Circulating Insulin-like Growth Factor-1 Levels Research Articles

The mediating role of lower body muscle strength and IGF-1 level in the relationship between age and cognition. A MIDUS substudy

ObjectiveAging is a natural process associated with a decline in cognition. However, the mediating effect of physical function and circulating myokines on this relationship has yet to be fully clarified. This study investigated how muscle strength and circulating insulin-like growth factor-1 (IGF-1) levels mediate the relationship between age and cognitive functions. Subjects and methodsA total of 1255 participants aged 25–74 years included in the Midlife in the United States II study were retrospectively analyzed. In this cross-sectional analysis, we applied a serial mediation model to explore the mediating effects of muscle strength and circulating IGF-1 levels on the relationship between age and cognitive functions. We included potential confounding factors related to sociodemographics, lifestyle, and health status as covariates in the model. ResultsThe results showed that aging had both direct and indirect effects on cognition. As predicted, muscle strength and IGF-1 levels mediated the relationship between age and specific cognitive functions. In addition, mediation analyses indicated that the association between aging and cognitive flexibility, immediate and delayed memory, and inductive reasoning were partially mediated by muscle strength and IGF-1 levels in a serial manner. ConclusionsOur study demonstrated the serial multiple mediation roles of muscle strength and IGF-1 levels on the relationship between age and specific cognitive functions. Further longitudinal research should be performed to confirm the serial mediation results.

Anabolic myokine responses and muscular performance following 8 weeks of autoregulated compared to linear resistance exercise in recreationally active males.

To date, no studies, to our knowledge, have compared the efficacy of autoregulated periodized and linear resistance exercises on anabolic myokines and muscular performance among recreationally active individuals. This study aimed to compare the effects of an 8-week autoregulated periodized resistance exercise (APRE) program with a linear resistance exercise (LRE) program on insulin-like growth factor-1 (IGF-1), follistatin (FST), myostatin (MST), body composition, muscular strength, and power in recreationally active males. Thirty males were randomly assigned to either the APRE group (n = 15) or the LRE group (n = 15). Participants completed training three times a week for 8 weeks. The outcome measures included serum IGF-1, FST, MST, muscular strength (isometric knee extension and handgrip), power (vertical jump), lean body mass, and fat mass. IGF-1 circulating levels increased over time following APRE (34%) and with no significant change following LRE (~-1%). There were no significant differences over time or between groups for FST or MST. Muscular strength (knee extension [21.5 vs. ~16%] and handgrip [right: 31 vs. 25%; left: 31.7 vs. 28.8%]) and power (~ 33 vs. ~26%) significantly increased to a greater extent following APRE compared to LRE. Interestingly, the results revealed that lean body mass increased over time only after APRE (~ 3%), but not LRE. These findings suggest that APRE may be more effective than LRE in increasing muscular strength, power, and lean body mass, as well as circulating IGF-1 levels, in recreationally active males. The observed differences may be attributed to the increased training volume associated with APRE. However, further research is needed to directly assess muscle protein synthesis.

Tmem263 deletion disrupts the GH/IGF-1 axis and causes dwarfism and impairs skeletal acquisition

Genome-wide association studies (GWAS) have identified a large number of candidate genes believed to affect longitudinal bone growth and bone mass. One of these candidate genes, TMEM263, encodes a poorly characterized plasma membrane protein. Single nucleotide polymorphisms in TMEM263 are associated with bone mineral density in humans and mutations are associated with dwarfism in chicken and severe skeletal dysplasia in at least one human fetus. Whether this genotype-phenotype relationship is causal, however, remains unclear. Here, we determine whether and how TMEM263 is required for postnatal growth. Deletion of the Tmem263 gene in mice causes severe postnatal growth failure, proportional dwarfism, and impaired skeletal acquisition. Mice lacking Tmem263 show no differences in body weight within the first 2 weeks of postnatal life. However, by P21 there is a dramatic growth deficit due to a disrupted growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis, which is critical for longitudinal bone growth. Tmem263-null mice have low circulating IGF-1 levels and pronounced reductions in bone mass and growth plate length. The low serum IGF-1 in Tmem263-null mice is associated with reduced hepatic GH receptor (GHR) expression and GH-induced JAK2/STAT5 signaling. A deficit in GH signaling dramatically alters GH-regulated genes and feminizes the liver transcriptome of Tmem263-null male mice, with their expression profile resembling wild-type female, hypophysectomized male, and Stat5b-null male mice. Collectively, our data validates the causal role for Tmem263 in regulating postnatal growth and raises the possibility that rare mutations or variants of TMEM263 may potentially cause GH insensitivity and impair linear growth.

Tmem263 deletion disrupts the GH/IGF-1 axis and causes dwarfism and impairs skeletal acquisition.

Genome-wide association studies (GWAS) have identified a large number of candidate genes believed to affect longitudinal bone growth and bone mass. One of these candidate genes, TMEM263, encodes a poorly characterized plasma membrane protein. Single nucleotide polymorphisms in TMEM263 are associated with bone mineral density in humans and mutations are associated with dwarfism in chicken and severe skeletal dysplasia in at least one human fetus. Whether this genotype-phenotype relationship is causal, however, remains unclear. Here, we determine whether and how TMEM263 is required for postnatal growth. Deletion of the Tmem263 gene in mice causes severe postnatal growth failure, proportional dwarfism, and impaired skeletal acquisition. Mice lacking Tmem263 show no differences in body weight within the first 2 weeks of postnatal life. However, by P21 there is a dramatic growth deficit due to a disrupted growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis, which is critical for longitudinal bone growth. Tmem263-null mice have low circulating IGF-1 levels and pronounced reductions in bone mass and growth plate length. The low serum IGF-1 in Tmem263-null mice is associated with reduced hepatic GH receptor (GHR) expression and GH-induced JAK2/STAT5 signaling. A deficit in GH signaling dramatically alters GH-regulated genes and feminizes the liver transcriptome of Tmem263-null male mice, with their expression profile resembling wild-type female, hypophysectomized male, and Stat5b-null male mice. Collectively, our data validates the causal role for Tmem263 in regulating postnatal growth and raises the possibility that rare mutations or variants of TMEM263 may potentially cause GH insensitivity and impair linear growth.

Association between metabolic syndrome, insulin resistance, and IGF-1 in breast cancer survivors of DIANA-5 study

PurposeCirculating insulin-like growth factor-1 (IGF-1) is positively associated with the risk of BC recurrence, and is more frequently dysregulated in older people, especially in those with metabolic syndrome (MetS) and obesity. This study aimed to analyze the association between IGF-1 levels and indices of MetS and insulin resistance in BC survivors.MethodsBaseline data of 563 BC survivors enrolled in the DIet and ANdrogen-5 (DIANA-5; NCT05019989) study were analyzed.ResultsLower circulating IGF-1 levels in subjects with MetS than in those without MetS were found. After stratification of the patients according to the diagnosis of MetS, we highlighted that the insulin was the main predictor of elevated IGF-1 levels only in subjects without MetS. Moreover, we found an interaction between high-density lipoprotein cholesterol (HDL-C), glycemia, and IGF-1 levels, showing a positive correlation between HDL-C and IGF-1, especially in subjects with higher values of glycemia and without a diagnosis of MetS.ConclusionsWhile IGF-1 levels appear to be much more impaired in subjects diagnosed with MetS, in non-MetS subjects, IGF-1 levels may respond better to metabolic parameters and lifestyle changes. Further studies are needed to analyze the role of physical activity and/or dietary intervention in modulating IGF-1 concentrations in BC survivors.Implications for cancer survivorsThese results could have important clinical implications for planning customized strategies aimed at modulating IGF-1 levels in BC survivors. In fact, while the IGF-1 system seems to be much more compromised in subjects with a diagnosis of MetS, in noMetS subjects, IGF-1 levels could better respond to lifestyle changes.

Insulin-Like Growth Factor -1 (IGF-1) and Glucose Dysregulation in Young Adult Patients with β-Thalassemia Major: Causality or Potential Link?

Insulin-like growth factor-1 (IGF-1) has been shown to lower blood glucose through stimulating glucose transport to fat and muscle and inhibiting hepatic glucose output. Although previous cross-sectional reports reported an association between low circulating concentrations of IGF-1 and glucose dysregulation (GD), its role is still debated. The present retrospective study was designed to assess the circulating IGF-1 levels in β-thalassemia major (β -TM) patients with normal oral glucose tolerance test (NGT-OGTT) and (GD) referred for an endocrine evaluation to explore the potential link between low IGF-1 and GD. Our study included 34 young adult patients with β-TM; 12 patients with NGT after OGTT, 7 with impaired glucose tolerance (IGT), 9 with impaired fasting glucose (IFG) plus IGT, and 6 patients with β-TM-related diabetes mellitus (β-TM- DM). Twenty-two β-TM patients with GD or β-TM- DM and 1 patient with NGT had IGF-1 levels below the 2.5th percentile. Correlation of IGF-1 with fasting plasma glucose, HOMA-IR (homeostatic model assessment for insulin resistance) and OGIS (oral glucose insulin sensitivity) was found. Moreover, a negative correlation was documented between ALT and the Insulinogenic Index (IGI) and a positive correlation between serum ferritin and PG 2-h after OGTT. This study reports for the first time an association between low levels of IGF-1 and GD in β-TM patients. Despite some limitations, our study can serve to generate proposals for more convenient and efficient methods to identify and treat early GD in patients with β-TM, and to conduct more extensive studies. www.actabiomedica.it).

Age-related decline in circulating IGF-1 associates with impaired neurovascular coupling responses in older adults

Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) to the increased oxygen and energy requirements of active brain regions via neurovascular coupling (NVC) contributes to the genesis of age-related cognitive impairment. Aging is associated with marked deficiency in the vasoprotective hormone insulin-like growth factor-1 (IGF-1). Preclinical studies on animal models of aging suggest that circulating IGF-1 deficiency is causally linked to impairment of NVC responses. The present study was designed to test the hypotheses that decreases in circulating IGF-1 levels in older adults also predict the magnitude of age-related decline of NVC responses. In a single-center cross-sectional study, we enrolled healthy young (n = 31, 11 female, 20 male, mean age: 28.4 + / − 4.2 years) and aged volunteers (n = 32, 18 female, 14 male, mean age: 67.9 + / − 4.1 years). Serum IGF-1 level, basal CBF (phase contrast magnetic resonance imaging (MRI)), and NVC responses during the trail making task (with transcranial Doppler sonography) were assessed. We found that circulating IGF-1 levels were significantly decreased with age and associated with decreased basal CBF. Age-related decline in IGF-1 levels predicted the magnitude of age-related decline in NVC responses. In conclusion, our study provides additional evidence in support of the concept that age-related circulating IGF-1 deficiency contributes to neurovascular aging, impairing CBF and functional hyperemia in older adults.

Increased testicular insulin-like growth factor 1 is associated with gonadal activation by recombinant growth hormone in immature rats

BackgroundIn children, recombinant human growth hormone (rhGH) therapy for treatment of short stature has raised concerns of the early onset of puberty. Puberty is initiated by the activation of the hypothalamus-pituitary-gonad axis. Insulin-like growth factor-1 (IGF1) has been known to mediate physiologic effects of GH. To understand the mechanism of precocious sexual maturation following prepubertal GH therapy, the effects of rhGH on the hypothalamus-pituitary-gonad axis were examined in the immature male rats.MethodsImmature male rats were given by daily injection of rhGH (1 or 2 IU/kg) from postnatal day (PND) 21 to PND 23 or 30. The effects of rhGH on kisspeptin-GnRH-LH system in the hypothalamus-pituitary axis, systemic and testicular IGF1, spermatogenesis, steroidogenesis, and circulating testosterone levels were examined. The effects of rhGH on the IGF1 expression and steroidogenesis were examined in progenitor LCs in vitro.ResultsTesticular steroidogenic pathway and spermatogenesis marker mRNA levels, number and size of 17β-hydroxysteroid dehydrogenase (+) LCs, and blood testosterone levels of rhGH rats were significantly higher than those of controls on PNDs 24 and 31. Hypothalamic Kiss1 and Gnrh1 mRNA of rhGH rats were significantly higher than those of controls on PND 24, indicating early activation of hypothalamic kisspeptin-GnRH neurons by rhGH. Hypothalamic Igf1 mRNA levels of rhGH rats were significantly higher than those of controls on PND 24 but significantly lower than those of controls on PND 31. Testicular Igf1 mRNA levels were significantly higher in rhGH rats than in the controls on PNDs 24 and 31 whereas circulating IGF1 levels were not. In progenitor LCs, rhGH significantly increased Igf1 and steroidogenic pathway mRNA levels and testosterone production.ConclusionsLocal increases in testicular IGF1 might be an important mediator of gonadal maturation via activation of LCs steroidogenesis in immature rats given rhGH.

Effects of Astragalus Extract Mixture HT042 on Circulating IGF-1 Level and Growth Hormone Axis in Rats.

Astragalus extract mixture HT042 is a standardized functional food granted by the Korean FDA for promoting “Children’s Height Growth”. In this study, we determined whether HT042 affects circulatory Insulin-like growth factor-1 (IGF-1) after administration and investigated whether Growth hormone (GH), Growth hormone-releasing hormone receptor (GHRH-R), and Growth hormone secretagogue receptor (GHS-R) mRNAs are expressed in the pituitary, and whether Growth hormone-releasing hormone (GHRH) and Somatostatin (SST) are expressed in the hypothalamus. We also evaluated the growth effect of HT042 on endochondral bone formation. Male Sprague-Dawley rats in the control and HT042 groups were orally administered a single dose of the control and HT042, respectively, and those in the recombinant human GH (rhGH) group were subcutaneously injected with rhGH. Tetracycline was injected intraperitoneally 72 h prior to sacrifice to decide endochondral bone formation. To determine the endocrine or paracrine/autocrine mechanism, we evaluated the expression of local BMP-2 and IGF-1, an immunohistochemical study after HT042 administration. It was confirmed that the growth-promoting effect of HT042 can be contributed to the increase in serum IGF-1, which can be stimulated by GH secretion. Administration of HT042 modulated the activity of GHRH-R and GHR-S in the pituitary gland and promoted GH secretion, thereby changing longitudinal growth through GH/IGF-1 mediation. Results for GHRH and SST expression demonstrated that the hypothalamus can be influenced and mediated by HT042 through a complex neuroendocrine regulatory system. In addition, it was confirmed by oral administration for 10 days that HT042 increased bone formation in cartilage, which is important for height growth. The effect of HT042 could be owing to upregulation of local Bone morphogenetic protein-2 (BMP-2) and IGF-1 expression in the growth plate, which could be regarded as a GH-dependent autocrine/paracrine pathway, as well as circulatory IGF-1.

Effects of experimental increase in insulin-like growth factor 1 on feather growth rate, moult intensity and feather quality in a passerine bird.

Moulting is a crucial, yet often overlooked life-history stage in many animals, when they renew their integumental structures. This life-history stage is an energetically demanding somatic growth event that has particular importance in birds because feathers play a crucial role in flight, insulation and communication. Somatic growth processes are regulated by the evolutionarily conserved peptide hormone insulin-like growth factor 1 (IGF-1). However, the role of IGF-1 in feather growth remains unknown. In this study, we captured 41 juvenile free-living bearded reedlings (Panurus biarmicus) that had started their first complete moult and brought them into captivity. Then, we manipulated their circulating IGF-1 levels using poly-(lactic-co-glycolid acid) microparticles (microspheres) that provide a sustained release of IGF-1. The treatment increased IGF-1 levels but did not affect the feather growth rate. However, 2weeks after the treatment, birds in the increased IGF-1 group were moulting more feathers simultaneously than the controls and were at a more advanced stage of moult. Birds with experimentally increased IGF-1 levels had better quality feathers (measured by a lower number of fault bars) than the controls. These results suggest that an increase in IGF-1 does not speed up feather growth, but may alter moult intensity by initiating the renewal of several feathers simultaneously. This may shorten the overall moulting time but may imply costs in terms of IGF-1-induced oxidative stress.

Antagonism of Growth Hormone Receptor Suppresses Cancer Growth and Drug Resistance in Mice

Abstract Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) play important roles in different stages of progression and drug resistance in many types of cancers, including breast, colon, endometrial, liver cancer and melanoma. GH receptor (GHR) is highly expressed in melanoma and promotes cancer proliferation and multidrug efflux pumps mediated drug resistance. Knockdown of GHR in melanoma cells significantly increased their drug sensitivity in vitro. Thus, a GHR antagonist could become a therapeutic molecule in suppressing melanoma cancer growth and sensitizing the tumor to chemotherapy in vivo. Here, we used GHR antagonist (GHA) transgenic mice which constitutively express a GHA to specifically suppress GH/IGF-1 axis. We found have circulating IGF-1 level was significantly lowered in these mice as a result of GHR antagonism. Furthermore, the sera from the mice could inhibit the growth of melanoma cells in culture. Recombinant GHA produced in our laboratory was able to suppress the phosphorylation of STAT5, a well-established marker of GH action, and the phosphorylation of MAPK, a critical signaling component of cell growth. The GHA mice were intradermally inoculated with mouse melanoma cells (B16-F10) or subcutaneously inoculated with mouse liver cancer cells (Hepa1-6) to generate syngeneic mouse tumor models. We observed that tumor size and tumor weight were markedly reduced and that phosphorylation of STAT5 and MAPK was suppressed in the livers from these mice. In parallel, the activation of GH signaling and the expression level of various types of multidrug efflux pumps were reduced in these tumors. To test the effect of GHA on drug synergy, the GHA mice or WT controls with liver cancer cells were treated with sorafenib or vehicle. Sorafenib is an FDA-approved tyrosine kinase inhibitor, widely used to treat advanced hepatocarcinoma, but has a reduced efficacy in application due to the multidrug efflux pump ABCG2. In vitro, recombinant bovine GH increased the IC50 of sorafenib and the expression of ABCG2. In vivo, GHA mice treated with sorafenib had the smallest tumors compared with WT mice, or in mice treated with sorafenib or GHA alone. Furthermore, ABCG2 mRNA levels were also suppressed in the liver tumors from GHA mice. All these findings from functional and mechanistic investigations confirm that a GHA or Pegvisomant is effective in cancer treatment in vivo and may be a novel therapeutic strategy or molecule to suppress the tumor growth and to sensitize different types of cancers to anti-cancer therapies. Acknowledgments: This work was supported by the State of Ohio’s Eminent Scholar Program that includes a gift from Milton and Lawrence Goll to J.K.; NIH-R01AG059779, the AMVETS, Edison Biotechnology Institute and Diabetes Institute at Ohio University; OURC funding and Baker Fund to Y.Q.; the PURF Fund and the John J. Kopchick Molecular Cell Biology Undergraduate Student Fund to N.A and J.T.

High circulating insulin-like growth factor-1 reduces the risk of renal cell carcinoma: a Mendelian randomization study.

Insulin and insulin-like growth factors play important roles in carcinogenesis. Circulating insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-3 (IGFBP-3) have been linked to cancer susceptibility. The associations of circulating IGF-1 and IGFBP-3 with the risk of renal cell carcinoma (RCC) are inconsistent. Recent large genome-wide association studies have identified 413 single nucleotide polymorphisms (SNPs) associated with IGF-1 and 4 SNPs associated with IGFBP-3. In this large case-control study consisting of 2069 RCC patients and 2052 healthy controls of European ancestry, we used a two-sample Mendelian randomization (MR) approach to investigate the associations of genetically predicted circulating IGF-1 and IGFBP-3 with RCC risk. We used an individual level data-based genetic risk score (GRS) and a summary statistics-based inverse-variance weighting (IVW) method in MR analyses. We found that genetically predicted IGF-1 was significantly associated with RCC risk in both the GRS analysis [odds ratio (OR) = 0.43 per SD increase, 95% confidence interval (CI), 0.34-0.53] and the IVW analysis (OR = 0.46 per SD increase, 95% CI, 0.37-0.57). Dichotomized at the median GRS value of IGF-1 in controls, individuals with high GRS had a 45% reduced RCC risk (OR = 0.55, 95% CI, 0.48-0.62) compared with those with low GRS. Genetically predicted circulating IGFBP-3 was not associated with RCC risk. This is the largest RCC study of circulating IGF-1 and IGFBP-3 to date and our data suggest a strong inverse relationship between circulating IGF-1 level and RCC risk.

Pseudo-Starvation Driven Energy Expenditure Negatively Affects Ovarian Follicle Development.

In the present investigation, we examined whether a change in whole body energy fluxes could affect ovarian follicular development, employing mice ectopically expressing uncoupling protein 1 in skeletal muscle (UCP1-TG). Female UCP1-TG and wild-type (WT) mice were dissected at the age of 12 weeks. Energy intake and expenditure, activity, body weight and length, and body composition were measured. Plasma insulin, glucose, leptin, plasma fibroblast growth factor 21 (FGF21) and plasma insulin-like growth factor 1 (IGF1) levels were analyzed and ovarian follicle and corpus luteum numbers were counted. IGF1 signaling was analyzed by immunohistochemical staining for the activation of insulin receptor substrate 1/2 (IRS1/2) and AKT. UCP1-TG female mice had increased energy expenditure, reduced body size, maintained adiposity, and decreased IGF1 concentrations compared to their WT littermates, while preantral and antral follicle numbers were reduced by 40% and 60%, respectively. Corpora lutea were absent in 40% of the ovaries of UCP1-TG mice. Phospho-IRS1, phospho-AKT -Ser473 and -Thr308 immunostaining was present in the granulosa cells of antral follicles in WT ovaries, but faint to absent in the antral follicles of UCP1-TG mice. In conclusion, the reduction in circulating IGF1 levels due to the ectopic expression of UCP1 is associated with reduced immunostaining of the IRS1-PI3/AKT pathway, which may negatively affect ovarian follicle development and ovulation.

Elucidating the genetic architecture underlying IGF1 levels and its impact on genomic instability and cancer risk

Background: Insulin-like growth factor-1 (IGF1) has been implicated in mitogenic and anti-apoptotic mechanisms that promote susceptibility to cancer development and growth. Previous epidemiological studies have described phenotypic associations between higher circulating levels of IGF1 in adults with higher risks for breast, prostate, ovarian, colorectal, melanoma and lung cancers. However, such evidence is prone to confounding and reverse causality. Furthermore, it is unclear whether IGF1 promotes only the survival and proliferation of cancerous cells, or also the malignant transformation of healthy cells. Methods: We perform a genome-wide association study in 428,525 white European ancestry individuals in the UK Biobank study (UKBB) and identify 831 independent genetic determinants of circulating IGF1 levels, double the number previously reported. Results: Collectively these signals explain ~7.5% of the variance in circulating IGF1 levels in EPIC-Norfolk, with individuals in the highest 10% of genetic risk exhibiting ~1 SD higher levels than those in the lowest 10%. Using a Mendelian randomization approach, we demonstrate that genetically higher circulating IGF1 levels are associated with greater likelihood of mosaic loss of chromosome Y in leukocytes in men in UKBB (OR per +1 SD = 1.038 (95% CI: 1.010-1.067), P=0.008) and 23andMe, Inc. (P=6.8×10-05), a biomarker of genomic instability involved in early tumorigenesis. Genetically higher IGF1 is also associated with higher risks for colorectal (OR = 1.126 (1.048-1.210), P=1.3×10-03) and breast cancer (OR= 1.075 (1.048-1.103), P=3.9×10-08), with similar effects on estrogen positive (ER+) (OR = 1.069 (1.037-1.102), P=2.3×10-05) and estrogen negative (ER-) (OR = 1.074 (1.025-1.125), P=3.9×10-08) subtypes. Conclusions: These findings give an insight into the genetic regulation of circulating IGF1 levels and support a causal role for IGF1 in early tumorigenesis and risks for breast and colorectal cancers.

Lifelong Excess in GH Elicits Sexually Dimorphic Effects on Skeletal Morphology and Bone Mechanical Properties.

Excess in growth hormone (GH) levels, seen in patients with acromegaly, is associated with increases in fractures. This happens despite wider bones and independent of bone mineral density. We used the bovine GH (bGH) transgenic mice, which show constitutive excess in GH and insulin-like growth factor 1 (IGF-1) in serum and tissues, to study how lifelong increases in GH and IGF-1 affect skeletal integrity. Additionally, we crossed the acid labile subunit (ALS) null (ALSKO) to the bGH mice to reduce serum IGF-1 levels. Our findings indicate sexually dimorphic effects of GH on cortical and trabecular bone. Male bGH mice showed enlarged cortical diameters, but with marrow cavity expansion and thin cortices as well as increased vascular porosity that were associated with reductions in diaphyseal strength and stiffness. In contrast, female bGH mice presented with significantly smaller-diameter diaphysis, with greater cortical bone thickness and with a slightly reduced tissue elastic modulus (by microindentation), ultimately resulting in overall stronger, stiffer bones. We found increases in C-terminal telopeptide of type 1 collagen and procollagen type 1N propeptide in serum, independent of circulating IGF-1 levels, indicating increased bone remodeling with excess GH. Sexual dimorphism in response to excess GH was also observed in the trabecular bone compartment, particularly at the femur distal metaphysis. Female bGH mice preserved their trabecular architecture during aging, whereas trabecular bone volume in male bGH mice significantly reduced and was associated with thinning of the trabeculae. We conclude that pathological excess in GH results in sexually dimorphic changes in bone architecture and gains in bone mass that affect whole-bone mechanical properties, as well as sex-specific differences in bone material properties. © 2022 American Society for Bone and Mineral Research (ASBMR).

Embryonic stem cell-derived mesenchymal stem cells promote colon epithelial integrity and regeneration by elevating circulating IGF-1 in colitis mice.

Rationale: Mesenchymal stem cells (MSCs) show promising therapeutic potential in treating inflammatory bowel disease (IBD) due to their immunomodulatory and trophic functions. However, their efficacy is influenced by tissue origin, donator condition, isolation, and expansion methods. Here, we generated phenotypically uniform MSCs from human embryonic stem cells (T-MSCs) and explored the molecular mechanisms involved in promoting mucosal integrity and regeneration in colitis mice.Methods: T-MSCs were injected intravenously into mice with dextran sulfate sodium (DSS)-induced colitis, and the in vivo distribution and therapeutic efficacy were evaluated. We performed serum cytokine antibody microarrays to screen potentially effective proteins and examined the therapeutic effect of insulin-like growth factor-1 (IGF-1). Colon epithelial regeneration potential was evaluated, and RNA sequencing was employed to determine the underlying molecular mechanisms. Finally, in vitro IGF-1 stimulation was performed to assess its effect on cell functions and organoid growth.Results: Intravenous administration of T-MSCs alleviated colitis in both acute and chronic DSS mouse models. Labeled T-MSCs were mainly distributed in the lungs, liver, and spleen after systemic infusion. The antibody array analysis of serum cytokines indicated that the IGF-1 level was increased in the treatment group, and serum ELISA further confirmed its elevation in the regeneration stage. Intraperitoneal injection of IGF-1 receptor inhibitors abrogated the anti-inflammatory activity of T-MSCs. The colonic epithelium of the treatment group showed greater regenerative potency than the controls and the IGF1R-PI3K-AKT pathway was up-regulated. RNA sequencing showed that T-MSC treatment contributed to colonic cell integrity and promoted xenobiotic metabolism. In vitro IGF-1 stimulation promoted the growth and proliferation of colon cells and organoids.Conclusions: Intravenous infusion of T-MSCs alleviated colitis in mice by elevating the circulating IGF-1 level. Increased IGF-1 maintained the integrity of epithelial cells and contributed to their repair and regeneration. Our study has identified T- MSCs as a potential cell resource for IBD treatment.

A Novel Homozygous Mutation of the Acid-Labile Subunit <i>(IGFALS)</i> Gene in a Male Adolescent

Acid-labile subunit (ALS) forms ternary complexes with insulin like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) and is essential for normal circulating IGF-1 levels. The IGFALS gene encodes the ALS and mutations in IGFALS cause ALS deficiency. We describe a patient with ALS deficiency with a novel homozygous frameshift mutation in IGFALS presenting with short stature and delayed puberty but ultimately achieving an adult height (AH) comparable to his target height (TH). A 15.25 year old boy presented with short stature (149.9 cm, -3.04 standard deviation score). The patient had a low circulating IGF-1 concentration, extremely low IGFBP-3 concentration, insulin resistance and osteopenia. The peak growth hormone (GH) response to GH stimulation test was high (31.6 ng/mL). Sequencing of IGFALS revealed a novel, homozygous, frameshift mutation (p.Ser555Thrfs.19). His mother and elder sister were heterozygous carriers. Although he had delayed puberty and short stature at the onset of puberty, he reached his TH and an AH similar to those of his heterozygous mother and sister. The heterozygous carriers had normal or low IGF-1 concentrations and low IGFBP-3 concentrations but not as markedly low as that of the patient. They had normally timed puberty, insulin metabolism and bone mineral density (BMD). The phenotype of ALS deficiency is quite variable. Despite short stature and delayed puberty, patients can achieve normal pubertal growth and AH. ALS deficiency may cause osteopenia and hyperinsulinemia. Heterozygous carriers may have normal prenatal growth, puberty, insulin metabolism and BMD.

Interaction between CA repeat microsatellites and HIF1α regulated the transcriptional activity of porcine IGF1 promoter.

Insulin-like growth factor 1 (IGF1) is pivotal in the regulation of animal growth. Highly polymorphic CA repeat microsatellites have been identified in the IGF1 promoter region of different breeds of pigs. Previous studies showed that CA repeat microsatellites are associated with circulating IGF1 level. However, the mechanisms by which CA repeat microsatellites regulate IGF1 expression remain unclear. This study aimed to detect the association of CA repeat microsatellites with the transcriptional regulation of porcine IGF1 and the possible mechanisms. Results revealed that the number of CA repeats in porcine IGF1 promoter was 14-18, and a promoter with 14 or 15 CA repeats had a higher transcriptional activity (P < 0.01). Transcription factor hypoxia-inducible factor 1 subunit alpha (HIF1α) was confirmed to bind to the binding site upstream of CA repeat microsatellites. The microsatellites with 14 or 15 CA repeats were more sensitive to changes in the HIF1α expression level (P < 0.01). These results suggested that CA repeat microsatellites and HIF1α affected the transcriptional activity of each other in the regulation of IGF1 expression, thereby implying an interaction between them. Overall, this study provided novel evidence for elucidating the effects of CA repeat microsatellites on the transcriptional regulation of porcine IGF1.

Circulating Insulin-like Growth Factor-1 Levels in Patients with Rheumatoid Arthritis: A Meta-analysis.

Insulin-like growth factor-1 (IGF-1) levels have been investigated in rheumatoid arthritis (RA), however, produced inconsistent results. The purpose of this meta-analysis was to derive a more precise conclusion about serum/plasma IGF-1 levels in RA patients. PubMed, Embase and the Cochrane Library databases were searched up to December 2018 in English, and the studies comparing serum/plasma IGF-1 levels between RA group and healthy control group were what we are interested in. The Newcastle-Ottawa Scale (NOS) was used to assess the methodological quality of the included studies. The heterogeneity test was performed by the Cochrane Q statistic and I2 -statistic. The publication bias was evaluated by the funnel plot and Egger's test. The standard mean difference (SMD) with 95% confidence interval (CI) was calculated by the fixed-effects or random-effects model. A total of eleven articles with 334 cases and 261 controls were finally included. Compared with the healthy group, the RA group had lower circulating IGF-1 levels (pooled SMD= -0.936, 95% CI= -1.382 to -0.489, p<0.001). The subgroup analysis showed that RA patients from Asia (SMD= -0.645, 95% CI= -1.063 to -0.228, p= 0.002) and Europe (SMD= -1.131, 95% CI= -1.767 to -0.495, p<0.001) had lower circulating IGF-1 levels, no significant difference in plasma/serum IGF-1 levels was observed in RA patients from America. Sensitivity analysis indicated the stability and credibility of the overall effect sizes. Patients with RA have lower circulating IGF-1 level than healthy controls, particularly for patients from Asia and Europe. Further studies are necessary to elucidate the role of IGF-1 in the pathological process of RA.

Circulating IGF-1 promotes prostate adenocarcinoma via FOXO3A/BIM signaling in a double-transgenic mouse model.

High circulating insulin-like growth factor-1 (IGF-1) levels increase the risk of prostate cancer. However, whether circulating IGF-1 levels directly aggravate prostate cancer remains elusive. In this study, we crossed a transgenic prostate adenocarcinoma mouse model, Hi-Myc mice, with a liver-specific IGF-1 transgenic mouse model (HIT) to increase their circulating IGF-1 levels to investigate the impact of the elevated circulating IGF-1 on prostate cancer development in vivo. The Hi-Myc/HIT mice had increased incidence and invasiveness of prostate cancer. IGF-1 elevation led to the accumulation of FOXO3A in the cytosol of prostate tumor cells and downregulation of its target gene Bim, which resulted in the apoptosis inhibition and prostate cancer overgrowth. The differential expressions of IGF-1R, FOXO3A, and BIM in the benign versus malignant prostate tissues supported a negative association between the FOXO3A/BIM axis and IGF-1R expression in human prostate adenocarcinoma. Our findings suggest that targeting the IGF-1/FOXO3A/BIM signaling axis could be an attractive strategy for prostate cancer prevention or treatment.