Insulin-like Growth Factor-1 Supplementation Research Articles

Insulin-like growth factor-1 effects on kidney development in preterm piglets.

Preterm birth disrupts fetal kidney development, potentially leading to postnatal acute kidney injury. Preterm infants are deficient in insulin-like growth factor 1 (IGF-1), a growth factor that stimulates organ development. By utilizing a preterm pig model, this study investigated whether IGF-1 supplementation enhances preterm kidney maturation. Cesarean-delivered preterm pigs were treated systemically IGF-1 or vehicle control for 5, 9 or 19 days after birth. Blood, urine, and kidney tissue were collected for biochemical, histological and gene expression analyses. Age-matched term-born pigs were sacrificed at similar postnatal ages and served as thereference group. Compared with term pigs, preterm pigs exhibited impaired kidney maturation, as indicated by analyses of renal morphology, histopathology, and inflammatory and injury markers. Supplementation with IGF-1 reduced signs of kidney immaturity, particularly in the first week of life, as indicated by improved morphology, upregulated expression of key developmental genes, reduced severity and incidence of microscopic lesions, and decreased levels of inflammatory and injury markers. No association was seen between the symptoms of necrotizing enterocolitis and kidney defects. Preterm birth in pigs impairs kidney maturation and exogenous IGF-1 treatment partially reverses this impairment. Early IGF-1 supplementation could support the development of preterm kidneys. Preterm birth may disrupt kidney development in newborns, potentially leading to morphological changes, injury, and inflammation. Preterm pigs have previously been used as models for preterm infants, but not for kidney development. IGF-1 supplementation promotes kidney maturation and alleviates renal impairments in the first week of life in preterm pigs. IGF-1 may hold potential as a supportive therapy for preterm infants sensitive to acute kidney injury.

Gut development following insulin-like growth factor-1 supplementation to preterm pigs

BackgroundReduced insulin-like growth factor-1 (IGF-1) levels may contribute to impaired organ development in preterm infants. Using preterm pigs as a model, we hypothesized that IGF-1 supplementation improves health and gut development during the first three weeks of life.MethodsFirst, clinical and organ endpoints were compared between artificially-reared, cesarean-delivered preterm pigs and vaginally-delivered, sow-reared term pigs at 5, 9 and 19 days. Next, preterm pigs were treated with recombinant human IGF-1 for 19 days (2.25 mg/kg/day, systemically).ResultsRelative to term pigs, preterm pigs had lower body weight, fat, bone contents, relative weights of liver and spleen and a longer and thinner intestine at 19 days. Preterm birth reduced intestinal villi heights and peptidase activities, but only at 5 and 9 days. In preterm pigs, IGF-1 reduced mortality primarily occurring from gastrointestinal complications and with a tendency towards salvaging smaller pigs. IGF-1 supplementation also increased spleen and kidney weights, small intestine length and maltase to lactase activity, reflecting gut maturation.ConclusionPreterm birth affects body composition and gut maturation in the first 1–2 weeks, but differences are marginal thereafter. Supplemental IGF-1 may improve gut health in pigs and infants in the first few weeks after preterm birth.ImpactInsulin-like growth factor 1 (IGF-1) supplementation may improve gut health and development in prematurity, but whether the effects are sustained beyond the immediate postnatal period is unclear.In preterm pigs, the prematurity effects on IGF-1 and gut health deficiencies are most pronounced during the first week of life and diminishes thereafter.In preterm pigs, IGF-1 supplementation beyond the first week of life reduced mortality.The present study provides evidence of a sustained effect of IGF-1 supplementation on the gastrointestinal tract after the immediate postnatal period.

Insulin-like growth factor 1 associated with altered immune responses in preterm infants and pigs

BackgroundPreterm infants show low blood levels of insulin-like growth factor 1 (IGF-1), known to be negatively correlated with Interleukin-6 (IL-6). We hypothesized that circulating IGF-1 is associated with systemic immune-markers following preterm birth and that exogenous IGF-1 supplementation modulates immune development in preterm pigs, used as model for preterm infants.MethodsPlasma levels of IGF-1 and 29 inflammatory markers were measured in very preterm infants (n = 221). In preterm pigs, systemic immune development, assessed by in vitro challenge, was compared between IGF-1 treated (2.25 mg/kg/day) and control animals.ResultsPreterm infants with lowest gestational age and birth weight showed the lowest IGF-1 levels, which were correlated not only with IL-6, but a range of immune-markers. IGF-1 supplementation to preterm pigs reduced plasma IL-10 and Interferon-γ (IFN-γ), IL-2 responses to challenge and reduced expression of genes related to Th1 polarization. In vitro addition of IGF-1 (100 ng/mL) further reduced the IL-2 and IFN-γ responses but increased IL-10 response.ConclusionsIn preterm infants, plasma IGF-1 correlated with several immune markers, while supplementing IGF-1 to preterm pigs tended to reduce Th1 immune responses. Future studies should document whether IGF-1 supplementation to preterm infants affects immune development and sensitivity to infection.ImpactSupplementation of insulin-like growth factor 1 (IGF-1) to preterm infants has been proposed to promote postnatal growth, but its impact on the developing immune system is largely unknown.In a cohort of very preterm infants, low gestational age and birth weight were the primary predictors of low plasma levels of IGF-1, which in turn were associated with plasma immune markers. Meanwhile, in immature preterm pigs, experimental supplementation of IGF-1 reduced Th1-related immune responses in early life.Supplementation of IGF-1 to preterm infants may affect the developing immune system, which needs consideration when evaluating overall impact on neonatal health.

Insulin-like growth factor 1 supplementation supports motor coordination and affects myelination in preterm pigs.

Preterm infants have increased risk of impaired neurodevelopment to which reduced systemic levels of insulin-like growth factor 1 (IGF-1) in the weeks after birth may play a role. Hence, we hypothesized that postnatal IGF-1 supplementation would improve brain development in preterm pigs, used as a model for preterm infants. Preterm pigs delivered by cesarean section received recombinant human IGF-1/IGF binding protein-3 complex (rhIGF-1/rhIGFBP-3, 2.25 mg/kg/day) or vehicle from birth to postnatal day 19. Motor function and cognition were assessed by monitoring of in-cage and open field activities, balance beam test, gait parameters, novel object recognition and operant conditioning tests. Collected brains were subject to magnetic resonance imaging (MRI), immunohistochemistry, gene expression analyses and protein synthesis measurements. The IGF-1 treatment increased cerebellar protein synthesis rates (both in vivo and ex vivo). Performance in the balance beam test was improved by IGF-1 but not in other neurofunctional tests. The treatment decreased total and relative caudate nucleus weights, without any effects to total brain weight or grey/white matter volumes. Supplementation with IGF-1 reduced myelination in caudate nucleus, cerebellum, and white matter regions and decreased hilar synapse formation, without effects to oligodendrocyte maturation or neuron differentiation. Gene expression analyses indicated enhanced maturation of the GABAergic system in the caudate nucleus (decreased NKCC1:KCC2 ratio) with limited effects in cerebellum or hippocampus. Supplemental IGF-1 during the first three weeks after preterm birth may support motor function by enhancing GABAergic maturation in the caudate nucleus, despite reduced myelination. Supplemental IGF-1 may support postnatal brain development in preterm infants, but more studies are required to identify optimal treatment regimens for subgroups of very or extremely preterm infants.

Insulin-like growth factor-1 supplementation promotes brain maturation in preterm pigs.

Very preterm infants show low levels of insulin-like growth factor-1 (IGF-1), which is associated with postnatal growth restriction and poor neurological outcomes. It remains unknown whether supplemental IGF-1 may stimulate neurodevelopment in preterm neonates. Using cesarean-delivered preterm pigs as a model of preterm infants, we investigated the effects of supplemental IGF-1 on motor function and regional and cellular brain development. Pigs were treated with 2.25 mg/kg/day of recombinant human IGF-1/IGF binding protein 3 complex from birth until Day 5 or 9 before collection of brain samples for quantitative immunohistochemistry (IHC), RNA-seq and qPCR analyses. Brain protein synthesis was measured using in vivo labeling with [2H5] phenylalanine. We showed that the IGF-1 receptor was widely distributed in the brain and largely coexisted with immature neurons. Region-specific quantification of IHC labeling showed that IGF-1 treatment promoted neuronal differentiation, increased subcortical myelination, and attenuated synaptogenesis in a region- and time-dependent manner. The expression levels of genes involved in neuronal and oligodendrocyte maturation, angiogenic and transport functions were altered, reflecting enhanced brain maturation in response to IGF-1 treatment. Cerebellar protein synthesis was increased by 19% at Day 5 and 14% at Day 9 after IGF-1 treatment. Treatment had no effect on Iba1-positive microglia or regional brain weights and did not affect motor development or the expression of genes related to IGF-1 signaling. In conclusion, the data show that supplemental IGF-1 promotes brain maturation in newborn preterm pigs. The results provide further support for IGF-1 supplementation therapy in the early postnatal period in preterm infants.SIGNIFICANCE STATEMENTDeficiency of systemic insulin-like growth factor-1 (IGF-1) is associated with delayed neurological development in preterm infants. Here, we show that the IGF-1 receptor is primarily expressed in immature neurons in the developing brain of the translational preterm pig model. Supplementation with IGF-1 accelerates neuron differentiation in the hippocampus and promotes myelination in subcortical white matter regions in a time-dependent way. Furthermore, systemic IGF-1 supplementation stimulates cerebral protein synthesis. Our study suggests that IGF-1 therapy in the early postnatal period might be supportive for neurodevelopment in preterm infants.

Insulin-like Growth Factor-1 Prevents Hypoxia/Reoxygenation-Induced White Matter Injury in Sickle Cell Mice

Occlusion of cerebral blood vessels causes acute cerebral hypoxia-an important trigger of ischemic white matter injury and stroke in sickle cell disease (SCD). While chronic hypoxia triggers compensatory neuroprotection via insulin-like growth factor-1 (IGF-1) and hypoxia inducible factor-1α (HIF-1α), severe bouts of acute hypoxia and subsequent restoration of blood flow (hypoxia/reoxygenation, H/R) overwhelm compensatory mechanisms and cause neuroaxonal damage-identified as white matter lesions-in the brain. The neuroprotective role of IGF-1 in the pathogenesis of white matter injury in SCD has not been investigated; however, it is known that systemic IGF-1 is reduced in individuals with SCD. We hypothesized that IGF-1 supplementation may prevent H/R-induced white matter injury in SCD. Transgenic sickle mice homozygous for human hemoglobin S and exposed to H/R developed white matter injury identified by elevated expression of non-phosphorylated neurofilament H (SMI32) with a concomitant decrease in myelin basic protein (MBP) resulting in an increased SMI32/MBP ratio. H/R-challenge also lowered plasma and brain IGF-1 expression. Human recombinant IGF-1 prophylaxis significantly induced HIF-1α and averted H/R-induced white matter injury in the sickle mice compared to vehicle-treated mice. The expression of the IGF-1 binding proteins IGFBP-1 and IGFBP-3 was elevated in the IGF-1-treated brain tissue indicating their potential role in mediating neuroprotective HIF-1α signaling. This study provides proof-of-concept for IGF-1-mediated neuroprotection in SCD.

Clinical outcome and gut development after insulin-like growth factor-1 supplementation to preterm pigs.

BackgroundElevation of circulating insulin-like growth factor-1 (IGF-1) within normal physiological levels may alleviate several morbidities in preterm infants but safety and efficacy remain unclear. We hypothesized that IGF-1 supplementation during the first 1–2 weeks after preterm birth improves clinical outcomes and gut development, using preterm pigs as a model for infants.MethodsPreterm pigs were given vehicle or recombinant human IGF-1/binding protein-3 (rhIGF-1, 2.25 mg/kg/d) by subcutaneous injections for 8 days (Experiment 1, n = 34), or by systemic infusion for 4 days (Experiment 2, n = 19), before collection of blood and organs for analyses.ResultsIn both experiments, rhIGF-1 treatment increased plasma IGF-1 levels 3-4 fold, reaching the values reported for term suckling piglets. In Experiment 1, rhIGF-1 treatment increased spleen and intestinal weights without affecting clinical outcomes like growth, blood biochemistry (except increased sodium and gamma-glutamyltransferase levels), hematology (e.g., red and white blood cell populations), glucose homeostasis (e.g., basal and glucose-stimulated insulin and glucose levels) or systemic immunity variables (e.g., T cell subsets, neutrophil phagocytosis, LPS stimulation, bacterial translocation to bone marrow). The rhIGF-1 treatment increased gut protein synthesis (+11%, p < 0.05) and reduced the combined incidence of all-cause mortality and severe necrotizing enterocolitis (NEC, p < 0.05), but had limited effects on intestinal morphology, cell proliferation, cell apoptosis, brush-border enzyme activities, permeability and levels of cytokines (IL-1β, IL-6, IL-8). In Experiment 2, rhIGF-1 treated pigs had reduced blood creatine kinase, creatinine, potassium and aspartate aminotransferase levels, with no effects on organ weights (except increased spleen weight), blood chemistry values, clinical variables or NEC.ConclusionPhysiological elevation of systemic IGF-1 levels for 8 days after preterm birth increased intestinal weight and protein synthesis, spleen weight and potential overall viability of pigs, without any apparent negative effects on recorded clinical parameters. The results add further preclinical support for safety and efficacy of supplemental IGF-1 to hospitalized very preterm infants.

Transplantation of IGF-1-induced BMSC-derived NPCs promotes tissue repair and motor recovery in a rat spinal cord injury model

Bone marrow-derived mesenchymal stem cells (BMSCs) have therapeutic potential for spinal cord injury (SCI). We have shown that insulin-like growth factor 1 (IGF-1) enhances the cellular proliferation and survivability of BMSCs-derived neural progenitor cells (NPCs) by downregulating miR-22-3p. However, the functional application of BMSCs-derived NPCs has not been investigated fully. In this study, we demonstrate that knockdown of endogenous miR-22-3p in BMSCs-derived NPCs upregulates Akt1 expression, leading to enhanced cellular proliferation. RNASeq analysis reveals 3,513 differentially expressed genes in NPCs. The upregulated genes in NPCs enrich the gene ontology term associated with nervous system development. Terminally differentiated NPCs generate cells with neuronal-like morphology and phenotypes. Transplantation of NPCs in the SCI rat model results in better recovery in locomotor and sensory functions 4 weeks after transplantation. Altogether, the result of this study demonstrate that NPCs derived with IGF-1 supplementation could be differentiated into functional neural lineage cells and are optimal for stem cell therapy in SCI.

Engineered artificial articular cartilage made of decellularized extracellular matrix by mechanical and IGF-1 stimulation.

Cartilage engineering has the potential to overcome clinical deficiency in joint disorders. Decellularized extracellular matrix (dECM) has great biocompatibility and bioactivity and can be considered an appropriate natural scaffold for tissue engineering applications. Both insulin-like growth factor-1 (IGF-1) and mechanical compression stimulate the production of cartilage ECM, modulate mechanical properties, and gene expression. The current investigation aimed to fabricate a high-quality moldable artificial cartilage by exposing the chondrocytes in biomimicry conditions using cartilage dECM, IGF-1, and mechanical stimulations. In this study, an ad hoc bioreactor was designed to apply dynamic mechanical stimuli (10% strain, 1Hz) on chondrocyte-laden cartilage dECM-constructs with/without IGF-1 supplementation for 2weeks, 3h/day. Our data revealed that mechanical stimulation had no adverse effect on cell viability and proliferation. However, it elevated the expression of chondrogenic markers such as collagen type II (COL2A1), aggrecan (ACAN), and proteoglycan-4 (PRG-4), and reduced the expression of matrix metalloproteinase-3 (MMP-3). Mechanical stimulation also promoted higher newly formed glycosaminoglycan (GAG) and produced more aligned fibers that can be responsible for higher Young's modulus of the engineered construct. Even though IGF-1 demonstrated some extent of improvement in developing neocartilage, it was not as effective as mechanical stimulation. Neither IGF-1 nor compression elevated the collagen type I expression. Compression and IGF-1 showed a synergistic impact on boosting the level of COL2A1 but not the other factors. In conclusion, mechanical stimulation on moldable cartilage dECM can be considered a good technique to fabricate artificial cartilage with higher functionality.

Effects of gonadotropins, 11-ketotestosterone, and insulin-like growth factor-1 on target gene expression and growth of previtellogenic oocytes from shortfinned eels, Anguilla australis, in vitro.

Pituitary gonadotropins, metabolic hormones, and sex steroids are known factors affecting the advanced stages of ovarian development in teleost fish. However, the effects of these hormones and of the interactions between them on the growth of previtellogenic ovarian follicles are not known. In order to address this void in understanding, previtellogenic ovarian fragments from eel, Anguilla australis, were incubated in vitro with recombinant Japanese eel follicle-stimulating hormone (rec-Fsh), human chorionic gonadotropin (hCG), or 11-ketotestosterone (11-KT) in the presence or absence of recombinant human insulin-like growth factor-1 (IGF1). The results of long-term in vitro culture (21days) demonstrated that rec-Fsh and 11-KT, rather than hCG, caused significant increases in the diameter of previtellogenic oocytes. Meanwhile, only 11-KT induced a significant increase in lipid accumulation. Moreover, a greater effect on oocyte growth was observed when IGF1 supplementation was combined with 11-KT rather than with rec-Fsh or hCG. For short-term culture (24h), treatment with 11-KT in the presence or absence of IGF1 had no significant effects on mRNA levels of target genes (lhr, cyp19, cyp11b, lpl, and ldr) except for upregulation of fshr. There were no significant effects of rec-Fsh on expression of any target gene, whereas hCG downregulated the expression of these genes. There was no evidence for any interaction between the gonadotropins and IGF1 that resulted in growth of previtellogenic oocytes. Taken together, these results suggest that hormones from both the reproductive and the metabolic axes regulate the growth of previtellogenic oocytes in Anguilla australis.

IGF-1 Signaling Regulates Mitochondrial Remodeling during Myogenic Differentiation.

Skeletal muscle is essential for locomotion, metabolism, and protein homeostasis in the body. Mitochondria have been considered as a key target to regulate metabolic switch during myo-genesis. The insulin-like growth factor 1 (IGF-1) signaling through the AKT/mammalian target of rapamycin (mTOR) pathway has a well-documented role in promoting muscle growth and regeneration, but whether it is involved in mitochondrial behavior and function remains un-examined. In this study, we investigated the effect of IGF-1 signaling on mitochondrial remodeling during myogenic differentiation. The results demonstrated that IGF-1 signaling stimulated mitochondrial biogenesis by increasing mitochondrial DNA copy number and expression of genes such as Cox7a1, Tfb1m, and Ppargc1a. Moreover, the level of mitophagy in differentiating myoblasts elevated significantly with IGF-1 treatment, which contributed to mitochondrial turnover. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) were identified as two key mediators of IGF-1-induced mitochondrial biogenesis and mitophagy, respectively. In addition, IGF-1 supplementation could alleviate impaired myoblast differentiation caused by mitophagy deficiency, as evidenced by increased fusion index and myosin heavy chain expression. These findings provide new insights into the role of IGF-1 signaling and suggest that IGF-1 signaling can serve as a target for the research and development of drugs and nutrients that support muscle growth and regeneration.

The effect of IGF-1 plasma concentration on COVID-19 severity

BackgroundThe severity and fatality of Coronavirus disease 2019 (COVID-19) infection are not the same in the infected population. The host immune response and Immune-stimulating factors appear to play a role in COVID-19 infection outcome. insulin-like growth factor-1 (IGF-1) affects the immune system by controlling the endocrine system. Recently, the effect of IGF-1 levels on COVID-19 prognosis has been considered. ObjectiveTo investigate the difference between circulating IGF-1 and inflammatory cytokines concentration among COVID-19 patients, infected patients admitted to the Intensive Care Unit (ICU) (n = 40; 35 ± 5 y) and patients with mild cases of COVID-19 (n = 40; 35 ± 5 y) were screened prior to participation in the study. There was no significant difference between the groups in terms of gender and preexisting inflammatory state. Collected samples were evaluated by ELISA for IGF-1 and IL-6. ResultsThe study outcomes included a significant decrease in IGF-1 and an increase in IL-6 serum concentration, as an inflammatory marker, for infected patients admitted to the Intensive Care Unit (ICU) (P ≤ 0.001). Finally, there was a significant increase in the IGF-1 and a decrease in the IL-6 serum concentration of hospitalized patients. Discussionit appears that inflammatory cytokines (IL-6) serum concentration in the severe form of corona virus-based infections causes reduced defenses because of suppressed IGF-1. ConclusionsOur findings show that lower IGF-1 concentrations are associated with a Severe form of COVID-19 disease. It seems, IGF-1 supplementation or anti-inflammatory treatment rescued the severe form of COVID-19 infection. Further studies are required to determine how to design COVID-19 therapeutic strategies targeting the IGF-1 pathway.

IGF-1 supplementation in semen affects mitochondrial functional and calcium status of buffalo sperm following cryopreservation

This study was designed to examine the effects of seminal insulin-like growth factor-1 (IGF-1) supplementation on structural and functional properties of buffalo sperm post cryopreservation. Semen ejaculates from buffalo bulls (n = 6) were proportioned into four aliquots and diluted with egg yolk-based extender. Prior to equilibration, IGF-1 was added to extender as four treatments: group IGF0 (no supplementation), IGF150 (150 ng/mL), IGF250 (250 ng/mL) and IGF350 (350 ng/mL). The extended semen was transferred into 0.25 mL mini-straws, equilibrated (4 °C at 4 h), and cryopreserved. Total sperm motility was greater (P < 0.05) when there was the IGF150 treatment compared with values for other groups. Furthermore, with the IGF150 treatment there was the least and greatest (P < 0.05) mitochondrial superoxide status and membrane potential, respectively. Similarly, with the IGF150 treatment there was a greater (P < 0.05) sperm membrane integrity with a lesser (P < 0.05) calcium status compared to values for the other groups. In conclusion, seminal IGF-1 supplementation affects the structural and functional properties of buffalo sperm following cryopreservation.

Compromised IGF signaling causes caspase-6 activation in Huntington disease

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expansion of a polyglutamine repeat in the huntingtin (HTT) protein. Aberrant activation of caspase-6 and cleavage of mutant HTT generating the toxic N-terminal 586 HTT fragment are important steps in the pathogenesis of HD. Similarly, alterations in the insulin-like growth factor 1 (IGF-1) signaling pathway have been implicated in the disease as a result of decreased plasma IGF-1 levels in HD patients. In addition, two recent studies have demonstrated therapeutic benefit of IGF-1 treatment in mouse models of HD. Since IGF-1 promotes pro-survival pathways, we examined the relationship between IGF-1 signaling and aberrant caspase-6 activation in HD. Using immortalized mouse striatal cells expressing wild-type (STHdhQ7) or mutant HTT (STHdhQ111), we show that reduced levels of IGF-1 are associated with enhanced activation of caspase-6, increased cell death, and mutant HTT cleavage in a cellular stress paradigm. We demonstrate that IGF-1 supplementation reverses these effects and lowers the level of the toxic 586 HTT fragment. In addition, transcriptional analysis in the R6/2 HD transgenic mouse model demonstrated that the IGF-1 signaling system is dysregulated at multiple levels in several tissues including liver, muscle, and brain. Among these changes, we found increased expression of IGF-1 binding protein 3 (IGFBP-3), which may further reduce the bioavailability of IGF-1 as a consequence of increased IGF-1 binding. Our findings thus suggest that the therapeutic benefit of IGF-1 supplementation in HD may be significantly improved if other defects in the IGF-1 signaling pathway are corrected concurrently.

Insulin-Independent Reversal of Type-1 Diabetes Following Transplantation of Adult Brown Adipose Tissue Supplemented With IGF-1.

Background.As our previous publications show, it is feasible to reverse type 1 diabetes (T1D) without insulin in multiple mouse models, through transplantation of embryonic brown adipose tissue (BAT) in the subcutaneous space. Embryonic BAT transplants result in rapid and long-lasting euglycemia accompanied by decreased inflammation and regenerated healthy white adipose tissue, with no detectable increase in insulin. To translate this approach to human patients, it is necessary to establish practical alternatives for embryonic tissue. Adult adipose tissue transplants or BAT-derived stem cell lines alone fail to reverse T1D. A likely reason is transplant failure resulting from lack of growth factors abundant in embryonic tissue. Adding growth factors may enable transplants to survive and vascularize as well as stimulate adipogenesis and decrease inflammation in the surrounding host tissue. Previous data points to insulin like growth factor 1 (IGF-1) as the most likely candidate. Embryonic BAT abundantly expresses IGF-1, and embryonic BAT transplant recipients exhibit increased plasma levels of IGF-1. Therefore, we tested the ability of temporary administration of exogenous IGF-1 to enable adult BAT transplants to correct T1D.Methods.Fresh BAT from healthy adult CB7BL/6 donors were transplanted in the subcutaneous space of hyperglycemic nonobese diabetic recipients. Exogenous IGF-1 was administered daily for a week following transplant, at 100 µg/kg SC.Results.Adult BAT transplants with IGF-1 supplementation produced rapid long-lasting euglycemia at a 57% success rate, in contrast with no recovery in the control groups who received adult BAT alone, IGF-1 alone, or no treatment.Conclusions.Temporary supplementation with IGF-1 enables adult BAT transplants to correct T1D phenotypes independent of insulin, providing a possible route to translate this treatment to human patients.

Somatotropic Axis Dysfunction in Non-Alcoholic Fatty Liver Disease: Beneficial Hepatic and Systemic Effects of Hormone Supplementation

Background: Somatotropic axis dysfunction associated with non-alcoholic fatty liver disease (NAFLD) has potential multisystemic detrimental effects. Here, we analysed the effects of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) supplementation on liver histology, adipokine profile and muscle function in an NAFLD model. Methods: C57BL/6 mice were fed with a high fat diet (HFD) for 12 weeks and were separated into three groups treated for 4 weeks with: (1) High fat diet (HFD) (n = 10); (2) HFD + GH 9 μg/g/d (n = 10); (3) HFD + IGF-1 0.02 µg/g/d (n = 9). A control group fed a chow diet was included (n = 6). Liver histology, liver triglycerides content, serum alanine aminotransferase (ALT) activity, adiponectin and leptin serum levels, in vivo muscle strength, tetanic force and muscle fibre cross-sectional area (CSA) were measured. Results: HFD + GH and HFD + IGF-1 groups showed significantly lower ALT activity compared to HFD (p < 0.01). Liver triglyceride content in HFD + GH was decreased compared to HFD (p < 0.01). Histologic steatosis score was increased in HFD and HFD + GH group (p < 0.01), whereas HFD + IGF-1 presented no difference compared to the chow group (p = 0.3). HFD + GH group presented lower serum leptin and adiponectin levels compared to HFD. GH and IGF-1 supplementation therapy reverted HFD-induced reduction in muscle strength and CSA (sarcopenia). Conclusions: GH and IGF-1 supplementation induced significant improvement in liver steatosis, aminotransferases and sarcopenia in a diet-induced NAFLD model.

Enhancing engineered vascular networks in vitro and in vivo: The effects of IGF1 on vascular development and durability

Creation of functional, durable vasculature remains an important goal within the field of regenerative medicine. Engineered biological vasculature has the potential to restore or improve human tissue function. We hypothesized that the pleotropic effects of insulin-like growth factor 1 (IGF1) would enhance the engineering of capillary-like vasculature. The impact of IGF1 upon vasculogenesis was examined in in vitro cultures for a period of up to 40days and as subcutaneous implants within immunodeficient mice. Co-cultures of human umbilical vein endothelial cells and human bone marrow-derived mesenchymal stem cells in collagen-fibronectin hydrogels were supplemented with either recombinant IGF1 protein or genetically engineered cells to provide sustained IGF1. Morphometric analysis was performed on the vascular networks that formed in four concentrations of IGF1. IGF1 supplementation significantly enhanced de novo vasculogenesis both in vitro and in vivo. Effects were long-term as they lasted the duration of the study period, and included network density, vessel length, and diameter. Bifurcation density was not affected. However, the highest concentrations of IGF1 tested were either ineffective or even deleterious. Sustained IGF1 delivery was required in vivo as the inclusion of recombinant IGF1 protein had minimal impact. IGF1 supplementation can be used to produce neovasculature with significantly enhanced network density and durability. Its use is a promising methodology for engineering de novo vasculature to support regeneration of functional tissue.

Effect of human milk formula with bovine colostrum supplementation on bone mineral density in infant cynomolgus macaques.

Insulin-like growth factor 1 (IGF1) is a regulator of human growth during infancy and childhood, known to promote bone and muscle growth as well as lipid accumulation. This study aimed to investigate the effects of formula milk with or without IGF1 supplementation (in the form of pure IGF1 or bovine colostrum) on growth and body composition in infant cynomolgus macaques during the first 6 months of life. Three groups of infants were nursery-reared and received formula milk with or without IGF1 or bovine colostrum supplementation for 4 months, and a fourth group consisting of breast-fed infants was included for comparison (n=6 for each group). Ranked-based analysis of covariance was used to detect differences between adjusted means for sex. No differences in weight, height, fat mass, and fat-free mass could be detected between groups. However, bone mineral density (BMD) was significantly different between groups at the end of formula feeding. Infants that received bovine colostrum supplementation displayed higher mean BMD than infants of all other groups, with no differences between the latter three groups. In conclusion, our results suggest that supplementation with bovine colostrum can enhance BMD in formula-fed infants, an effect that apparently does not depend on IGF1. Bovine colostrum supplementation could be beneficial for long-term bone health in infants with suboptimal bone growth.

MEK/ERK signaling is involved in the role of VEGF and IGF1 in cardiomyocyte differentiation of mouse adipose tissue-derived stromal cells

BackgroundWe found that mouse brown adipose tissue-derived stromal cells (BATDCs), but not white adipose tissue-derived stromal cells (WATDCs), could spontaneously differentiate into cardiomyocyte-like cells in a simple culture medium. This study would find out some critical trophic factors that were responsible for such difference in differentiation, and further determine the involved signaling pathway. Methods and resultsThe cardiomyocyte differentiation capacity of cells was identified by morphological observations, immunofluorescence staining, and evaluation of expression of cardiomyocyte specific markers. The amount of vascular endothelial growth factor (VEGF) and insulin-like growth factor 1 (IGF1) secreted by cells was determined by ELISA analysis. Results indicated that BATDCs secreted higher levels of VEGF and IGF1 than WATDCs. Supplementation of BATDCs with antibodies against VEGF receptor Flt-1 or IGF1 receptor Igf-1rα significantly suppressed the cardiac differentiation capacity of the cells. Additionally, anti-Flt-1 and anti-Igf-1rα antibodies decreased phosphorylation of ERK1/2 in BATDCs. Inhibition of MEK/ERK activity by the inhibitor PD0325901 or by RNA interference blunted the cardiac differentiation of BATDCs. Loading recombinant VEGF and IGF1, or transfecting their expression vectors into WATDCs, promoted cardiac differentiation of the cells. Preincubation with PD0325901, before VEGF and IGF1 supplementation or vector transfections, blocked the stimulation of cardiac differentiation in WATDCs. ConclusionsThese findings indicated that VEGF and IGF1 were critical factors for the spontaneous cardiac differentiation of BATDCs, and MEK/ERK signaling was involved in the role of VEGF and IGF1. VEGF and IGF1 could be used to promote the development of cardiomyocyte phenotype in WATDCs.

Insulin-like growth factor 1 and hearing impairment in older adults: results from the English Longitudinal Study of Ageing

BackgroundAge-related hearing impairment is the most common hearing disorder, affecting two-thirds of people aged over 70 years in the UK. It is a major cause of disability, with considerable social and health implications, accompanied by a major economic burden. With the condition essentially incurable, the focus becomes identification of risk factors. The biological determinants of hearing impairment remain poorly understood. Despite a suggestion from animal studies that insulin-like growth factor 1 (IGF-1) is implicated in the development of hearing impairment, we know of no studies in human beings. Methods4398 participants with no missing data (mean age at baseline 64·2 years [SD 8·1], 55% women) from the English Longitudinal Study of Ageing provided serum concentrations of IGF-1 in 2008 and 2012. We used the average of these two measurement when available, one if not. Hearing acuity was measured with a HearCheck Screener (Siemens, Erlangen, Germany) in 2014. Hearing impairment was defined as hearing fewer than all six tones, three with decreasing intensity at two frequencies (1 kHz and 3 kHz). Logistic regression models were used to estimate odds ratios (OR) of hearing impairment across five quintiles of IGF-1 concentration. Presence of interaction and non-linearity were assessed by likelihood ratio tests. FindingsMean IGF-1 was 16·1 nmol/L (SD 5·2). In the full analytical sample, IGF-1 was not associated with subsequent hearing impairment (OR per 5 nmol increase in IGF-1 1·01, 95% CI 0·94–1·09). However, this association differed by age (pinteraction=0·03). Thus, in participants younger than 60 years (n=1402), IGF-1 was linearly associated with a lower risk of hearing impairment (0·85, 0·73–0·99) after adjustment for age, sex, smoking, height, body-mass index, cognitive function, education, and self-reported hearing at baseline. Among participants 60 years and older, there was some evidence of a J-shaped association (pcurvature=0·02). Compared with the lowest quintile of IGF-1, ORs for quintiles 2, 3, 4, and 5 were 0·94 (0·72–1·22), 1·13 (0·86–1·48), 0·97 (0·74–1·27), and 1·24 (0·95–1·62), respectively, but associations were not statistically significant. InterpretationIn people at the lower end of the older-age spectrum, there was some support for lower levels of IGF-1 being linked with hearing impairment. These results warrant replication and then testing in trials of IGF-1 supplementation. FundingThe English Longitudinal Study of Ageing is supported by the National Institute on Aging (grant numbers 2RO1AG7644 and 2RO1AG017644-01A1) and a consortium of the UK government departments coordinated by the Economic and Social Research Council. The funding bodies had no role in the study design; collection, analysis, and interpretation of data; writing of the abstract; and decision to submit the abstract for publication.