Role Of IGF-I Research Articles

Transcript abundance and apoptosis in day-7 porcine blastocyst cultured with exogenous insulin-like growth factor-I

Exogenous growth factors may increase the efficiency of embryo development in vitro. The aim of the present study was to examine the effects of insulin-like growth factor (IGF)-I on porcine embryo development. Porcine embryos obtained by in vitro fertilization were cultured for seven days in the presence of IGF-I (50, 100 or 150ng/ml). Subsequently, relative transcript abundance (RA) of IGF-related genes (IGFR1, IGFBP2, and IGFBP3), glucose transporter genes (SLC2A4 and SLC2A8), and apoptosis-related genes (BAX and BCL-XL) was analyzed. No differences were observed in the cleavage rate on day 2 post insemination (pi) and blastocysts rate on day 7pi between IGF-treated and control embryos. IGF-I treatment did not affect RA of IGFR1, IGFBP3, and SLC2A4 genes, but decreased RA of IGFBP2 and SLC2A8 genes. The percentage of TUNEL-positive nuclei in blastocysts did not differ between the experimental groups. However, RA of BAX and BCL-XL genes decreased in response to all IGF-I concentrations, whereas the BCL-XL/BAX RA ratio was enhanced when embryos were cultured in medium containing 150ng/ml of IGF-I. These results indicate that IGF-I did not stimulate in vitro development of porcine embryos through the IGF signaling system, nor did IGF-I stimulate RA of glucose transporter genes. However, IGF-I at the highest dose was able to increase the BCL-XL/BAX transcript expression ratio. This may indicate that the primary role of IGF-I during the first days of embryo development in the pig is associated with anti-apoptotic actions rather than with growth stimulation.

Adult GH deficiency - the value of IGF-I estimation

In patients with growth hormone (GH) deficiency (GHD) the diagnostic value of IGF-I levels has been recently revisited. A normal IGF-I value does not exclude GHD, because its secretion is complex and depends by several factors other than GH, such as age, nutritional status, obesity, as well as catabolic illness. Due to the complexity and costs of GH stimulation tests, several authors have analyzed the predictive and diagnostic value of the concentration of plasma IGF-I in patients suspected for GHD. The evaluation of IGF-I is also determinant to individualized dose-titration strategies, able to avoid the common adult side effects of substitutive therapy with recombinant GH. Current recommendations in clinical practice for GH replacement therapy, in GHD adults, agree on GH dosing regimens to be individualized independently of body weight using IGF-I levels as a biomarker of the treatment. For these reasons, in a clinical setting, appropriate normative values in different age groups in a large healthy population must be established in single laboratories, while, considering the relatively small sex difference, a different reference range for sex seems not necessary. This review discusses the more recent debated issues in the literature on the role of IGF-I, as well as other IGF system components, in the management of adult patients with GHD.

Insulin-like growth factor I: Could it be a marker of prematurity in the foal?

Insulin-like growth factor (IGF)-I represents one of the most important growth regulators, playing a central role in fetal and neonatal growth. Plasma IGF-I levels increase rapidly after birth, and they are influenced by numerous factors, including sex, age, nutritional state, and premature birth. The aims of this study were: (1) to evaluate the IGF-I plasma profile in healthy newborn foals during the first 2 weeks of life; (2) to assess the possible influence of sex and birth weight on this hormone; (3) to analyze the percentage increment of IGF-I values in healthy foals; (4) to evaluate the influence of prematurity on IGF-I profile; (5) to verify the role of IGF-I as a diagnostic marker of prematurity; and (6) to analyze the percentage increment of IGF-I in premature foals. Thirty-four healthy term foals were enrolled as the control group and from each foal plasma was collected within 6 hours from birth, at 12 hours, daily from Day 1 to Day 7, and at Days 10 and 14 after birth. Eleven foals aged younger than 1 week and diagnosed as premature and hospitalized at a Equine Perinatology Unit were also enrolled; from each foal plasma was collected daily from the day of admission to discharge or death. Insulin-like growth factor I was analyzed by RIA. In the control group, an increasing trend of IGF-I concentrations was found, with higher values from Day 4 to 10 compared with data obtained at less than 6 hours of life, and from Day 5 to 10 compared with 12 and 24 hours and 3 days. No differences were found in healthy foals analyzed in relation to birth weight and sex. In premature foals an increasing trend was observed but no statistical differences were found among sampling times, and no differences were found between healthy and premature foals. The IGF value in premature foals at admission was always higher compared with the lowest recorded level in healthy age-matched foals, thus this parameter does not seem to have a diagnostic role for prematurity in foals. Finally, the evaluation of the percentage increment of IGF-I concentrations showed a significant increase in full-term foals on Day 5, 6, 7, and 10 compared with 12 and 24 hours, and no differences were observed in premature foals. In conclusion, prematurity in newborn foals seems to affect only partially IGF-I plasma concentrations and it does not seem to be a reliable marker for this pathological condition.

DEFICIENCY OF INSULIN-LIKE GROWTH FACTOR 1 REDUCES VULNERABILITY TO CHRONIC ALCOHOL INTAKE-INDUCED CARDIOMYOCYTE MECHANICAL DYSFUNCTION: ROLE OF AMPK

ObjectivesCirculating insulin-like growth factor I (IGF-1) levels are closely associated with cardiac performance although the role of IGF-1 in alcoholic cardiac dysfunction is unknown. This study was designed to evaluate...

Assessment of immunolocalization of Fas antigen in the ovarian follicle and the role of IGF-I in Fas-L induced granulosa cell apoptosis in water buffalo

Primordial follicle pool size in the ovary is small and rate of follicular atresia is high in water buffaloes. The objective of this experiment was to study the expression of Fas antigen in granulosa cells of water buffalo ovarian follicle, and to know the role of insulin like growth factor-1(IGF-I) on Fas-ligand (Fas-L) mediated apoptosis. The Fas expression was observed mainly in the granulosa cells of the follicles. The expression was higher in the granulosa cells, which were denuded from basement membrane, indicating apoptosis. Healthy follicles which had intact multilaminar granulosa cell layer showed negative reaction for Fas antigen. The granulosa cells from 3–6 mm diameter follicles of the buffalo ovaries collected from the slaughterhouse ovaries were cultured in vitro to assess the effect of Fas-L at 10, 20 and 50ng/ ml on granulosa cell viability. The Fas-L even at the lowest dose tested (10ng/ml) significantly decreased granulosa cells viability as compared to control; whereas addition of IGF-I to the culture significantly improved granulosa cell viability. Addition of IGF-I could significantly improve the granulosa cells viability in the Fas-L treated culture. Overall this study demonstrated the existence of Fas and Fas mediated apoptosis in the granulosa cells of the buffalo follicle, and also suggested that IGF-I could rescue granulosa cells from Fas-L mediated apoptosis.

CAMP-dependent regulation of ovulatory response genes is amplified by IGF1 due to synergistic effects on Akt phosphorylation and NF-κB transcription factors

Granulosa cells play a crucial role as mediator of the LH-dependent ovulatory response. The intraovarian factor IGF1 is produced by ovarian somatic cells of healthy follicles during the ovulatory response. The objective of this study was to identify mechanisms by which IGF1, alone or in combination with LH, regulates the expression of genes in granulosa cells, which are crucial for ovulation. To achieve this objective, short-term, primary murine granulosa cell cultures were treated for 2-8 h with 1 mM 8-bromoadenosine 3',5'-cAMP to mimic the LH surge and/or 100 ng/ml IGF1. While cAMP induced significant increases in the expression of important ovulatory response genes including amphiregulin (Areg), epiregulin (Ereg), betacellulin (Btc), or interleukin 6 (Il6), IGF1 alone had no effect. However, co-treatment of cells with IGF1 and cAMP had a synergistic effect on Areg, Ereg, Btc, and Il6 mRNA abundance. Pretreatment of granulosa cells with the MEK1/2 inhibitor U0126 demonstrated that cAMP-dependent increases in Areg, Ereg, Btc, and Il6 were mediated by extracellular regulated kinase 1/2 phosphorylation. However, western blot analyses coupled with pretreatment of cells with the PI3K inhibitor LY294002 indicated that the synergistic effect of cAMP and IGF1 on transcript levels was due in part to cooperative increases in Akt phosphorylation. Western blot analyses also demonstrated that IGF1 and the combined treatment of cAMP and IGF1 decreased NF-κB p65 phosphorylation and increased NF-κB p52 levels. Together, these data indicate that IGF1 may amplify cAMP-dependent regulation of ovulatory response gene expression above an important threshold level and therefore represents a novel role for IGF1 during ovulation.

Novel Nuclear Localization and Potential Function of Insulin-Like Growth Factor-1 Receptor/Insulin Receptor Hybrid in Corneal Epithelial Cells

BackgroundType I insulin-like growth factor receptor (IGF-1R) and insulin receptor (INSR) are highly homologous molecules, which can heterodimerize to form an IGF-1R/INSR hybrid (Hybrid-R). The presence and biological significance of the Hybrid-R in human corneal epithelium has not yet been established. In addition, while nuclear localization of IGF-1R was recently reported in cancer cells and human corneal epithelial cells, the function and profile of nuclear IGF-1R is unknown. In this study, we characterized the nuclear localization and function of the Hybrid-R and the role of IGF-1/IGF-1R and Hybrid-R signaling in the human corneal epithelium.Methodology/Principle FindingsIGF-1-mediated signaling and cell growth were examined in a human telomerized corneal epithelial (hTCEpi) cell line using co-immunoprecipitation, immunoblotting and cell proliferation assays. The presence of Hybrid-R in hTCEpi and primary cultured human corneal epithelial cells was confirmed by immunofluorescence and reciprocal immunoprecipitation of whole cell lysates. We found that IGF-1 stimulated Akt and promoted cell growth through IGF-1R activation, which was independent of the Hybrid-R. The presence of Hybrid-R, but not IGF-1R/IGF-1R, was detected in nuclear extracts. Knockdown of INSR by small interfering RNA resulted in depletion of the INSR/INSR and preferential formation of Hybrid-R. Chromatin-immunoprecipitation sequencing assay with anti-IGF-1R or anti-INSR was subsequently performed to identify potential genomic targets responsible for critical homeostatic regulatory pathways.Conclusion/SignificanceIn contrast to previous reports on nuclear localized IGF-1R, this is the first report identifying the nuclear localization of Hybrid-R in an epithelial cell line. The identification of a nuclear Hybrid-R and novel genomic targets suggests that IGF-1R traffics to the nucleus as an IGF-1R/INSR heterotetrameric complex to regulate corneal epithelial homeostatic pathways. The development of novel therapeutic strategies designed to target the IGF-1/IGF-1R pathway must take into account the modulatory roles IGF-1R/INSR play in the epithelial cell nucleus.

Role of IGF-I and the TNFα/NF-κB pathway in the induction of muscle atrogenes by acute inflammation

Several catabolic states (sepsis, cancer, etc.) associated with acute inflammation are characterized by a loss of skeletal muscle due to accelerated proteolysis. The main proteolytic systems involved are the autophagy and the ubiquitin-proteasome (UPS) pathways. Among the signaling pathways that could mediate proteolysis induced by acute inflammation, the transcription factor NF-κB, induced by TNFα, and the transcription factor forkhead box O (FOXO), induced by glucocorticoids (GC) and inhibited by IGF-I, are likely to play a key role. The aim of this study was to identify the nature of the molecular mediators responsible for the induction of these muscle proteolytic systems in response to acute inflammation caused by LPS injection. LPS injection robustly stimulated the expression of several components of the autophagy and the UPS pathways in the skeletal muscle. This induction was associated with a rapid increase of circulating levels of TNFα together with a muscular activation of NF-κB followed by a decrease in circulating and muscle levels of IGF-I. Neither restoration of circulating IGF-I nor restoration of muscle IGF-I levels prevented the activation of autophagy and UPS genes by LPS. The inhibition of TNFα production and muscle NF-κB activation, respectively by using pentoxifilline and a repressor of NF-κB, did not prevent the activation of autophagy and UPS genes by LPS. Finally, inhibition of GC action with RU-486 blunted completely the activation of these atrogenes by LPS. In conclusion, we show that increased GC production plays a more crucial role than decreased IGF-I and increased TNFα/NF-κB pathway for the induction of the proteolytic systems caused by acute inflammation.

Insulin-Like Growth Factor-I Molecular Pathways in Osteoblasts: Potential Targets for Pharmacological Manipulation

The insulin-like growth factors (IGFs) are the most abundant growth factors stored in bone and produced by osteoblasts. IGF-I is an important regulator of osteoblast function and required for optimal bone development and maintenance. IGF-I can act in an endocrine, paracrine or autocrine manner and is regulated by a family of six IGF binding proteins (IGFBPs). The IGFBPs are often found bound to IGF-I in the circulation or complexed with IGF-I in osteoblasts. IGFBP-3 and -5 are known stimulators of IGF-I actions, whereas IGFBP-1, -2, -4 and -6 are known inhibitors of IGF-I action in bone. Once IGF-I binds to its receptor (type 1 IGF receptor) it initiates a complex signaling pathway including the phosphoinositol 3-kinase (PI3-K)/3-PI-dependent kinase (PDK)-1/Akt pathway and the Ras/Raf/mitogen-activated protein (MAP) kinase pathway which stimulate cell function and/or survival. Based on the critical role for IGF-I in osteoblasts, it is a logical candidate for anabolic therapy. However, systemic administration of IGF-I is not cell specific and a limited number of long term experiments have been completed to date. Several recent findings indicate that many of the IGFBPs and specific proteins in the IGF-I signaling pathways are also potent anabolic factors in regulating osteoblast function. This review will focus on the role of these factors in mediating IGF-I action in osteoblasts and how they may serve as potential targets to stimulate osteoblast function and bone formation.

Molecular mechanism of unloading-mediated muscle atrophy and development of its countermeasures

The ubiquitin ligase Cbl-b plays a major role in skeletal muscle atrophy induced by unloading [1]. The mechanism of Cbl-b-induced muscle atrophy is unique in that it does not appear to involve the degradation of structural components of the muscle, but rather it impairs muscular trophic signals in response to unloading conditions. Recent studies on the molecular mechanisms of muscle atrophy have focused on the role of IGF-1/PI3K/Akt-1 signaling cascade as a vital pathway in the regulation of the balance between hypertrophy and atrophy [2,3]. These studies indicate that under muscle wasting conditions, such as disuse, diabetes and fasting, decreased IGF-1/PI3K/Akt-1 signaling augments the expression of atrogin-1, resulting in muscle atrophy. However, these studies did not address the mechanisms of unloading-induced impairment of growth factor signaling. In the present study, we found that under both in vitro and in vivo experimental conditions, Cbl-b ubiquitinated and induced specific degradation of IRS-1, a key intermediate of skeletal muscle growth regulated by IGF-1/insulin and growth hormone, resulting in inactivation of Akt-1. Inactivation of Akt-1 led to upregulation of atrogin-1 through dephosphorylation (activation) of FOXO3, as well as reduced mitogen response, in skeletal muscle. Thus, activation of Cbl-b may be an important mechanism underlying the failure of atrophic muscle to respond to growth factor-based treatments such as IGF-1 (Figure ​(Figure11). Figure 1 Possible mechanism of unloading-mediated muscle atrophy.

Role of IGF-1 and glycaemic control in diabetic retinopathy: the authors reply

Role of IGF-1 and glycaemic control in diabetic retinopathy: the authors reply

Role of IGF-1 and glycaemic control in diabetic retinopathy

Role of IGF-1 and glycaemic control in diabetic retinopathy

Role of insulin‐like growth factors (IGFs), their receptors and genetic regulation in the chondrogenesis and growth of the mandibular condylar cartilage

Growth of the mandibular condylar cartilage (MCC) is reviewed as a function of genetic and epigenetic factors. The growth centers around the differential spatial concentration of the chondrocytes, influence of growth factors like TGF-β and heterogeneity in the number of IGF receptors, control the action of IGF. Besides these factors, growth of the mandibular condyle is influenced by differential response of chondrocytes as a function of their source/ageing, which in turn is regulated by TGF-β, BMPs and IGFs. While IGF-1 promotes proteoglycan synthesis and survival of the chondrocytes to maintain cartilage homeostasis, TGF-β synergistically catalysed the effect of IGF-1, while BMPs catalysed proteolysis as and when physiologically needed. To understand these processes, role of IGF-1 and its six receptors is at the center to a number of physiological processes being regulated by its mode of application for the growth and differentiation. Probing deeper, biological functions of IGFs seemed to depend on their level of free status rather than bound status to respective IGF-binding proteins (IGF-BPs), considered prerequisite to modulate their biological functions. Genetic regulation of their secretion has thrown light on their insulin-like structural homology, level and response in osteo-arthritis (OA), rheumatic arthritis (RA) and diabetes type-II. Biochemistry and spatial distribution of IGF receptors in different domains exerts control on IGF-1 activities. In ultimate analysis, IGF-axis conserved during the evolution to regulate cell growth and proliferation affect nearly every organ in the body as judged from the techniques determining skeletal maturity and decision making dependent on it for orthodontic, orthognathic/orthopedic and dental implant applications.

Long-Term Therapy with Growth Hormone: Bringing Sagacity to SAGHE

GH is an anterior pituitary protein secreted by somatotrophs under complex neural, hormonal, and metabolic control (1). So named because of its remarkable effects on growth when in excess (gigantism-acromegaly) or deficient (dwarfism), the hormone also has profound metabolic actions, antagonizing insulin action, promoting lipolysis in fat, and augmenting protein synthesis. These actions facilitate the integration of growth with metabolism but may have deleterious effects when in excess, including the unmasking of diabetes and diabetic complications such as retinopathy and atherosclerosis (2). Moreover, the term “growth” encompasses and envisions both normal and aberrant growth as occurs in neoplasia. Whereas deficiency of GH signaling pathways in diverse organisms such as yeast, mice, and man extends life span and decreases cancer (3), circumstantial and in vitro evidence suggests a role for IGF-I in inducing cancer in man (4). These considerations guide the ethical use of GH therapy for a variety of disorders in childhood characterized by short stature; concerns that GH may have deleterious effects that outweigh benefits surface periodically (5). GH has now been available for such treatment for over 50 yr. Initially extracted from cadaveric pituitaries, the materials were made available only to investigators for human studies via centralized, government-sponsored agencies, which also facilitated centralized monitoring of beneficial or adverse events. The use of such pituitaryextracted GH was discontinued in 1985 after the tragic occurrence of Jakob Creutzfeldt disease was recognized in several recipients in the United States and elsewhere. The tragedy of Jakob Creutzfeldt disease was particularly painful in France, where it received wide media attention, earned stiff penalties for those held responsible for GH distribution, and caused introspection for those charged with preventing such tragedies resulting from the use of GH in the future (6). Almost simultaneously, recombinant DNA-derived GH became available in abundance, enabling the broadening of indications to various forms of short stature and other entities such as chronic renal failure and AIDS wasting. Monitoring of potential adverse events was rigorously maintained by government agencies, pharmaceutical companies, the Pediatric Endocrine Society, and related organizations in the United States and throughout the world. With the exception of the use of GH for critically ill adults, which resulted in increased mortality (7) for the most part, despite valid concerns (5), the outcomes of children treated with GH have remained remarkably free of serious complications (8–12). For example, a recent analysis of safety and efficacy of GH treatment in 54,996 children monitored over a period of 20 yr (1985–2006), revealed an overall favorable safety profile without an increased risk of leukemia, a concern still expressed despite no evidence to support this concern from scientific reports over the past 25 yr (9). However, the study did identify an increased risk for a second neoplasm in those who previously received irradiation. Similarly, an increased risk for a second neoplasm in long-term survivors of childhood cancer treated with GH has been reported, although risk diminished with increased length of follow-up in this report from the Childhood Cancer Survivor Study (12). In children without a history of prior cancer or conditions that might predispose to cancer, no evidence for increased risk of cancer relative to that expected in the normal population was found in the KIGS (Pfizer International Growth Database) study as recently reported (8). None of these extensive databases have to date reported excess mortality from cardiovascular causes, and all emphasize the importance of continued and

Common Genetic Variation in the IGF1 Associates with Maximal Force Output

We clarified the effect of insulin-like growth factor-1 (IGF1), IGF-binding protein-3 (IGFBP3), interleukin-6 (IL6), and its receptor (IL6R) gene variants on muscular and aerobic performance, body composition, and on circulating levels of IGF-1 and IL-6. Single nucleotide polymorphisms (SNPs) may, in general, influence gene regulation or its expression, or the structure and function of the corresponding protein, and modify its biological effects. IGF-1 is involved in the anabolic pathways of skeletal muscle. IL-6 plays an important role in muscle energy homeostasis during strenuous physical exercise. Eight hundred forty-one healthy Finnish male subjects of Caucasian origin were genotyped for IGF1 (rs6220 and rs7136446), IGFBP3 (rs2854744), IL6 (rs1800795), and IL6R (rs4537545) SNPs, and studied for associations with maximal force of leg extensor muscles, maximal oxygen consumption, body fat percent, and IGF-1 and IL-6 levels. Analytic methods included dynamometer, bicycle ergometer, bioimpedance, ELISA, and polymerase chain reaction assays. All investigated SNPs conformed to Hardy-Weinberg equilibrium with allele frequencies validated against CEU population. Genotype CC of rs7136446 associated with higher body fat and increased maximal force production. Genotype CC of the IGFBP3 SNP rs2854744 and TT genotype of the IL6R SNP rs4537545 associated with higher IL-6 levels. In logistic regression analysis, allele C of the rs2854744 decreased odds for lower body fat. None of the studied SNPs associated with aerobic performance. Our data suggest that common variation in the IGF1 gene may affect maximal force production, which can be explained by the role of IGF-1 in the anabolic pathways of muscle and neurotrophy. Variations in the IGF1 and IGFBP3 gene may result in higher body fat and be related to alterations of IGF-1-mediated tissue growth.

Abstract A208: Pharmacodynamic properties and antitumor efficacy of BI 836845, a fully human IGF ligand neutralizing antibody.

Abstract Insulin-like growth factor (IGF) signaling is thought to play an important role in the development of tumors and resistance to existing cancer therapies. The proliferative and pro-survival signals driven by the IGF ligands, IGF-1 and IGF-2, are transmitted through their binding to the IGF-1 receptor (IGF-1R). In addition, IGF-2 activates the insulin receptor variant A (IR-A) that is expressed during embryonic development as well as in many cancers. To target IGF signaling for cancer therapy we have developed BI 836845, a fully human IgG1 antibody derived from an antibody phage display library that can bind to and neutralize the functions of both IGF-1 and IGF-2. Surface plasmon resonance (Biacore) analysis demonstrated that BI 836845 has an affinity (KD) of 0.07 nM and 0.8 nM for human IGF-1 and IGF-2, respectively. BI 836845 also shows comparable affinities to mouse as well as rat IGF-1 and IGF-2, allowing a comprehensive pre-clinical characterization of the pharmacodynamic properties of the antibody in these species. Cell-based ELISA assays were used to demonstrate that BI 836845 potently neutralizes the ability of IGF-1 and IGF-2 to phosphorylate the human IGF-1R. Similarly, BI 836845 inhibits phosphorylation of IR-A driven by IGF-2. BI 836845 was also shown to completely and potently inhibit IGF bioactivity in human serum samples ex vivo. Pharmacodynamic effects of BI 836845 were studied in growing rats treated intravenously once weekly with 20, 60, or 200 mg/kg antibody. Inhibition of IGF bioactivity as determined by ex vivo IGF-1R phosphorylation potential in the plasma was observed at all dose levels, despite a corresponding increase in total IGF-1 levels. An increase in total IGF-1 levels has also been seen with IGF-1R targeted antibodies in clinical studies and is thought to be due to blockade of a growth hormone mediated physiological feedback mechanism. Treatment with BI 836845 resulted in a marked dose dependent reduction of rat body weight gain at all dose levels, consistent with the known role for IGFs in normal growth and development. BI 836845 potently inhibits the in vitro proliferation of cell lines derived from various cancers, with mesenchymal-derived cancer cell lines being particularly sensitive (EC50 values in the low nanomolar range). In a model of Ewing s sarcoma, using immunodeficient nude mice subcutaneously transplanted with human RD-ES cells, twice-weekly treatment with BI 836845 resulted in partial inhibition of tumor growth. Treatment in combination with rapamycin resulted in improved efficacy at tolerated doses. In conclusion, BI 836845 is a potent IGF ligand neutralizing antibody whose pharmacological profile warrants further investigation in clinical studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A208.

The effects of type 1 IGF receptor inhibition in a mouse model of diabetic kidney disease

Objective We have recently shown increased sensitivity to IGF-I induced signal transduction in kidneys of diabetic mice. Accordingly we investigated the effects of PQ401, a novel diarylurea compound that inhibits IGF1R autophosphorylation in type I diabetes. Methods Control (C) and Diabetic (D) mice were administered PQ401 (CP, DP) or vehicle (C, D) for 3 weeks. Results CP animals showed a decrease in renal phosphorylated (p-)AKT and p-IGF1R. However, PQ401 had no effect on diabetic state (hyperglycemia, weight loss) or renal disease parameters (hypertrophy, hyperfiltration and albuminuria). Type IV collagen as well as TGF-β mRNA increased in DP and D compared to C. In the CP group renal hypertrophy with fat accumulation in proximal tubuli and increased renal IGF-I, collagen IV and TGF-β mRNA were seen. Conclusions IGF1R inhibition by PQ401 exerted no significant effects on diabetic kidney disease parameters, arguing against a role for IGF-I in the pathogenesis of diabetic kidney disease. However, PQ401 affects normal kidneys, inducing renal hypertrophy as well as collagen and fat accumulation, with increased renal IGF-I mRNA, suggestive of a damage-regeneration process. Therefore, this diarylurea compound is not beneficial in early diabetic kidney disease. Its potential deleterious effects on kidney tissue need to be further investigated.

Human colon cancer stem cells are enriched by insulin-like growth factor-1 and are sensitive to figitumumab

Cancer stem cells (CSCs) are recognized as contributors to cancer progression and therapeutic resistance in liquid and solid malignancies. We analyzed a panel of human colon cancer cell lines for CSC populations by side population and aldehyde dehydrogenase activity. IGF-1 enriches these putative colon CSC populations in a β-catenin-dependent manner. Chemical inhibition of Akt depletes SP cells, and conversely, the overexpression of a constitutively active mutant version of Akt is sufficient to enrich CSC populations. CP-751,871, a fully human antibody with specificity to the IGF-1 receptor, is currently being tested in clinical trials for a variety of solid tumors. CP-751,871 reduces CSC populations in colon cancer cell lines in vitro and reduces tumor growth in vivo. We have identified a novel role for IGF-1 in the enrichment of chemo-resistant CSC populations. Our results suggest that CP-751,871 has preferential activity against putative CSC populations and, therefore, may complement current standard chemotherapeutic regimens that target cycling cells.

Deficiency of insulin-like growth factor 1 reduces vulnerability to chronic alcohol intake-induced cardiomyocyte mechanical dysfunction: role of AMPK

Circulating insulin-like growth factor I (IGF-1) levels are closely associated with cardiac performance although the role of IGF-1 in alcoholic cardiac dysfunction is unknown. This study was designed to evaluate the impact of severe liver IGF-1 deficiency (LID) on chronic alcohol-induced cardiomyocyte contractile and intracellular Ca2+ dysfunction. Adult male C57 and LID mice were placed on a 4% alcohol diet for 15 weeks. Cardiomyocyte contractile and intracellular Ca2+ properties were evaluated including peak shortening (PS), maximal velocity of shortening/relengthening (±dL/dt), time-to-relengthening (TR90), change in fura-fluorescence intensity (ΔFFI) and intracellular Ca2+ decay. Levels of apoptotic regulators caspase-3, Bcl-2 and c-Jun NH2-terminal kinase (JNK), the ethanol metabolizing enzyme mitochondrial aldehyde dehydrogenase (ALDH2), as well as the cellular fuel gauge AMP-activated protein kinase (AMPK) were evaluated. Chronic alcohol intake enlarged myocyte cross-sectional area, reduced PS, ± dL/dt and ΔFFI as well as prolonged TR90 and intracellular Ca2+ decay, the effect of which was greatly attenuated by IGF-1 deficiency. The beneficial effect of LID against alcoholic cardiac mechanical defect was ablated by IGF-1 replenishment. Alcohol intake increased caspase-3 activity/expression although it down-regulated Bcl-2, ALDH2 and pAMPK without affecting JNK and AMPK. IGF-1 deficiency attenuated alcoholism-induced responses in all these proteins with the exception of Bcl-2. In addition, the AMPK agonist 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside abrogated short-term ethanol incubation-elicited cardiac mechanical dysfunction. Taken together, these data suggested that IGF-1 deficiency may reduce the sensitivity to ethanol-induced myocardial mechanical dysfunction. Our data further depicted a likely role of Caspase-3, ALDH2 and AMPK activation in IGF-1 deficiency induced ‘desensitization’ of alcoholic cardiomyopathy.

Effects of IGF-I on the Proliferation of Testis Sertoli Cells in Mouse

Sertoli cells are an important part of the male reproductive system. Except the function of promoting spermatogenesis such as supporting, providing nutrition and secreting, it also can maintain the immune privilege of testis through the expression of a special surface molecule named FasL. This feature aviods the immune response triggered by self antigen (germ cells) contacting with the body, which can be used to provide immune privilege environment for transplanted cells in areas other than the testis. In this article, we purified mouse sertoli cells, through adding different concentrations of IGF-I and IGF-I receptor inhibitor PPP, we study the role of IGF-I in the proliferation of sertoli cells. The results demonstrated that 30ng/mL IGF-I can promote the proliferation of sertoli cells while 2nmol/L PPP obviously inhibited the proliferation of sertoli cells. This result has a certain significance to obtain the high activity sertoli cells and increase the success rate of xenotransplantation.