Insulin-like Growth Factor-1 Supplementation Research Articles

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.

Insulin-like growth factor-1 (IGF-1) enhances developmental competence of cat embryos cultured singly by modulating the expression of its receptor (IGF-1R) and reducing developmental block

ObjectiveThe aim of this study is to determine the effects of insulin-like growth factor-1 (IGF-1) and the mRNA expression of IGF-1 receptor (IGF-1R) during the in vitro development of cat embryos cultured in groups versus singly. MethodsCumulus-oocyte complexes (COCs) were matured and fertilized in vitro with frozen-thawed semen. Cleaved embryos (48h post-fertilization) were randomly assigned to one of the following treatments: 1) group embryo culture without IGF-1 (10 embryos per 50μl droplet), 2) single-embryo culture without IGF-1, and 3) to 6) single-embryo culture (50μl droplet per embryo) supplemented with different concentrations of IGF-1 (5, 25, 50 and 100ng/ml, respectively). During in vitro culture, the embryos were analyzed for development to the morula, blastocyst and hatching blastocyst stage. Relative mRNA expression of IGF-1R was also examined by qPCR at the morula and blastocyst stages. In addition, the mRNA expression of IGF-1R in morula-stage embryos treated with IGF-1 was determined. The influence of IGF-1 to preimplantation embryo development was then explored by co-incubation with 0.5μM IGF-1R inhibitor (Picropodophyllin; PPP). ResultsGroup embryo culture led to a significantly higher blastocyst development rate compared with single-embryo culture (P<0.05). The poor development of singly cultured embryos coincided with the significantly lower IGF-1R expression in morulae than in group-cultured morulae. IGF-1 (25 or 50ng/ml) supplementation significantly improved the blastocyst formation rate of single embryos to a level similar to group culture by promoting the morula-to-blastocyst transition. IGF-1 supplementation (25 or 50ng/ml) of singly cultured embryos upregulated the expression of IGF-1R mRNA in morula-stage embryos to the same level as that observed in group-cultured embryos (without IGF-1). The beneficial effects of IGF-1 on singly cultured embryo were (P<0.05) suppressed by PPP even in the group culture embryo without growth factor supplementation. ConclusionIGF-1 supplementation improves the developmental competence of feline embryos cultured individually and also increases IGF-1R gene expression to levels similar to group-cultured embryos.

IGF-1 Intranasal Administration Rescues Huntington's Disease Phenotypes in YAC128 Mice

Huntington's disease (HD) is an autosomal dominant disease caused by an expansion of CAG repeats in the gene encoding for huntingtin. Brain metabolic dysfunction and altered Akt signaling pathways have been associated with disease progression. Nevertheless, conflicting results persist regarding the role of insulin-like growth factor-1 (IGF-1)/Akt pathway in HD. While high plasma levels of IGF-1 correlated with cognitive decline in HD patients, other data showed protective effects of IGF-1 in HD striatal neurons and R6/2 mice. Thus, in the present study, we investigated motor phenotype, peripheral and central metabolic profile, and striatal and cortical signaling pathways in YAC128 mice subjected to intranasal administration of recombinant human IGF-1 (rhIGF-1) for 2weeks, in order to promote IGF-1 delivery to the brain. We show that IGF-1 supplementation enhances IGF-1 cortical levels and improves motor activity and both peripheral and central metabolic abnormalities in YAC128 mice. Moreover, decreased Akt activation in HD mice brain was ameliorated following IGF-1 administration. Upregulation of Akt following rhIGF-1 treatment occurred concomitantly with increased phosphorylation of mutant huntingtin on Ser421. These data suggest that intranasal administration of rhIGF-1 ameliorates HD-associated glucose metabolic brain abnormalities and mice phenotype.

Combined Exercise and Insulin-Like Growth Factor-1 Supplementation Induces Neurogenesis in Old Rats, but Do Not Attenuate Age-Associated DNA Damage

We have investigated the effects of 2 weeks of insulin-like growth factor-1 (IGF-1) supplementation (5 μg/kg per day) and 6 weeks of exercise training (60% of the maximal oxygen consumption [VO₂ max]) on neurogenesis, DNA damage/repair, and sirtuin content in the hippocampus of young (3 months old) and old (26 months old) rats. Exercise improved the spatial memory of the old group, but IGF-1 supplementation eliminated this effect. An age-associated decrease in neurogenesis was attenuated by exercise and IGF-1 treatment. Aging increased the levels of 8-oxo-7,8-dihydroguanine (8-oxoG) and the protein Ku70, indicating the role of DNA damage in age-related neuropathology. Acetylation of 8-oxoguanine DNA glycosylase (OGG1) was detected in vivo, and this decreased with aging. However, in young animals, exercise and IGF-1 treatment increased acetylated (ac) OGG1 levels. Sirtuin 1 (SIRT1) and SIRT3, as DNA damage-associated lysine deacetylases, were measured, and SIRT1 decreased with aging, resulting in a large increase in acetylated lysine residues in the hippocampus. On the other hand, SIRT3 increased with aging. Exercise-induced neurogenesis might not be a causative factor of increased spatial memory, because IGF-1 plus exercise can induce neurogenesis in the hippocampus of older rats. Data revealed that the age-associated increase in 8-oxoG levels is due to decreased acetylation of OGG1. Age-associated decreases in SIRT1 and the associated increase in lysine acetylation, in the hippocampus, could have significant impact on function and thus, could suggest a therapeutic target.

IGF-1 Has Plaque-Stabilizing Effects in Atherosclerosis by Altering Vascular Smooth Muscle Cell Phenotype

Insulin-like growth factor-1 (IGF-1) signaling is important for the maintenance of plaque stability in atherosclerosis due to its effects on vascular smooth muscle cell (vSMC) phenotype. To investigate this hypothesis, we studied the effects of the highly inflammatory milieu of the atherosclerotic plaque on IGF-1 signaling and stability-related phenotypic parameters of murine vSMCs in vitro, and the effects of IGF-1 supplementation on plaque phenotype in an atherosclerotic mouse model. M1-polarized, macrophage-conditioned medium inhibited IGF-1 signaling by ablating IGF-1 and increasing IGF-binding protein 3, increased vSMC apoptosis, and decreased proliferation. Expression of α-actin and col3a1 genes was strongly attenuated by macrophage-conditioned medium, whereas expression of matrix-degrading enzymes was increased. Importantly, all of these effects could be corrected by supplementation with IGF-1. In vivo, treatment with the stable IGF-1 analog Long R3 IGF-1 in apolipoprotein E knockout mice reduced stenosis and core size, and doubled cap/core ratio in early atherosclerosis. In advanced plaques, Long R3 IGF-1 increased the vSMC content of the plaque by more than twofold and significantly reduced the rate of intraplaque hemorrhage. We believe that IGF-1 in atherosclerotic plaques may have a role in preventing plaque instability, not only by modulating smooth muscle cell turnover, but also by altering smooth muscle cell phenotype.

Pigs and humans with cystic fibrosis have reduced insulin-like growth factor 1 (IGF1) levels at birth

People with cystic fibrosis (CF) exhibit growth defects. That observation has been attributed, in part, to decreased insulin-like growth factor 1 (IGF1) levels, and the reduction has been blamed on malnutrition and pulmonary inflammation. However, patients with CF already have a reduced weight at birth, a manifestation not likely secondary to poor nutrition or inflammation. We found that, like humans, CF pigs were smaller than non-CF littermates and had lower IGF1 levels. To better understand the basis of IGF1 reduction, we studied newborn pigs and found low IGF1 levels within 12 h of birth. Moreover, humerus length and bone mineral content were decreased, consistent with less IGF1 activity in utero. These findings led us to test newborn humans with CF, and we found that they also had reduced IGF1 levels. Discovering lower IGF1 levels in newborn pigs and humans indicates that the decrease is not solely a consequence of malnutrition or pulmonary inflammation and that loss of cystic fibrosis transmembrane conductance regulator function has a more direct effect. Consistent with this hypothesis, we discovered reduced growth hormone release in organotypic pituitary slice cultures of newborn CF pigs. These findings may explain the long-standing observation that CF newborns are smaller than non-CF babies and why some patients with good clinical status fail to reach their growth potential. The results also suggest that measuring IGF1 levels might be of value as a biomarker to predict disease severity or the response to therapeutics. Finally, they raise the possibility that IGF1 supplementation beginning in infancy might be beneficial in CF.

Chondrogenic differentiation of growth factor-stimulated precursor cells in cartilage repair tissue is associated with increased HIF-1α activity

To investigate the chondrogenic potential of growth factor-stimulated periosteal cells with respect to the activity of Hypoxia-inducible Factor 1alpha (HIF-1alpha). Scaffold-bound autologous periosteal cells, which had been activated by Insulin-like Growth Factor 1 (IGF-1) or Bone Morphogenetic Protein 2 (BMP-2) gene transfer using both adeno-associated virus (AAV) and adenoviral (Ad) vectors, were applied to chondral lesions in the knee joints of miniature pigs. Six weeks after transplantation, the repair tissues were investigated for collagen type I and type II content as well as for HIF-1alpha expression. The functional role of phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling on BMP-2/IGF-1-induced HIF-1alpha expression was assessed in vitro by employing specific inhibitors. Unstimulated periosteal cells formed a fibrous extracellular matrix in the superficial zone and a fibrocartilaginous matrix in deep zones of the repair tissue. This zonal difference was reflected by the absence of HIF-1alpha staining in superficial areas, but moderate HIF-1alpha expression in deep zones. In contrast, Ad/AAVBMP-2-stimulated periosteal cells, and to a lesser degree Ad/AAVIGF-1-infected cells, adopted a chondrocyte-like phenotype with strong intracellular HIF-1alpha staining throughout all zones of the repair tissue and formed a hyaline-like matrix. In vitro, BMP-2 and IGF-1 supplementation increased HIF-1alpha protein levels in periosteal cells, which was based on posttranscriptional mechanisms rather than de novo mRNA synthesis, involving predominantly the MEK/ERK pathway. This pilot experimental study on a relatively small number of animals indicated that chondrogenesis by precursor cells is facilitated in deeper hypoxic zones of cartilage repair tissue and is stimulated by growth factors which enhance HIF-1alpha activity.

Effect of Enteral IGF‐1 Supplementation on Feeding Tolerance, Growth, and Gut Permeability in Enterally Fed Premature Neonates

The gastrointestinal tract of the premature newborn functions suboptimally with regard to digestion, absorption, and feeding tolerance. Human milk contains trophic factors, such as insulin-like growth factor-1 (IGF-1), that are believed to stimulate gut growth and function. The objective of this double blind, randomized, controlled trial was to assess the effects of enteral IGF-1 supplementation on whole body growth measured by weight gain (in grams per kilogram per day), days to regain birth weight, and anthropometrical characteristics, and gut maturation and permeability (measured by sugar absorption tests). The study included 60 premature infants (birth weight 750-1250 g) during the first month of life. Patients received either standard infant formula or standard infant formula supplemented with IGF-1 in a concentration twice that of human colostrum (10 microg/100 mL of formula). Primary endpoints were days to full enteral feeding, days to regain birth weight, and growth rate. Sugar absorption tests were performed weekly to assess the secondary endpoints gut permeability and maturation. None of the primary endpoints differed to statistical significance between groups at any point. However, gut permeability was significantly lower in the IGF-1 supplement group on day 14 compared with the control group. At day 21, lactulose/mannitol excretion ratios were (again) comparable between the groups. Although gut permeability showed a faster decrease in the IGF-1 supplement group, our data do not support IGF-1 supplementation to infant formula.

Insulin-like growth factor I (IGF-1) supplementation prevents diabetes-induced alterations in coenzymes Q9 and Q10.

Diabetes, which causes enhanced oxidative stress, is a multifactorial disease that leads to deleterious effects in many organ systems within the body. Ubiquinones (coenzyme Q(9) and Q(10)) are amphipathic molecular components of the electron transport chain that function also as endogenous antioxidants and attenuate the diabetes-induced decreases in antioxidant defense mechanisms. Insulin-like growth factor 1 (IGF-1) is considered to be an "essential surviving factor", the level and function of which are compromised in diabetes. This study investigated the impact of IGF-1 supplementation on ubiquinone levels in a rat model of type I diabetes. Adult male Sprague-Dawley rats were divided into four groups: control, control plus IGF-1, diabetic and diabetic plus IGF-1. Diabetic animals received a single intravenous injection of streptozotocin (STZ, 55 mg/kg). IGF-1 supplementation groups received a daily intraperitoneal dose of 3 mg IGF-1 per kilogram body weight for 7 weeks. Coenzyme Q(9) and Q(10) levels were assessed by ultraviolet detection on high pressure liquid chromatography. STZ caused a significant reduction in body weight and an elevation in blood glucose level, which were not prevented by IGF-1 supplementation. In addition Q(9) and Q(10) levels in diabetic liver were significantly elevated. IGF-1 supplementation prevented liver alterations in Q(10) but not Q(9) levels. Q(9) and Q(10) levels in diabetic kidney were significantly depressed, and these deleterious effects were abolished by IGF-1 treatment. These data suggest that IGF-1 antagonizes the diabetes-induced alterations in endogenous antioxidants including coenzyme Q(10), and hence may have a therapeutic role in diabetes.

Insulin-like Growth Factor-1-mediated AKT Activation Postpones the Onset of Ultraviolet B-induced Apoptosis, Providing More Time for Cyclobutane Thymine Dimer Removal in Primary Human Keratinocytes

Insulin-like growth factor-1 (IGF-1) acts as a potent survival factor in numerous cell lines, primarily through activation of the AKT signaling pathway. Although some targets of this pathway have known anti-apoptotic functions, its relationship with the improved survival of cells after exposure to environmental stresses, including UVB, remains largely unclear. We report that in growth factor-deprived keratinocytes, IGF-1 significantly and consistently delayed the onset of UVB-induced apoptosis by >7 h. This delay allowed IGF-1-supplemented keratinocytes to repair significantly more cyclobutane thymine dimers than their growth factor-deprived counterparts. This increase in cyclobutane thymine removal resulted in enhanced survival if the amount of DNA damage was not too high. To increase cell survival after UVB irradiation, IGF-1 supplementation was required only during this initial time period in which extra repair was executed. Finally, we show that IGF-1 mediated this delay in the onset of UVB-induced apoptosis through activation of the AKT signaling pathway. We therefore believe that the AKT signaling pathway increases cell survival after a genotoxic insult such as UVB irradiation not by inhibiting the apoptotic stimulus, but only by postponing the induction of apoptosis, giving the DNA repair mechanism more time to work.