontal cortex of 55 autopsy-confirmed AD and 31 control brains from the Quebec Founder Population (QFP) cohort, a unique population isolated from Eastern Canada. CSF IGFBP2 progressively increased over 5 years in asymptomatic PREVENT-AD participants. Baseline CSF IGFBP2 was positively correlated with CSF AD biomarkers and synaptic biomarkers, and negatively correlated with longitudinal changes in delayed memory (P = 0.024) and visuospatial abilities (P = 0.019). CSF IGFBP2 was negatively correlated at a trend-level with entorhinal cortex volume (P = 0.082) and cortical thickness in the piriform (P = 0.039), inferior temporal (P = 0.008), middle temporal (P = 0.014) and precuneus (P = 0.033) regions. In ADNI-1, CSF (P = 0.009) and plasma (P = 0.001) IGFBP2 were significantly elevated in Stage 2 [CSF Aβ(+)/t-tau(+)]. In survival analyses in ADNI-1, elevated plasma IGFBP2 was associated with a greater rate of AD conversion (hazard ratio = 1.62, P = 0.021). In the QFP cohort, IGFBP2 mRNA was reduced (P = 0.049); however, IGFBP2 protein levels did not differ in the frontal cortex of autopsy-confirmed AD brains (P = 0.462). Nascent AD pathology may induce an upregulation in IGFBP2 in asymptomatic individuals. CSF and plasma IGFBP2 may be valuable markers for identifying CSF Aβ(+)/t-tau(+) individuals and those with a greater risk of AD conversion. [ABSTRACT FROM AUTHOR]

Childhood stunting and wasting, or decreased linear and ponderal growth associated with undernutrition, continue to be a major global public health challenge. Although many of the current therapeutic and dietary interventions have significantly reduced childhood mortality caused by undernutrition, there remain great inefficacies in improving childhood stunting. Longitudinal bone growth in children is governed by different genetic, nutritional and other environmental factors acting systemically on the endocrine system and locally at the growth plate. Recent studies have shown that this intricate interplay between nutritional and hormonal regulation of the growth plate could involve the gut microbiota, highlighting the importance of a holistic approach in tackling childhood undernutrition. In this review, I focus on the mechanistic insights provided by these recent advances in gut microbiota research and discuss ongoing development of microbiota‐based therapeutics in humans, which could be the missing link in solving undernutrition and childhood stunting. What is the topic of this review?This review is about the mechanisms by which the gut microbiota regulates bone growth.What advances does it highlight?There is in vivo evidence for regulation of the gut microbiota on the growth hormone–insulin‐like growth factor I axis. An association exists between gut microbiota immaturity and undernutrition. Clinical trials of microbiota‐based therapeutics are underway. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor I (IGF-I) has been suggested as an important factor in the pathogenesis of bronchopulmonary dysplasia (BPD). In turn, nutrition has been associated with IGF-I levels and could be of importance in the pathogenesis of BPD. This study aimed to explore the association between nutrition, the IGF-I axis and the occurrence of BPD. Eighty-six preterm infants (44 male, mean gestational age: 29.0 weeks (standard deviation: 1.7 weeks)) were enrolled in an observational study. Serum IGF-I (µg/L) and insulin-like growth factor binding protein 3 (IGFBP-3; mg/L) were measured at birth and at 2, 4 and 6 weeks postnatal age. BPD was diagnosed at 36 weeks postmenstrual age. Twenty-nine infants were diagnosed with BPD. For every µg/L per week increase in IGF-I, the odds of BPD decreased (0.68, 95% CI 0.48–0.96, corrected for gestational age). The change in IGF-I in µg/L/week, gestational age in weeks and a week of predominant donor human milk feeding were associated with the occurrence of BPD in the multivariable analysis (respectively, OR 0.63 (0.43–0.92), OR 0.44 (0.26–0.76) and 7.6 (1.2–50.4)). IGFBP-3 was not associated with the occurrence of BPD in the multivariable analysis. In conclusion, a slow increase in IGF-I levels and a lower gestational age increase the odds of BPD. Donor human milk might increase the odds of BPD and should be further explored. [ABSTRACT FROM AUTHOR]

Background: Cannabidiol (CBD) is becoming increasingly popular for the treatment of clinical conditions including as an aid for muscle recovery. Previous work demonstrated that CBD exhibited mild effects on skeletal muscle, with a tendency to increase anabolic signaling and decrease inflammatory signaling. Methods: To gain mechanistic insight and extend these findings, we conducted a set of experiments using C2C12 myotubes. Results: Increasing the dose of CBD (1-5 μM) provided with insulin-like growth factor 1 (IGF-1) showed no effect on anabolic signaling through mTORC1 (S6K1 [Thr389], p=0.27; rpS6 [Ser240/244], p=0.81; or 4E-BP1 [Thr37/46], p=0.87). Similarly, inflammatory signaling through nuclear factor kappa B (NF-κB) (p105, p=0.88; p50, p=0.93; or phosphorylated p65 [Ser536], p=0.84) in response to tumor necrosis factor α (TNFα) was unaffected by CBD (2.5 μM), whereas dioscin, a natural product that blocks NF-κB signaling, reduced p105 and phosphorylated p65 (Ser536) compared with the TNFα and the TNFα + CBD condition (p

This review intends to provide the reader with a practical overview of several (patho)physiological conditions in which knowledge of the interplay between growth hormone (GH), insulin-like growth factor-1 (IGF-1), and insulin is important. This might help treating physicians in making the right decisions on how to intervene and improve metabolism for the benefit of patients, and to understand why and how metabolism responds in their specific cases. We will specifically address the interplay between GH, IGF-1, and insulin in type 1 and 2 diabetes mellitus, liver cirrhosis, and acromegaly as examples in which this knowledge is truly necessary.

Abstract Backgrounds Nonalcoholic fatty liver disease (NAFLD) exhibits a close association with osteoporosis. This work aims to assess the potential effects of NAFLD on the progression of osteopenia in animal models. Methods Forty-eight C57BL/6 female mice were randomly divided to wild-type (WT) group and high-fat diet (HFD) group. The corresponding detections were performed after sacrifice at 16, 24 and 32 weeks, respectively. Results At 16 weeks, an remarkable increase in body weight and lipid aggregation in the hepatocytes of HFD group was observed compared to the WT group, while the bone structure parameters showed no significant difference. At 24 weeks, the levels of TNF-α and IL-6 in NAFLD mice were significantly increased, while the level of osteoprotegerin mRNA in bone tissue was decreased, and the level of receptor activator of nuclear factor Kappa-B ligand mRNA was increased. Meanwhile, the function of osteoclasts was increased, and the bone microstructure parameters showed significant changes. At 32 weeks, in the HFD mice, the mRNA levels of insulin-like growth factor-1 (IGF-1), runt-related transcription factor 2, and osterix mRNA were reduced, while the insulin-like growth factor binding protein-1 (IGFBP-1) level was increased. Simultaneously, the osteoblast function was decreased, and the differences of bone structure parameters were more significant, showing obvious osteoporosis. Conclusions The bone loss in HFD mice is pronounced as NAFLD progresses, and the changes of the TNF-α, IL-6, IGF-1, and IGFBP-1 levels may play critical roles at the different stages of NAFLD in HFD.

Since our discovery in 2006 that acromegaly is associated with an increased risk of vertebral fractures, many authors have confirmed this finding in both cross-sectional and prospective studies. Due to the high epidemiological and clinical impact of this newly discovered comorbidity of acromegaly, this topic has progressively become more important and prominent over the years, and the pertinent literature has been enriched by new findings on the pathophysiology and treatment. The aim of this narrative review was to discuss these novel findings, integrating them with the seminal observations, in order to give the reader an updated view of how the field of acromegaly and bone is developing, from strong clinical observations to a mechanistic understanding and possible prevention and treatment.

Context: Although the role of insulin-like growth factor I (IGF-1) in nonalcoholic fatty liver disease (NAFLD) has garnered attention in recent years, few studies have examined both reduced and elevated levels of IGF-1. Objective: The aim of this study was to examine the potential relationship between IGF-1 levels and the risk of new-onset NAFLD in patients with pituitary neuroendocrine tumors (PitNET). Methods: We employed multivariable Cox regression models and two-piecewise regression models to assess the association between IGF-1 and new-onset NAFLD. Hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were calculated to quantify this association. Furthermore, a dose-response correlation between lgIGF-1 and the development of NAFLD was plotted. Additionally, we also performed subgroup analysis and a series sensitivity analysis. Results: A total of 3,291 PitNET patients were enrolled in the present study, and the median duration of follow-up was 65 months. Patients with either reduced or elevated levels of IGF-1 at baseline were found to be at a higher risk of NAFLD compared to PitNET patients with normal IGF-1(log-rank test, P < 0.001). In the adjusted Cox regression analysis model (model IV), compared with participants with normal IGF-1, the HRs of those with elevated and reduced IGF-1 were 2.33 (95% CI 1.75, 3.11) and 2.2 (95% CI 1.78, 2.7). Furthermore, in non-adjusted or adjusted models, our study revealed a U-shaped relationship between lgIGF-1 and the risk of NAFLD. Moreover, the results from subgroup and sensitivity analyses were consistent with the main results. Conclusions: There was a U-shaped trend between IGF-1 and new-onset NAFLD in patients with PitNET. Further evaluation of our discoveries is warranted. [ABSTRACT FROM AUTHOR]

This review intends to provide the reader with a practical overview of several (patho)physiological conditions in which knowledge of the interplay between growth hormone (GH), insulin-like growth factor-1 (IGF-1), and insulin is important. This might help treating physicians in making the right decisions on how to intervene and improve metabolism for the benefit of patients, and to understand why and how metabolism responds in their specific cases. We will specifically address the interplay between GH, IGF-1, and insulin in type 1 and 2 diabetes mellitus, liver cirrhosis, and acromegaly as examples in which this knowledge is truly necessary. [ABSTRACT FROM AUTHOR]

Purpose: The 14th Acromegaly Consensus Conference was convened to consider biochemical criteria for acromegaly diagnosis and evaluation of therapeutic efficacy. Methods: Fifty-six acromegaly experts from 16 countries reviewed and discussed current evidence focused on biochemical assays; criteria for diagnosis and the role of imaging, pathology, and clinical assessments; consequences of diagnostic delay; criteria for remission and recommendations for follow up; and the value of assessment and monitoring in defining disease progression, selecting appropriate treatments, and maximizing patient outcomes. Results: In a patient with typical acromegaly features, insulin-like growth factor (IGF)-I > 1.3 times the upper limit of normal for age confirms the diagnosis. Random growth hormone (GH) measured after overnight fasting may be useful for informing prognosis, but is not required for diagnosis. For patients with equivocal results, IGF-I measurements using the same validated assay can be repeated, and oral glucose tolerance testing might also be useful. Although biochemical remission is the primary assessment of treatment outcome, biochemical findings should be interpreted within the clinical context of acromegaly. Follow up assessments should consider biochemical evaluation of treatment effectiveness, imaging studies evaluating residual/recurrent adenoma mass, and clinical signs and symptoms of acromegaly, its complications, and comorbidities. Referral to a multidisciplinary pituitary center should be considered for patients with equivocal biochemical, pathology, or imaging findings at diagnosis, and for patients insufficiently responsive to standard treatment approaches. Conclusion: Consensus recommendations highlight new understandings of disordered GH and IGF-I in patients with acromegaly and the importance of expert management for this rare disease. [ABSTRACT FROM AUTHOR]

Aims Numerous studies have established that resistance training is highly effective in preventing and addressing age-related muscle loss (sarcopenia) by enhancing the physiological function of skeletal muscle tissue. Thus, the objective of this study was to assess the impact of 12 weeks of incremental resistance training on the serum levels of myostatin, follistatin, and insulin-like growth factor-1 (IGF-I) in sedentary elderly men. Materials & Methods Thirty sedentary elderly men voluntarily participated in this semiexperimental study and were randomly assigned to either a control group (15 men) with an average age of 62.1±3.7 years and weight of 85.1±7.7 kg, or a resistance training group (15 men) with an average age of 61.3±1.6 years and weight of 82.3±7.8 kg. The resistance training group undertook a 12-week training protocol, while the control group did not engage in any training program during this time. Blood samples and body composition measurements (using dual X-ray absorptiometry) were taken before the study commenced and 48 hours after the last training session concluded. Serum levels of myostatin, follistatin, and IGF-I were determined using the ELISA method. An independent t-test was employed to establish statistical significance between the groups, utilizing SPSS 21 software. Findings After 12 weeks of resistance training, there was a significant decrease in serum myostatin levels and significant increases in serum follistatin and IGF-I levels in comparison to the control group (p=0.05). Conclusion Incremental resistance training proves to be an effective intervention for preventing sarcopenia in elderly individuals by decreasing serum levels of myostatin and increasing serum levels of follistatin and IGF-I. [ABSTRACT FROM AUTHOR]

Backgrounds: Nonalcoholic fatty liver disease (NAFLD) exhibits a close association with osteoporosis. This work aims to assess the potential effects of NAFLD on the progression of osteopenia in animal models. Methods: Forty-eight C57BL/6 female mice were randomly divided to wild-type (WT) group and high-fat diet (HFD) group. The corresponding detections were performed after sacrifice at 16, 24 and 32 weeks, respectively. Results: At 16 weeks, an remarkable increase in body weight and lipid aggregation in the hepatocytes of HFD group was observed compared to the WT group, while the bone structure parameters showed no significant difference. At 24 weeks, the levels of TNF-α and IL-6 in NAFLD mice were significantly increased, while the level of osteoprotegerin mRNA in bone tissue was decreased, and the level of receptor activator of nuclear factor Kappa-B ligand mRNA was increased. Meanwhile, the function of osteoclasts was increased, and the bone microstructure parameters showed significant changes. At 32 weeks, in the HFD mice, the mRNA levels of insulin-like growth factor-1 (IGF-1), runt-related transcription factor 2, and osterix mRNA were reduced, while the insulin-like growth factor binding protein-1 (IGFBP-1) level was increased. Simultaneously, the osteoblast function was decreased, and the differences of bone structure parameters were more significant, showing obvious osteoporosis. Conclusions: The bone loss in HFD mice is pronounced as NAFLD progresses, and the changes of the TNF-α, IL-6, IGF-1, and IGFBP-1 levels may play critical roles at the different stages of NAFLD in HFD. Main Points: Bone loss in the HFD mice becomes increasingly apparent with NAFLD progression. The changes of the TNF-α, IL-6, IGF-1, and IGFBP-1 levels are important at the different stages of NAFLD in the HFD mice. [ABSTRACT FROM AUTHOR]

Endoplasmic Reticulum Stress (ERS) is a key factor in the development of Non-Alcoholic Fatty Liver Disease (NAFLD) in diabetes. The current study aimed to examine the effects of exercise and IGF-I on ERS markers in liver tissue. Rats were divided into five groups (n = 8 per group), including control (CON), diabetes (DIA), diabetes + exercise (DIA + EX), diabetes + IGF-I (DIA + IGF-I), and diabetes + exercise + IGF-I (DIA + EX + IGF-I). Type 1 diabetes was induced by an I.P. injection of streptozotocin (60 mg/kg). After 30 days of treatment with exercise or IGF-I alone or in combination, liver tissue was assessed for caspase 12, 8, and CHOP protein levels, and expression of ERS markers (ATF-6, PERK, IRE-1A) and lipid metabolism-involved genes (FAS, FXR, SREBP-1c) by western immunoblotting. In addition, for the evaluation of histopathological changes in the liver, Hematoxylin - Eosin and Masson's Trichrome staining were done. Compared to the control group, diabetes significantly caused liver fibrosis, induced ERS, increased caspase 12 and 8 levels in the liver, and changed expression levels of genes associated with lipid metabolism, including FAS, FXR, and SREBP-1c. Treatment with either exercise or IGF-I reduced fibrosis levels suppressed ER stress markers and apoptosis, and improved expression of genes associated with lipid metabolism. In addition, simultaneous treatment with exercise and IGF-I showed a synergistic effect compared to DIA + E and DIA + IGF-I. The results suggest that IGF-1 and exercise reduced liver fibrosis possibly by reducing ERS, creating adaptive ER stress status, and improving protein folding.

The goal of this project was to determine if standardized ileal digestible (SID) lysine provided at 40% above estimated requirements, with the concomitant increase in protein intake, from days 90 to 110 of gestation would stimulate mammary development in gilts. From day 90 of gestation, Yorkshire × Landrace gilts were fed 2.65 kg of either a conventional diet (CTL, control, n = 19) providing 18.6 g/d of SID Lys or a diet providing 26.0 g/d of SID Lys via additional soybean meal (HILYS, n = 19). Both diets were isoenergetic. Jugular blood samples obtained on days 90 and 110 of gestation were used to measure concentrations of insulin-like growth factor-1 (IGF-1), metabolites, and amino acids (AA). Gilts were necropsied on day 110 ± 1 of gestation to obtain mammary glands for compositional analyses, immunohistochemistry, and analysis of mRNA abundance for AA transporters and markers of cell proliferation and differentiation. The HILYS gilts gained more body weight (P < 0.01) during the experimental period compared with CTL gilts, and had greater fetal weights (1.29 vs. 1.21 ± 0.03 kg, P < 0.05). There was no difference in circulating IGF-1, glucose, or albumin (P > 0.10) between HILYS and CTL gilts on day 110 of gestation, whereas concentrations of urea and free fatty acids were greater (P < 0.01), and those of Trp and Ala were lower (P < 0.05), in HILYS than CTL gilts. The provision of lysine at 40% above estimated requirements increased total mammary parenchymal mass by 44%, as well as total parenchymal fat, protein, DNA, and RNA (P < 0.01). The mRNA abundance of ACACA was greater (P < 0.05) in HILYS than CTL gilts, while only the AA transporter SLC6A14 tended (P < 0.10) to be greater. Results demonstrate that providing dietary Lys above current National Research Council recommendations in late gestation increases mammary development in gilts. Results also indicate that Lys may have been limiting for protein retention. These data suggest that the use of a two-phase feeding strategy during gestation, whereby dietary Lys is increased from day 90, could benefit potential sow milk yield in the subsequent lactation.

Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied extensively. Experimental studies showing the permissive role of GH/insulin-like growth factor 1 (IGF-I) in carcinogenesis have raised concerns regarding the safety of GH replacement in children and adults who have received treatment for cancer and those with intracranial and pituitary tumours. A consensus statement was produced to guide decision-making on GH replacement in children and adult survivors of cancer, in those treated for intracranial and pituitary tumours and in patients with increased cancer risk. With the support of the European Society of Endocrinology, the Growth Hormone Research Society convened a Workshop, where 55 international key opinion leaders representing 10 professional societies were invited to participate. This consensus statement utilized: (1) a critical review paper produced before the Workshop, (2) five plenary talks, (3) evidence-based comments from four breakout groups, and (4) discussions during report-back sessions. Current evidence reviewed from the proceedings from the Workshop does not support an association between GH replacement and primary tumour or cancer recurrence. The effect of GH replacement on secondary neoplasia risk is minor compared to host- and tumour treatment-related factors. There is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors. Patients with pituitary tumour or craniopharyngioma remnants receiving GH replacement do not need to be treated or monitored differently than those not receiving GH. GH replacement might be considered in GH-deficient adult cancer survivors in remission after careful individual risk/benefit analysis. In children with cancer predisposition syndromes, GH treatment is generally contraindicated but may be considered cautiously in select patients.

Aberrant insulin-like growth factor 1 (IGF-1) signaling has been proposed as a contributing factor to the development of neurodegenerative disorders including diabetic neuropathy, and delivery of exogenous IGF-1 has been explored as a treatment for Alzheimer's disease and amyotrophic lateral sclerosis. However, the role of autocrine/paracrine IGF-1 in neuroprotection has not been well established. We therefore used in vitro cell culture systems and animal models of diabetic neuropathy to characterize endogenous IGF-1 in sensory neurons and determine the factors regulating IGF-1 expression and/or affecting neuronal health. Single-cell RNA sequencing (scRNA-Seq) and in situ hybridization analyses revealed high expression of endogenous IGF-1 in non-peptidergic neurons and satellite glial cells (SGCs) of dorsal root ganglia (DRG). Brain cortex and DRG had higher IGF-1 gene expression than sciatic nerve. Bidirectional transport of IGF-1 along sensory nerves was observed. Despite no difference in IGF-1 receptor levels, IGF-1 gene expression was significantly (P

PURPOSE: Brutons tyrosine kinase (BTK) is an essential protein in B-cell antigen receptor (BCR) signaling pathway and is known to be related to pathogenetic effect on B-cell related malignancies and various autoimmune diseases. In this study, we investigated the therapeutic effect of ibrutinib, an orally bioavailable BTK inhibitor in the pathogenesis of Graves orbitopathy (GO) in in vitro model. METHODS: Expression of BTK in orbital tissues from GO and normal control subjects were evaluated by real-time polymerase chain reaction (PCR). Primary cultured orbital fibroblasts from each subject were exposed to ibrutinib and stimulated with interleukin (IL)-1β or insulin like growth factor (IGF)-1. Production of inflammatory cytokines was evaluated by real time PCR and enzyme-linked immunosorbent assays (ELISA). The downstream transcription factors were also determined by western blot assays. RESULTS: The expression of BTK in GO tissues were significantly higher than in healthy controls. After stimulation of GO orbital fibroblasts with IL-1β or IGF-1, BTK mRNA and phosphorylated (p)- BTK protein expression was also enhanced. Ibrutinib reduced the expression of BTK mRNA and proteins of p-BTK, and inhibited the IL-1β- and IGF-1-induced production of proinflammatory cytokines including IL-6, IL-8 and COX-2 in both GO and normal cells. Ibrutinib also significantly attenuated phosphorylation of Akt, p38, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) in IL-1β stimulated GO cells and Akt, JNK, and NF-κB in IL-1ß stimulated normal cells. CONCLUSIONS: BTK expression is enhanced in GO tissue and orbital fibroblasts. Ibrutinib, a BTK inhibitor suppresses proinflammatory cytokine production as well as phosphorylation of Akt and NF-κB protein. Our results suggest the potential role of BTK in GO inflammatory pathogenesis and possibility of a novel therapeutic target of GO.

Lung development is precisely controlled by underlying gene regulatory networks (GRN). Disruption of genes in the network can interrupt normal development and cause diseases such as bronchopulmonary dysplasia (BPD) - a chronic lung disease in preterm infants with morbid and sometimes lethal consequences characterized by lung immaturity and reduced alveolarization. Here, we generated a transgenic mouse exhibiting a moderate severity BPD phenotype by blocking IGF1 signaling in secondary crest myofibroblasts (SCMF) at the onset of alveologenesis. Using approaches mirroring the construction of the model GRN in sea urchin's development, we constructed the IGF1 signaling network underlying alveologenesis using this mouse model that phenocopies BPD. The constructed GRN, consisting of 43 genes, provides a bird's eye view of how the genes downstream of IGF1 are regulatorily connected. The GRN also reveals a mechanistic interpretation of how the effects of IGF1 signaling are transduced within SCMF from its specification genes to its effector genes and then from SCMF to its neighboring alveolar epithelial cells with WNT5A and FGF10 signaling as the bridge. Consistently, blocking WNT5A signaling in mice phenocopies BPD as inferred by the network. A comparative study on human samples suggests that a GRN of similar components and wiring underlies human BPD. Our network view of alveologenesis is transforming our perspective to understand and treat BPD. This new perspective calls for the construction of the full signaling GRN underlying alveologenesis, upon which targeted therapies for this neonatal chronic lung disease can be viably developed.

BackgroundInsulin-like growth factor 1 (IGF-1) signaling has been implicated in Alzheimer's disease pathogenesis, and further evidence suggests inflammation can be a moderator of this association. However, most research to date has been conducted on older adults.ObjectiveTo investigate the association of serum IGF-1 and IGF binding protein 3 (IGFBP-3) concentrations with MRI markers of Alzheimer's disease in predominantly middle-aged adults, and further assess moderation by chronic inflammation.MethodsWe included participants from the Framingham Heart Study (n = 1,852, mean age 46±8, 46% men) and the Study of Health in Pomerania (n = 674, mean age 50±13, 42% men) with available serum IGF-1, IFGBP-3, as well as brain MRI. IGF-1 and IFGBP-3 were related to MRI outcomes (i.e., total brain, cortical gray matter, white matter, white matter hyperintensities (WMH), and hippocampal volumes) using multivariable regression models adjusting for potential confounders. Subgroup analyses by C-reactive protein (CRP) concentrations were also performed. Cohort-specific summary statistics were meta-analyzed using random-effects models and corrected for multiple comparisons.ResultsMeta-analysis results revealed that higher IGF-1 concentrations were associated with lower WMH (estimate [β] [95% CI], -0.05 [-0.09, -0.02], p = 0.006) and larger hippocampal volumes (0.07 [0.02, 0.12], p = 0.01), independent of vascular risk factors. These associations occurred predominantly in individuals with CRP concentrations

BackgroundCirculating lipids and insulin-like growth factor 1 (IGF-I) have been reliably associated with breast cancer. Observational studies suggest an interplay between lipids and IGF-I, however, whether these relationships are causal and if pathways from these phenotypes to breast cancer overlap is unclear.MethodsMendelian randomization (MR) was conducted to estimate the relationship between lipids or IGF-I and breast cancer risk using genetic summary statistics for lipids (low-density lipoprotein cholesterol, LDL-C; high-density lipoprotein cholesterol, HDL-C; triglycerides, TGs), IGF-I and breast cancer from GLGC/UKBB (N = 239,119), CHARGE/UKBB (N = 252,547), and Breast Cancer Association Consortium (N = 247,173), respectively. Cross-sectional observational and MR analyses were conducted to assess the bi-directional relationship between lipids and IGF-I in SHIP (N = 3,812) and UKBB (N = 422,389), and using genetic summary statistics from GLGC (N = 188,577) and CHARGE/UKBB (N = 469,872).ResultsIn multivariable MR (MVMR) analyses, the OR for breast cancer per 1-SD increase in HDL-C and TG was 1.08 [95% confidence interval (CI), 1.04-1.13] and 0.94 (95% CI, 0.89-0.98), respectively. The OR for breast cancer per 1-SD increase in IGF-I was 1.09 (95% CI, 1.04-1.15). MR analyses suggested a bi-directional TG-IGF-I relationship (TG-IGF-I β per 1-SD: -0.13; 95% CI, -0.23 to -0.04; and IGF-I-TG β per 1-SD: -0.11; 95% CI, -0.18 to -0.05). There was little evidence for a causal relationship between HDL-C and LDL-C with IGF-I. In MVMR analyses, associations of TG or IGF-I with breast cancer were robust to adjustment for IGF-I or TG, respectively.ConclusionsOur findings suggest a causal role of HDL-C, TG, and IGF-I in breast cancer. Observational and MR analyses support an interplay between IGF-I and TG; however, MVMR estimates suggest that TG and IGF-I may act independently to influence breast cancer.ImpactOur findings should be considered in the development of prevention strategies for breast cancer, where interventions are known to modify circulating lipids and IGF-I.

Abstract Background Exercise training is a major factor in controlling type 1 diabetes mellitus (T1DM) in children. The present study aimed to assess the effect of concurrent resistance-aerobic training on selected inflammatory factors and hormones related to blood glucose homeostasis in children with T1DM. Methods In this randomized controlled clinical trial, 40 children (with the mean age of 11.11 ± 2.29 years) were randomly assigned to an experimental (N = 20) or control group (N = 20). They underwent a 16-week training program, composed of concurrent resistance-aerobic training performed intermittently for 60 min three times a week. Before and after training, blood samples were analyzed for glucose homeostasis, selected inflammatory factors, and growth factors. Data were analyzed by paired t-test and analysis of covariance (ANCOVA) in IBM SPSS version 22. Results The exercise training intervention reduced fasting blood sugar index (P = 0.002) and glycosylated hemoglobin significantly (P = 0.003). The growth hormone levels were increased significantly only in the experimental group (P = 0.037), whereas no significant difference was noted in the insulin-like growth factor-1 (P = 0.712). It was also found that interleukin-1β and high-sensitivity C-reactive protein did not change in the experimental or control group as compared to the pretest (P > 0.05). Conclusion As it was shown, it seems that concurrent resistance-aerobic training may improve blood glucose homeostasis and growth hormone. Therefore, these findings may suggest the benefit from exercise training of moderate intensity in children with T1DM. Besides, we recommend undertaking further clinical trials to determine if the exercise training was effective. Trial registration This study was registered in the Iranian Registry of Clinical Trials under the code IRCT20150531022498N30: https://en.irct.ir/trial/41031 . Registered on July 26, 2019. All experiments on the participants were following the Declaration of Helsinki.

Despite decades of intense research, disease-modifying therapeutic approaches for Alzheimer's disease (AD) are still very much needed. Apart from the extensively analyzed tau and amyloid pathological cascades, two promising avenues of research that may eventually identify new druggable targets for AD are based on a better understanding of the mechanisms of resilience and vulnerability to this condition. We argue that insulin-like growth factor I (IGF-I) activity in the brain provides a common substrate for the mechanisms of resilience and vulnerability to AD. We postulate that preserved brain IGF-I activity contributes to resilience to AD pathology as this growth factor intervenes in all the major pathological cascades considered to be involved in AD, including metabolic impairment, altered proteostasis, and inflammation, to name the three that are considered to be the most important ones. Conversely, disturbed IGF-I activity is found in many AD risk factors, such as old age, type 2 diabetes, imbalanced diet, sedentary life, sociality, stroke, stress, and low education, whereas the Apolipoprotein (Apo) E4 genotype and traumatic brain injury may also be influenced by brain IGF-I activity. Accordingly, IGF-I activity should be taken into consideration when analyzing these processes, while its preservation will predictably help prevent the progress of AD pathology. Thus, we need to define IGF-I activity in all these conditions and develop a means to preserve it. However, defining brain IGF-I activity cannot be solely based on humoral or tissue levels of this neurotrophic factor, and new functionally based assessments need to be developed. [ABSTRACT FROM AUTHOR]

In this article we review the cellular and molecular mechanisms of gastric ulcer healing. A gastric ulcer (GU) is a deep defect in the gastric wall penetrating through the entire mucosa and the muscularis mucosae. GU healing is a regeneration process that encompasses cell dedifferentiation, proliferation, migration, re-epithelialization, formation of granulation tissue, angiogenesis, vasculogenesis, interactions between various cells and the matrix, and tissue remodeling, all resulting in scar formation. All these events are controlled by cytokines and growth factors (e.g., EGF, TGFα, IGF-1, HGF, bFGF, TGFβ, NGF, VEGF, angiopoietins) and transcription factors activated by tissue injury. These growth factors bind to their receptors and trigger cell proliferation, migration, and survival pathways through Ras, MAPK, PI3K/Akt, PLC-γ, and Rho/Rac/actin signaling. The triggers for the activation of these growth factors are tissue injury and hypoxia. EGF, its receptor, IGF-1, HGF, and COX-2 are important for epithelial cell proliferation, migration, re-epithelialization, and gastric gland reconstruction. VEGF, angiopoietins, bFGF, and NGF are crucial for blood vessel regeneration in GU scars. The serum response factor (SRF) is essential for VEGF-induced angiogenesis, re-epithelialization, and blood vessel and muscle restoration. Local therapy with cDNA of human recombinant VEGF165 in combination with angiopoietin1, or with the NGF protein, dramatically accelerates GU healing and improves the quality of mucosal restoration within ulcer scars. The future directions for accelerating and improving healing include local gene and protein therapies with growth factors, their combinations, and the use of stem cells and tissue engineering.

BackgroundInsulin-like growth factor I (IGF-I) is the most important hormonal promoter of linear growth in infants and young children.ObjectivesThe objectives of this study were to compare plasma IGF-I concentration in a low- compared with a high-income country and characterize biological pathways leading to reduced IGF-I concentration in children in a low-income setting.MethodsWe analyzed plasma IGF-I concentration from 716 Malawian and 80 Finnish children at 6-36 mo of age. In the Malawian children, we studied the association between IGF-I concentration and their environmental exposures; nutritional status; systemic and intestinal inflammation; malaria parasitemia and viral, bacterial, and parasitic enteric infections; as well as growth at 18 mo of age. We then conducted a pathway analysis to identify direct and indirect associations between these predictors and IGF-I concentration.ResultsThe mean IGF-I concentrations were similar in Malawi and Finland among 6-mo-old infants. At age 18 mo, the mean ± SD concentration was almost double among the Finns compared with the Malawians [24.2 ± 11.3 compared with 12.5 ± 7.7 ng/mL, age- and sex-adjusted difference in mean (95% CI): 11.8 (9.9, 13.7) ng/mL; P

The insulin-like growth factors (IGFs)/insulin resistance (IR) axis is the major metabolic hormonal pathway mediating the biologic mechanism of several complex human diseases, including type 2 diabetes (T2DM) and cancers. The genomewide association study (GWAS)-based approach has neither fully characterized the phenotype variation nor provided a comprehensive understanding of the regulatory biologic mechanisms. We applied systematic genomics to integrate our previous GWAS data for IGF-I and IR with multi-omics datasets, e.g., whole-blood expression quantitative loci, molecular pathways, and gene network, to capture the full range of genetic functionalities associated with IGF-I/IR and key drivers (KDs) in gene-regulatory networks. We identified both shared (e.g., T2DM, lipid metabolism, and estimated glomerular filtration signaling) and IR-specific (e.g., mechanistic target of rapamycin, phosphoinositide 3-kinases, and erb-b2 receptor tyrosine kinase 4 signaling) molecular biologic processes of IGF-I/IR axis regulation. Next, by using tissue-specific gene-gene interaction networks, we identified both well-established (e.g., IRS1 and IGF1R) and novel (e.g., AKT1, HRAS, and JAK1) KDs in the IGF-I/IR-associated subnetworks. Our results, if validated in additional genomic studies, may provide robust, comprehensive insights into the mechanisms of IGF-I/IR regulation and highlight potential novel genetic targets as preventive and therapeutic strategies for the associated diseases, e.g., T2DM and cancers.

Alterations in myelin, the protective and insulating sheath surrounding axons, affect brain function, as is evident in demyelinating diseases where the loss of myelin leads to cognitive and motor dysfunction. Recent evidence suggests that changes in myelination, including both hyper- and hypo-myelination, may also play a role in numerous neurological and psychiatric diseases. Protecting myelin and promoting remyelination is thus crucial for a wide range of disorders. Oligodendrocytes (OLs) are the cells that generate myelin, and oligodendrogenesis, the creation of new OLs, continues throughout life and is necessary for myelin plasticity and remyelination. Understanding the regulation of oligodendrogenesis and myelin plasticity within disease contexts is, therefore, critical for the development of novel therapeutic targets. In our companion manuscript, we review literature demonstrating that multiple hormone classes are involved in the regulation of oligodendrogenesis under physiological conditions. The majority of hormones enhance oligodendrogenesis, increasing oligodendrocyte precursor cell differentiation and inducing maturation and myelin production in OLs. Thus, hormonal treatments present a promising route to promote remyelination. Here, we review the literature on hormonal regulation of oligodendrogenesis within the context of disorders. We focus on steroid hormones, including glucocorticoids and sex hormones, peptide hormones such as insulin-like growth factor 1, and thyroid hormones. For each hormone, we describe whether they aid in OL survival, differentiation, or remyelination, and we discuss their mechanisms of action, if known. Several of these hormones have yielded promising results in both animal models and in human conditions; however, a better understanding of hormonal effects, interactions, and their mechanisms will ultimately lead to more targeted therapeutics for myelin repair.

Background: Exercise training is a major factor in controlling type 1 diabetes mellitus (T1DM) in children. The present study aimed to assess the effect of concurrent resistance-aerobic training on selected inflammatory factors and hormones related to blood glucose homeostasis in children with T1DM. Methods: In this randomized controlled clinical trial, 40 children (with the mean age of 11.11 ± 2.29 years) were randomly assigned to an experimental (N = 20) or control group (N = 20). They underwent a 16-week training program, composed of concurrent resistance-aerobic training performed intermittently for 60 min three times a week. Before and after training, blood samples were analyzed for glucose homeostasis, selected inflammatory factors, and growth factors. Data were analyzed by paired t-test and analysis of covariance (ANCOVA) in IBM SPSS version 22. Results: The exercise training intervention reduced fasting blood sugar index (P = 0.002) and glycosylated hemoglobin significantly (P = 0.003). The growth hormone levels were increased significantly only in the experimental group (P = 0.037), whereas no significant difference was noted in the insulin-like growth factor-1 (P = 0.712). It was also found that interleukin-1β and high-sensitivity C-reactive protein did not change in the experimental or control group as compared to the pretest (P > 0.05). Conclusion: As it was shown, it seems that concurrent resistance-aerobic training may improve blood glucose homeostasis and growth hormone. Therefore, these findings may suggest the benefit from exercise training of moderate intensity in children with T1DM. Besides, we recommend undertaking further clinical trials to determine if the exercise training was effective. Trial registration: This study was registered in the Iranian Registry of Clinical Trials under the code IRCT20150531022498N30: https://en.irct.ir/trial/41031. Registered on July 26, 2019. All experiments on the participants were following the Declaration of Helsinki. [ABSTRACT FROM AUTHOR]

A 35-day trial was set to explore the effects of different dietary zinc sources on growth, insulin-like growth factor I (IGF-I) mRNA expression, meat quality, immune response, antioxidant activity, and immunohistochemistry of nuclear factor kappa B (NF-κ7B) of broiler chickens. Ross 308 broiler chicks (n = 156) were randomly assigned into four experimental groups. The G1 received the basal control diet without zinc supplementation; the G2, G3, and G4 were supplemented with zinc oxide, zinc lysine, and nano zinc oxide, respectively, at a level of 40 mg Zn/kg diet. The data revealed that nano zinc oxide linearly improved the overall growth performance parameters. Nano zinc oxide linearly elevated (P < 0.001) mRNA expression of IGF-I followed by G3. The pH value of breast muscle in G4 shows a linearly decreasing value (P < 0.001). Also, the linearly highest expressible release volume percentage and lightness (L*) value with the lowest redness (a*) value (P < 0.05) were recorded in G4 and G3. A numerical increase in the total antibody titer was recorded on the 35th day in the G3 and G4. A numerical elevation in the superoxide dismutase (SOD) and a numerical reduction in the serum malondialdehyde (MDA) were recorded in the G4. The section of the liver from G4 revealed significantly very low expression of NF-κB staining. It is concluded that nano zinc oxide is considered the more trending zinc source. It had no negative effects on the health status and can be used in broiler diet premix. [ABSTRACT FROM AUTHOR]

Adult respiratory distress syndrome (ARDS) is the leading cause of death associated with SARS-CoV-2 infection and COVID-19. IGF-1 has been implicated in ARDS, yet its role in relation to COVID-19-related lung injury has not been investigated. We hypothesize that blockage of the IGF-1 receptor (IGF-1R) mitigates lung injury and decreases the risk of death in patients COVID-19-related ARDS. Patients with fibroproliferative ARDS have been shown to have increased IGF-1 and IGF-1R staining in lung tissue specimens. Rising levels of IGF-1 in bronchioalveolar fluid (BAL) and increased IGF-1 mRNA expression in lung tissues (but declining serum IGF-1 levels) have been found in late stage ARDS compared with early lung injury. Blockage of IGF-1R decreases lung tissue damage and increases survival in bleomycin-induced as well as H1N1 influenza-related lung injury in animal models. Teprotumumab is a monoclonal antibody directed against the IGF-1R that was FDA-approved in 2020 for the treatment of Graves' orbitopathy. In order to determine if teprotumumab may reduce lung injury and death related to ARDS in the setting of COVID-19, preliminary clinical data is needed. IGF-1 levels in serum and BAL fluid must be measured in patients with COVID-19-related ARDS. Histopathology from lung samples from patients with COVID-19-related ARDS must be examined for increased expression of the IGF-1R. Once these are ascertained, and if the data support IGF-1 involvement, a randomized, placebo-controlled phase 2A trial of teprotumumab therapy in the setting of COVID-19-related ARDS and non-COVID-19-related ARDS designed to generate initial data on short-term efficacy, safety, dosing and administration should be performed.

Triple-negative breast cancer (TNBC) is an aggressive breast tumor subtype that currently lacks targeted treatment options. The role played by the insulin-like growth factor-1 (IGF-1) and its cognate receptor IGF-1R in TNBC has been reported. Nevertheless, the molecular mechanisms by which the IGF-1/IGF-1R system may contribute to TNBC progression still remains to be fully understood. By computational analysis of the vast cancer genomics information in public databases (TCGA and METABRIC), we obtained evidence that high IGF-1 or IGF-1R levels correlate with a worse clinical outcome in TNBC patients. Further bioinformatics analysis revealed that both the focal adhesion and the Hippo pathways are enriched in TNBC harboring an elevated expression of IGF-1 or IGF-1R. Mechanistically, we found that in TNBC cells, the IGF-1/IGF-1R system promotes the activation of the FAK signal transduction pathway, which in turn regulates the nuclear accumulation of YAP (yes-associated protein/yes-related protein) and the expression of its target genes. At the biological level, we found that the IGF-1/IGF-1R-FAK-YAP network cascade triggers the growth potential of TNBC cells, as evaluated in different experimental systems. Overall, our results suggest that the IGF-1/IGF-1R/FAK/YAP axis may contribute to the progression of the aggressive TNBC subtype.

Background/aimsCell migration and extracellular matrix remodeling underlie normal mammalian development and growth as well as pathologic tumor invasion. Skeletal muscle is no exception, where satellite cell migration replenishes nuclear content in damaged tissue and extracellular matrix reforms during regeneration. A key set of enzymes that regulate these processes are matrix metalloproteinases (MMP)s. The collagenase MMP-13 is transiently upregulated during muscle regeneration, but its contribution to damage resolution is unknown. The purpose of this work was to examine the importance of MMP-13 in muscle regeneration and growth in vivo and to delineate a satellite cell specific role for this collagenase.MethodsMice with total and satellite cell specific Mmp13 deletion were utilized to determine the importance of MMP-13 for postnatal growth, regeneration after acute injury, and in chronic injury from a genetic cross with dystrophic (mdx) mice. We also evaluated insulin-like growth factor 1 (IGF-1) mediated hypertrophy in the presence and absence of MMP-13. We employed live-cell imaging and 3D migration measurements on primary myoblasts obtained from these animals. Outcome measures included muscle morphology and function.ResultsUnder basal conditions, Mmp13-/- mice did not exhibit histological or functional deficits in muscle. However, following acute injury, regeneration was impaired at 11 and 14 days post injury. Muscle hypertrophy caused by increased IGF-1 was blunted with minimal satellite cell incorporation in the absence of MMP-13. Mmp13-/- primary myoblasts displayed reduced migratory capacity in 2D and 3D, while maintaining normal proliferation and differentiation. Satellite cell specific deletion of MMP-13 recapitulated the effects of global MMP-13 ablation on muscle regeneration, growth and myoblast movement.ConclusionThese results show that satellite cells provide an essential autocrine source of MMP-13, which not only regulates their migration, but also supports postnatal growth and resolution of acute damage.

The mechanism of gender disparity in cutaneous melanoma incidence remains unclear. Steroid hormones including estrogens have long been implicated in the course of melanoma, but the conclusion is controversial. Estrogen receptors (ERs) and insulin-like growth factor 1 receptor (IGF1R) show extensive crosstalk in cancer development, but how the ER/IGF1R network impacts melanoma is currently unclear. Here we studied the melanoma associations of selected SNPs from the ER/IGF1R network. Part of the International Genes, Environment, and Melanoma (GEM) cohort was used as a discovery set, and the Gene Environment Association Studies Initiative (GENEVA) dataset served as a validation set. Based on the associations with other malignant disease conditions, thirteen single nucleotide polymorphism (SNP) variants in ESR1, ESR2, IGF1, and IGF1R were selected for candidate gene association analyses. The rs1520220 in IGF1 and rs2229765 in IGF1R variants were significantly associated with melanoma risk in the GEM dataset after Benjamini-Hochberg multiple comparison correction, although they were not validated in the GENEVA set. The discrepancy may be caused by the multiple melanoma characteristics in the GEM patients. Further analysis of gender disparity was carried out for IGF1 and IGF1R SNPs in the GEM dataset. The GG phenotype in IGF1 rs1520220 (recessive model) presented an increased risk of melanoma (OR = 8.11, 95% CI: 2.20, 52.5, p = 0.006) in men but a significant opposite effect in women (OR = 0.15, 95% CI: 0.018, 0.86, p = 0.045). The AA genotype in IGF1R rs2229765 (recessive model) showed a significant protective effect in men (OR = 0.24, 95% CI: 0.07, 0.64, p = 0.008) and no effect in women. Results from the current study are warranted for further validation.

Alzheimer's disease (AD) is the main cause of dementia in the elderly. Although activation of brain insulin signaling has been shown to be neuroprotective, to preserve memory in AD models, and appears beneficial in patients, the role of insulin-like growth factor 1 (IGF1) remains incompletely understood. We found reduced active/inactive IGF1 ratio and increased IGF1R expression in postmortem hippocampal tissue from AD patients, suggesting impaired brain IGF1 signaling in AD. Active/inactive IGF-1 ratio was also reduced in the brains of mouse models of AD. We next investigated the possible protective role of IGF1 in AD models. We used a recombinant adenoviral vector, RAd-IGF1, to drive the expression of IGF1 in primary hippocampal neuronal cultures prior to exposure to AβOs, toxins that accumulate in AD brains and have been implicated in early synapse dysfunction and memory impairment. Cultures transduced with RAd-IGF1 showed decreased binding of AβOs to neurons and were protected against AβO-induced neuronal oxidative stress and loss of dendritic spines. Significantly, in vivo transduction with RAd-IGF1 blocked memory impairment caused by intracerebroventricular (i.c.v.) infusion of AβOs in mice. Our results demonstrate altered active IGF1 and IGF1R levels in AD hippocampi, and suggest that boosting brain expression of IGF1 may comprise an approach to prevent neuronal damage and memory loss in AD.

Targeted overexpression of angiotensin-converting enzyme (ACE), an amyloid-β protein degrading enzyme, to brain resident microglia and peripheral myelomonocytes (ACE10 model) substantially diminished Alzheimers-like disease in double-transgenic APPSWE/PS1ΔE9 (AD+) mice. In this study, we explored the impact of selective and transient angiotensin-converting enzyme overexpression on macrophage behaviour and the relative contribution of bone marrow-derived ACE10 macrophages, but not microglia, in attenuating disease progression. To this end, two in vivo approaches were applied in AD+ mice: (i) ACE10/GFP+ bone marrow transplantation with head shielding; and (ii) adoptive transfer of CD115+-ACE10/GFP+ monocytes to the peripheral blood. Extensive in vitro studies were further undertaken to establish the unique ACE10-macrophage phenotype(s) in response to amyloid-β1-42 fibrils and oligomers. The combined in vivo approaches showed that increased cerebral infiltration of ACE10 as compared to wild-type monocytes (∼3-fold increase; P < 0.05) led to reductions in cerebral soluble amyloid-β1-42, vascular and parenchymal amyloid-β deposits, and astrocytosis (31%, 47-80%, and 33%, respectively; P < 0.05-0.0001). ACE10 macrophages surrounded brain and retinal amyloid-β plaques and expressed 3.2-fold higher insulin-like growth factor-1 (P < 0.01) and ∼60% lower tumour necrosis factor-α (P < 0.05). Importantly, blood enrichment with CD115+-ACE10 monocytes in symptomatic AD+ mice resulted in pronounced synaptic and cognitive preservation (P < 0.05-0.001). In vitro analysis of macrophage response to well-defined amyloid-β1-42 conformers (fibrils, prion rod-like structures, and stabilized soluble oligomers) revealed extensive resistance to amyloid-β1-42 species by ACE10 macrophages. They exhibited 2-5-fold increased surface binding to amyloid-β conformers as well as substantially more effective amyloid-β1-42 uptake, at least 8-fold higher than those of wild-type macrophages (P < 0.0001), which were associated with enhanced expression of surface scavenger receptors (i.e. CD36, scavenger receptor class A member 1, triggering receptor expressed on myeloid cells 2, CD163; P < 0.05-0.0001), endosomal processing (P < 0.05-0.0001), and ∼80% increased extracellular degradation of amyloid-β1-42 (P < 0.001). Beneficial ACE10 phenotype was reversed by the angiotensin-converting enzyme inhibitor (lisinopril) and thus was dependent on angiotensin-converting enzyme catalytic activity. Further, ACE10 macrophages presented distinct anti-inflammatory (low inducible nitric oxide synthase and lower tumour necrosis factor-α), pro-healing immune profiles (high insulin-like growth factor-1, elongated cell morphology), even following exposure to Alzheimers-related amyloid-β1-42 oligomers. Overall, we provide the first evidence for therapeutic roles of angiotensin-converting enzyme-overexpressing macrophages in preserving synapses and cognition, attenuating neuropathology and neuroinflammation, and enhancing resistance to defined pathognomonic amyloid-β forms.

Insulin-like growth factors (IGFs) and insulin-like growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural and sociodemographic factors may play a role in cancer risk via IGF signalling, we examined the cross-sectional associations of these exposures with circulating concentrations of IGFs (IGF-I and IGF-II) and IGFBPs (IGFBP-1, IGFBP-2 and IGFBP-3). The Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset includes individual participant data from 16,024 male controls (i.e. without prostate cancer) aged 22-89 years from 22 prospective studies. Geometric means of protein concentrations were estimated using analysis of variance, adjusted for relevant covariates. Older age was associated with higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGF-I, IGF-II and IGFBP-3. Higher body mass index was associated with lower concentrations of IGFBP-1 and IGFBP-2. Taller height was associated with higher concentrations of IGF-I and IGFBP-3 and lower concentrations of IGFBP-1. Smokers had higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGFBP-3 than nonsmokers. Higher alcohol consumption was associated with higher concentrations of IGF-II and lower concentrations of IGF-I and IGFBP-2. African Americans had lower concentrations of IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 and Hispanics had lower IGF-I, IGF-II and IGFBP-3 than non-Hispanic whites. These findings indicate that a range of anthropometric, behavioural and sociodemographic factors are associated with circulating concentrations of IGFs and IGFBPs in men, which will lead to a greater understanding of the mechanisms through which these factors influence cancer risk.

Tissue Doppler echocardiography (TDI) is a convenient method to detect cardiac dysfunction in the infants of diabetic mothers (IDMs). Umbilical cord serum insulin-like growth factor-1 (IGF-1) is known to be higher in IDMs. We aimed to determine whether there is a relation between diastolic functions examined by TDI and cord serum IGF-1 levels of IDMs. Cord serum IGF-1 levels of 32 IDMs and 22 healthy infants were measured. The cardiac functions of the infants were evaluated by M-Mode and TDI. For statistical analysis, Mann–Whitney U and Spearman correlation tests were used for continuous variables, and the chi-square test was used for categorical variables. The cord serum IGF-1 levels of the IDMs were higher (p = 0.000). The left ventricle (LV) e', LVa', LV e'/a', and LV Tei index, indicating left ventricular diastolic dysfunction in IDMs, were detected (LV e' p = 0.016; LV a' p = 0.003; LV e'/ a' p = 0.000; LV Tei index p = 0.023). IDMs' cord serum IGF-1 levels were found weakly correlated with the interventricular septum (IVS) and left ventricle posterior wall (LVPW) thicknesses in M-Mode and LV e' and LV e'/a' in TDI (IVS r = 0.357, p = 0.008; LVPW r = 0.289, p = 0.034; LV e' r = 0.297, p = 0.029; LV e'/ a' r = 0.031, p = 0.014). Conclusion: To our knowledge, this is the first study to examine the relationship between cord serum IGF-1 levels and diastolic functions of IDMs assessed by TDI. A weak correlation was found between IGF-1 levels and IVS and LVPW thicknesses in M-Mode and LV e' and LV e'/a' parameters in TDI, revealing diastolic dysfunction in IDMs. What is Known: • The umbilical cord blood serum IGF-1 level of IDMs is higher than in infants of healthy mothers. • Diastolic dysfunction is a well-studied and frequently observed consequence in IDMs. What is New: • This is the first study to examine the relationship between cord serum IGF-1 levels and diastolic functions of IDMs assessed by TDI. • A weak correlation was detected between the median cord serum IGF-1 level of IDMs and the median values of IVS, LVPW, LV e', LV a', LV e'/a' ratio. [ABSTRACT FROM AUTHOR]

As major depressive disorder (MDD) is such a diverse condition, there are currently no clear ways for determining its severity, endophenotype, or therapy response. The distinctive nature of depression, the variability of analysis in literature and the large number of conceptually complicated biomarkers are some of the many reasons for the lack of progress. Markers are involved in the process of neurotrophic, metabolic, and inflammation as well as neuroendocrine and neurotransmitter systems’ components. Some clinical indicators are strong enough so that can be measured using assessments of proteomic, genetic, metabolomics, neuroimaging, epigenetic and transcriptomic. Markers of oxidative stress, endocrine, inflammatory, proteomic, and growth indicators are currently among the promising biologic systems/markers identified in this analysis. This narrative review examines succinct studies which investigated cytokines of inflammatory factors, peripheral factors of development, metabolic and endocrine markers as pathophysiological biomarkers of MDD, and treatment responses. Endocrine and metabolic alterations have also been linked to MDD in various studies. So, this study summarizes all of the numerous biomarkers that are significant in the detection or treatment of MDD patients. The paper also provides an overview of various biomarkers which are important for the regulation and its effects on MDD.

IntroductionDysferlin loss-of-function mutations cause muscular dystrophy, accompanied by impaired membrane repair and muscle weakness. Growth promoting strategies including insulin-like growth factor 1 (IGF-1) could provide benefit but may cause strength loss or be ineffective. The objective of this study was to determine whether locally increased IGF-1 promotes functional muscle hypertrophy in dysferlin-null (Dysf-/- ) mice.MethodsMuscle-specific transgenic expression and postnatal viral delivery of Igf1 were used in Dysf-/- and control mice. Increased IGF-1 levels were confirmed by enzyme-linked immunosorbent assay. Testing for skeletal muscle mass and function was performed in male and female mice.ResultsMuscle hypertrophy occurred in response to increased IGF-1 in mice with and without dysferlin. Male mice showed a more robust response compared with females. Increased IGF-1 did not cause loss of force per cross-sectional area in Dysf-/- muscles.DiscussionWe conclude that increased local IGF-1 promotes functional hypertrophy when dysferlin is absent and reestablishes IGF-1 as a potential therapeutic for dysferlinopathies.

ScopeThe action of brain disorders on peripheral metabolism is poorly understood. The impact of traumatic brain injury (TBI) on peripheral organ function and how TBI effects can be influenced by the metabolic perturbation elicited by fructose ingestion are studied.Methods and resultsIt is found that TBI affects glucose metabolism and signaling proteins for insulin and growth hormone in the liver; these effects are exacerbated by fructose ingestion. Fructose, principally metabolized in the liver, potentiates the action of TBI on hepatic lipid droplet accumulation. Studies in isolated cultured hepatocytes identify GH and fructose as factors for the synthesis of lipids. The liver has a major role in the synthesis of lipids used for brain function and repair. TBI results in differentially expressed genes in the hypothalamus, primarily associated with lipid metabolism, providing cues to understand central control of peripheral alterations. Fructose-fed TBI animals have elevated levels of markers of inflammation, lipid peroxidation, and cell energy metabolism, suggesting the pro-inflammatory impact of TBI and fructose in the liver.ConclusionResults reveal the impact of TBI on systemic metabolism and the aggravating action of fructose. The hypothalamic-pituitary-growth axis seems to play a major role in the regulation of the peripheral TBI pathology.