Showing papers in "Growth Hormone & Igf Research in 2010"
TL;DR: The metabolic effects of growth hormone (GH) on the adipose tissue, liver, and skeletal muscle with focus on lipid and carbohydrate metabolism are summarized.
Abstract: This review will summarize the metabolic effects of growth hormone (GH) on the adipose tissue, liver, and skeletal muscle with focus on lipid and carbohydrate metabolism. The metabolic effects of GH predominantly involve the stimulation of lipolysis in the adipose tissue resulting in an increased flux of free fatty acids (FFAs) into the circulation. In the muscle and liver, GH stimulates triglyceride (TG) uptake, by enhancing lipoprotein lipase (LPL) expression, and its subsequent storage. The effects of GH on carbohydrate metabolism are more complicated and may be mediated indirectly via the antagonism of insulin action. Furthermore, GH has a net anabolic effect on protein metabolism although the molecular mechanisms of its actions are not completely understood. The major questions that still remain to be answered are (i) What are the molecular mechanisms by which GH regulates substrate metabolism? (ii) Does GH affect substrate metabolism directly or indirectly via IGF-1 or antagonism of insulin action?
278 citations
TL;DR: The aim of this review is to discuss the current state of the art of IGF-I immunoassays and to present the current analytical problems with IGF-i measurements, and to suggest an agenda that may be used when trying to produce internationally accepted uniform requirements for future IGF- I assays.
Abstract: For almost three decades, the measurement of circulating IGF-I has constituted a highly important biochemical tool in the management of GH disorders. In fact, in acromegaly the importance of circulating IGF-I has increased following the introduction of the GH receptor antagonist pegvisomant, as the use of this drug makes it impossible to use circulating GH as a monitor of disease activity. In addition, determination of circulating IGF-I constitutes a valuable scientific tool in various research areas, from epidemiological investigations through clinical trials and experimental studies. The multiple facets of IGF-I physiology and patho-physiology may explain why numerous endocrine laboratories have invested in IGF-I assays, by means of either in-house assays or commercial kits. However, despite its widespread use, the measurement of IGF-I is by no means trivial. On the contrary, the pronounced binding of IGF-I to the high-affinity IGF-binding proteins (IGFBPs) constitutes a notorious source of error, which has necessitated the development of methods that more or less successfully circumvent interference from the IGFBPs. Furthermore, there are some unsolved issues with the international standardization of the different IGF-I assays and there is no consensus regarding the procedures used when collecting and storing samples for measurement of circulating IGF-I. The aim of this review is to discuss the current state of the art of IGF-I immunoassays and to present the current analytical problems with IGF-I measurements. Finally, we would like to suggest an agenda that may be used when trying to produce internationally accepted uniform requirements for future IGF-I assays.
176 citations
TL;DR: This review summarizes current practices for GH measurement with respect to the methods used, their limitations and the clinical consequences of the existing heterogeneity in GH immunoassay results.
Abstract: Measuring the concentration of growth hormone (GH) in blood samples taken during dynamic tests represents the basis for diagnosis of growth hormone related disorders, namely growth hormone deficiency and growth hormone excess. Today, a wide spectrum of immunoassays are in use, enabling rapid and sensitive determination of growth hormone concentrations in routine diagnostics. From a clinical point of view several difficulties exist with the use and interpretation of GH assay results in the assessment of GH related disorders: Many physiological factors such as fat mass, age and gender influence the outcome of dynamic tests, overall leading to significant inter-individual differences in GH responses. However, in addition to the physiological variability, considerable variability exists in GH assay results obtained by different immunoassays. Unfortunately, all the new technical advances in the field of GH measurement techniques have not reduced this methodological variability. To a large extent, the actual values reported for the GH concentration in a sample depend on the method used by the respective laboratory. Obviously, such discrepancies limit the applicability of consensus guidelines on diagnosis and treatment in clinical practice. This review summarizes current practices for GH measurement with respect to the methods used, their limitations and the clinical consequences of the existing heterogeneity in GH immunoassay results.
106 citations
TL;DR: It was shown that the diminished acidosis during HIT (B) attenuates the cortisol and hGH response, and suggests that HIT/acidosis is a stimulus for exercise-induced cortisol/hGH secretion, but not for IGF-1 and IGFBP-3 under these experimental conditions.
Abstract: Objective The purpose of the present study was to examine the acute hormonal response of a short term high-intensity training (HIT) versus a high volume endurance training (HVT) and to determine the contribution of the metabolic acidosis as a stimulus for possibly different reactions of circulating hGH, IGF-1, IGFBP-3 and cortisol. Design Eleven subjects participated in three experimental trials separated by one week. Two times subjects performed four 30s maximal effort exercise bouts on a cycle ergometer separated by 5min rest each. Before the exercise subjects either received (single-blinded) bicarbonate (HIT (B)) or a placebo (HIT (P)). The third exercise trail consisted of a constant load exercise for 1h at 50% VO 2 max (HVT). Venous blood samples were taken under resting conditions, 10min, 60min and 240min after each exercise condition to determine hGH, IGF-1, IGFBP-3 and cortisol serum concentrations. Capillary blood samples were taken to determine lactate concentrations and blood gas parameters. Results Power output, mean lactate concentrations and mean pH values were significantly higher during HIT (B) compared to HIT (P). Serum cortisol and hGH concentrations were significantly increased 10min post exercise in both HIT interventions. IGFBP-3 was only significantly increased after HIT (P), whereas IGF-1 was not affected by any of the interventions. HVT showed no significant effects on cortisol, hGH, IGF-1 and IGFBP-3 levels. Additionally it was shown that the diminished acidosis during HIT (B) attenuates the cortisol and hGH response. Conclusions The present study suggests that HIT/acidosis is a stimulus for exercise-induced cortisol/hGH secretion, but not for IGF-1 and IGFBP-3 under these experimental conditions. These findings might be relevant for arrangements of interval training, due to the fact that active or passive recovery during rest periods influence the acid base status and may therefore influence the hormonal response.
98 citations
TL;DR: Although the unique mode of action of MGF has been identified, the details remain elusive and the function of this IGF-I isoform in tissue protection is poorly understood.
Abstract: Insulin-like growth factor I (IGF-I) is an important growth factor for embryonic development, postnatal growth, tissue repair and maintenance of homeostasis. IGF-I functions and regulations are complex and tissue-specific. IGF-I mediates growth hormone signaling to target tissues during growth, but many IGF-I variants have been discovered, resulting in complex models to describe IGF-I function and regulation. Mechano-growth factor (MGF) is an alternative splicing variant of IGF-I and serves as a local tissue repair factor that responds to changes in physiological conditions or environmental stimuli. MGF expression is significantly increased in muscle, bone and tendon following damage resulting from mechanical stimuli and in the brain and heart following ischemia. MGF has been shown to activate satellite cells in muscle resulting in hypertrophy or regeneration, and functions as a neuroprotectant in brain ischemia. Both expression and processing of this IGF-I variant are tissue specific, but the functional mechanism is poorly understood. MGF and its short derivative have been examined as a potential therapy for muscular dystrophy and cerebral hypoxia-ischemia using experimental animals. Although the unique mode of action of MGF has been identified, the details remain elusive. Here we review the expression and regulation of MGF and the function of this IGF-I isoform in tissue protection.
70 citations
TL;DR: The abnormal body composition similar to that in non-PWS GHD adults increases the interest of GH treatment in the prevention of obesity in adults with PWS.
Abstract: Objective Prader-Willi syndrome (PWS) is a complex genetic disease associated with hypothalamic-pituitary dysfunction and severe obesity. The aim of the present study was to describe the relationships between body composition, metabolic and hormonal profiles in PWS adults. Method Forty six adults with genetically verified PWS, 25 women and 21 men, median age 28years were studied. Body composition was evaluated by standard anthropometric procedures and with computed tomography (CT) of the abdomen and at the mid-femur level. CT of abdomen was compared to 22 healthy, unmatched adults. Circulating lipids were measured and oral glucose tolerance test (OGTT) and hormonal screening including GH secretory capacity (GHRH/arginine test) was carried out. Results Median body mass index (BMI) was 27.2kg/m 2 , with women being more obese than men. Sixteen patients had dyslipidaemia, 10 impaired glucose tolerance and seven had diabetes. Fifty percent were hypogonadal and six fulfilled BMI related criteria for growth hormone deficiency (GHD). Visceral to subcutaneous abdominal fat ratio was reduced in PWS. Visceral abdominal fat fraction correlated with both subcutaneous fat, BMI and peak GH-response. Thigh muscle volume was about half of the thigh fat volume. Beneficial effects of sex-steroid replacement on body composition were not observed. Conclusions Body fat was primarily located subcutaneously and metabolic consequences of obesity limited. The abnormal body composition similar to that in non-PWS GHD adults increases the interest of GH treatment in the prevention of obesity in adults with PWS.
62 citations
TL;DR: These findings accentuate the importance of recognition of the clinical manifestations of arthropathy in patients with acromegaly despite long-term disease control.
Abstract: Objective Quality of life is decreased in patients with long-term control of acromegaly. In addition, these patients suffer from irreversible osteoarthritis. The aim of this study was to assess the impact of joint-specific complaints, clinical and radiological signs of arthropathy on different aspects of quality of life (QoL) in patients with acromegaly after long-term disease control. Design Cross-sectional study. Methods We studied 58 patients (31 males), mean age 60 years (range 32–81 years), with strict biochemical control of acromegaly for a mean duration of 15 years. QoL was assessed by four health-related QoL questionnaires (HADS, MFI-20, NHP, SF-36) and one disease specific QoL questionnaire (AcroQoL). The outcomes of these questionnaires were compared with joint-specific self-reported complaints of pain/stiffness, clinical osteoarthritis based on American College of Rheumatology (ACR) and radiological osteoarthritis based on the Kellgren-Lawrence (KL) scoring method. Results Long-term cured acromegaly patients had high pain scores of the spine, knee, and hip which limited physical functioning (mean difference −27.0, 95%-CI −9.5, −41.0) and psychological well-being (mean difference −44.4, 95%-CI −26.1, −60.9) (SF-36). Clinical osteoarthritis of the spine was associated mostly with impaired QoL scores, on physical, social, and emotional functioning, and on anxiety and depression. Remarkably, radiological osteoarthritis was not associated with impaired QoL. Conclusion These findings accentuate the importance of recognition of the clinical manifestations of arthropathy in patients with acromegaly despite long-term disease control.
58 citations
TL;DR: There remains a high prevalence of obesity in this population and given the worsening of insulin sensitivity in the short term with GHR, monitoring and aggressive treatment of established CV risk factors is essential to reduce premature atherosclerotic CVD in this patient population.
Abstract: Background Adult GHD syndrome is associated with clustering of adverse cardiovascular (CV) risk factors such as abnormal body composition, dyslipidemia, insulin resistance and abnormal haemostatic factors. There is a wealth of evidence linking CV events with elevated levels of inflammatory markers (hs-CRP and IL-6) in the general population; however data on their abnormalities in GHD and specially the effects of GH replacement (GHR) on these inflammatory markers are limited. Objective To study the effects of GHR on inflammatory markers, glucose homeostasis and body composition in a cohort of adults with recently diagnosed severe GHD due to hypothalamic pituitary disease. Design Fifteen hypopituitary adults (11 males, mean age 48.5 years) with recently diagnosed, severe GHD were recruited. Patients received GHR (in addition to other pituitary hormone replacements) titrated to clinical response and to normalize age and gender adjusted IGF-1 levels. Weight, waist hip ratio (WHR), body composition, fasting plasma glucose and insulin, insulin resistance index (HOMA–IR), fasting serum lipid levels, hs-CRP, IL-6 and TNF-α were measured at baseline and following a minimum 6 months of stable maintenance GHR. Results GHR resulted in a physiological increase in IGF-1 SDS [median −0.6 to +0.39, P P P = 0.01). There were no significant changes in body weight and composition. Levels of hs-CRP (log transformed, mean (SD)) were significantly reduced following GHR (pre 1.21 (0.9) vs. post 0.27 (0.9), P P = 0.003], fasting insulin (μU/mL) [9.4 (8.1) vs. 12.1 (9.2), P = 0.03] and HOMA–IR [1.2 (1.0) vs. 1.5 (1.1) P = 0.02] (all pre-GHR vs. post-GHR and mean (SD)) significantly increased following GHR indicating increased insulin resistance. Significant improvements were noted in fasting LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C) levels following GHR [3.4 (0.9) vs. 2.9 (0.7), P = 0.03 and 1.2 (0.2) vs. 1.3 (0.2), P = 0.02, respectively] (all pre-GHR vs. post-GHR and mean (SD)). Levels of total cholesterol and triglycerides did not change following GHR. Conclusions Physiological GHR for at least 6 months in hypopituitary adults with recently diagnosed severe GHD resulted in favourable changes in hs-CRP, WHR, fasting LDL-C and HDL-C levels all of which are recognised CV risk markers. However, there remains a high prevalence of obesity in this population and given the worsening of insulin sensitivity in the short term with GHR, monitoring and aggressive treatment of established CV risk factors is essential to reduce premature atherosclerotic CVD in this patient population.
51 citations
TL;DR: It appears that the synchronous presence of both effective agents of the HRT or the presence of yet unidentified microenvironmental factors providing proper paracrine signals naturally existing in the intact muscle tissue is critical for appropriate signaling via sex steroid-IGF-1 axis to occur.
Abstract: Objectives To investigate the effects of combined hormone replacement therapy (HRT) and its effective agents on the IGF-1 signaling pathway. Design and methods To examine the effects of HRT on skeletal muscle in vivo , we utilized pre- and post-intervention samples from a randomized double blinded trial with 50–57-year-old women. The intervention included the year-long use of either HRT preparation (2mg 17β-estradiol, E 2 ; 1mg norethisterone acetate, NETA, n=10) or placebo (CO, n=9). Microarray technology and quantitative PCR (qPCR) were used to study the expression of insulin-like growth factor I ( IGF-1 ) and its splice variants as well as IGF-1 receptor , Akt1 , mTOR , FOXO1 , FOXO3 , atrogin , estrogen receptors and androgen receptor in muscle samples. Serum concentrations of IGF-1, E 2 and testosterone were measured. C2C12 myotubes were fed with E 2 or NETA followed by analyzing the expression of essentially the same gene transcripts as in human samples by qPCR and phosphorylation of Akt and mTOR by Western blotting. Results The gene expression of IGF-1 and its splice variant, IGF-1Ec (also known as the mechano growth factor or MGF), mTOR , FOXO3 , and AR was up-regulated among the HRT users compared to the CO (P Akt1 was down-regulated (P IGF-1Ec transcript correlated positively with muscle size at post-intervention (r=0.5, P 2 or NETA at the level of gene transcripts studied were identified. The amount of phosphorylated Akt appeared to respond to NETA, albeit the response was not statistically significant. Phosphorylation of mTOR did not respond to either of the treatments. Conclusion Year-long postmenopausal HRT was found to affect the expression of the genes along the IGF-1 signaling cascade reflecting the higher muscle mass compared to the CO women. By using cell culture model we were, however, unable to confirm the possible differential role of E 2 and NETA. It appears that the synchronous presence of both effective agents of the HRT or the presence of yet unidentified microenvironmental factors providing proper paracrine signals naturally existing in the intact muscle tissue is critical for appropriate signaling via sex steroid-IGF-1 axis to occur.
48 citations
TL;DR: It is shown for the first time that peripheral bGH administration increases the generation of new brain cells in normal adult female rats, suggesting that bGH may stimulate cellular proliferation not only under GH-deficiency, but also under physiologic conditions.
Abstract: Growth hormone (GH) and insulin-like growth factor I (IGF-I) increase cell genesis in several regions of the brains of GH-IGF-I-deficient hypophysectomized rats. However, it is not known to what degree GH treatment stimulates adult cell genesis in pituitary-intact rodents. We investigated the effect of peripheral administration of bovine growth hormone (bGH) on cellular proliferation in various regions of the brains of normal adult female rats. To monitor cell division, bromodeoxyuridine (BrdU) was administered daily for 5 days. We studied the two areas of ongoing neurogenesis, the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus, as well as the corpus callosum, striatum, and the parietal and piriform cortices. After bGH treatment, the numbers of BrdU-positive cells increased 2.0- to 2.5-fold in all the brain regions, with the exception of the SVZ, in which there was no increase in the numbers of BrdU-positive cells. The present study shows for the first time that peripheral bGH administration increases the generation of new brain cells in normal adult female rats. Thus, bGH may stimulate cellular proliferation not only under GH-deficiency, but also under physiologic conditions. These findings have important implications for GH treatment strategies for patients who have normal or near-normal circulating levels of GH or IGF-I.
46 citations
TL;DR: The data suggest male and female fetuses institute different strategies in response to adverse pregnancy conditions such as asthma and cigarette use, and on the newborn insulin-like growth factor (IGF) axis.
Abstract: Background Fetal growth varies in a sex-specific manner in response to maternal asthma during pregnancy, but the mechanisms are unclear. Objective We examined the influence of maternal asthma severity and associated exposures, inhaled glucocorticoid treatment, maternal cigarette use, and fetal sex on fetal growth and placental function during pregnancy and on the newborn insulin-like growth factor (IGF) axis. Study subjects and design Fetal growth was assessed in a prospective cohort of asthmatic and non-asthmatic women (n = 145). At delivery, umbilical vein plasma was collected from male (n = 61, controls n = 16 and asthmatic n = 45) or female (n = 84, controls n = 22 and asthmatic n = 62) fetuses. Cord plasma insulin-like growth factor (IGF) binding protein (BP)-1, IGFBP-3, IGF-1 and IGF-2 were measured by radioimmunoassay and ELISA. Results Cord plasma IGF-1 was the main component of the neonatal IGF axis altered by asthma and cigarette use. IGF-1 was increased in the presence of mild asthma and a male fetus and decreased in the presence of a female fetus and maternal asthma with cigarette use. IGFBP-3 was also decreased in the female fetuses of pregnancies complicated by asthma and cigarette use. Inhaled glucocorticoid use for the treatment of asthma did not affect the IGF axis. The strongest overall predictor of female birth weight after accounting for asthma severity, inhaled glucocorticoid treatment and cigarette use was IGF-1. For males, the strongest predictor of birth weight was IGFBP-3. Conclusion The data suggest male and female fetuses institute different strategies in response to adverse pregnancy conditions such as asthma and cigarette use.
TL;DR: It is hypothesized that IGF-II plays a role in the survival disparity observed among AA breast cancer patients by stimulating rapid tumor growth, inhibiting apoptosis, and promoting metastasis.
Abstract: Objective: Increased risk of cancer and other adult diseases have been associated with perinatal exposure to adverse conditions such as stress and famine. Recently, Insulin-like growth factor II (IGF-II) was identified as the first gene associated with altered expression caused by fetal exposure to poor nutrition. IGF-II regulates fetal development and breast cancer cell survival, in part, by regulating anti-apoptotic proteins through activation of the IGF-I and insulin receptors. African–American (AA) women have a lower overall breast cancer (BC) incidence, however, they present with advanced disease at diagnosis, poorer prognosis and lower survival than Caucasian (CA) women. The reasons for the BC survival disparity are not well understood. We hypothesize that IGF-II plays a role in the survival disparity observed among AA breast cancer patients by stimulating rapid tumor growth, inhibiting apoptosis, and promoting metastasis. Design: This study examines IGF-II expression and regulation of the anti-apoptotic proteins Bcl-2, Bcl-X L , and survivin in Hs578t (ER−), CRL 2335 (ER−), and CRL 2329 (ER+) breast cancer cells and compares with the expression of these proteins in paired breast tissue samples from AA and CA women by qRT-PCR and Western blotting. Results: IGF-II expression was significantly higher in AA cell lines and tissue samples when compared to Caucasians. IGF-II siRNA treatment decreased anti-apoptotic protein levels in all cell lines (regardless of ER status). These effects were blocked by the addition of recombinant IGF-II. Of significance, IGF-II expression and regulation of Bcl-X L and survivin in cell lines correlated with their expression in paired breast tissues. Conclusions: IGF-II and the anti-apoptotic proteins differential expression among AA and CA patients may contribute to the breast cancer survival disparities observed between these ethnic groups.
TL;DR: Survival, growth, antrum formation and steroidogenesis are stimulated by IGF-I and bFGF, whereas TGF-α + TGF-β 1 inhibited growth and survival of PFs which led to induced oocyte apoptosis in buffalo PFs.
Abstract: Objective Investigate th e effect of various growth factors viz. IGF-I, TGF-α + TGF-β 1 and bFGF either alone or in combination, with FSH on in vitro growth, survival, antrum formation, steroidogenesis and apoptosis of buffalo preantral follicles (PFs). Methods Buffalo ovaries were collected from abattoir; PFs were isolated and divided into five treatment groups. TCM-199 supplemented with 10% FBS, 1% ITS + EGF + FSH control (group a), control + IGF-I (group b), control + TGF-α + TGF-β 1 (group c), control + IGF-I + TGF-α + TGF-β 1 (group d) and control + bFGF (group e). Progesterone (P 4 ) and 17β-estradiol (E 2 ) concentrations were evaluated by RIA and apoptosis by TUNEL assay. Results TGF-α + TGF-β 1 inhibited follicular survival and induced oocyte apoptosis, while IGF-I + TGF-α + TGF-β 1 suppressed this inhibitory action. IGF-I significantly ( P P 1 . Conclusion Survival, growth, antrum formation and steroidogenesis are stimulated by IGF-I and bFGF, whereas TGF-α + TGF-β 1 inhibited growth and survival of PFs which led to induced oocyte apoptosis in buffalo PFs.
TL;DR: The occurrence of null alleles, the inclusion of T2D patients in analyses of metabolic syndrome risk traits and the genetic model, are possible factors accounting for non-replications of IGF2BP2 associations with T1D.
Abstract: Objective Genetic variation at the insulin-like binding protein 2 ( IGF2BP2 ) gene has been associated with type 2 diabetes (T2D) by genome-wide association studies and by replication analyses. Our aim was to explore the underlying genetic model and mechanism of action, factors accounting for non-replications of the associations, and the effect of variation from pathway-related genes IGF2BP1 and IGF2BP3 . Method We analysed here the association between T2D (and related traits) and rs4402960 and rs1470579 in IGF2BP2 , and rs46522 and rs6949019 (marking IGF2BP1 and IGF2BP3 respectively) from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study ( N ∼2500 aged 65–96years). We undertook a retrospective analysis of the deviations from the multiplicative model in previous studies and the present study. Results We replicated an association between rs4402960 and T2D status, and reported significant associations with anthropometric traits, fasting insulin, HOMA-IR and HOMA-%B. These associations were also observed for rs1470579, but not for the SNPs marking IGF2BP1 and IGF2BP3 . Conclusions The lower fasting insulin levels and the impaired β-cell function associated with IGF2BP2 SNPs are independent of obesity phenotypes. The action of these SNPs on T2D may result from an effect on β-cell function. This could lead to lower insulin levels, the association with anthropometric traits being secondary. We discuss possible mechanisms of action relating IGF2BP2 with T2D traits. The occurrence of null alleles, the inclusion of T2D patients in analyses of metabolic syndrome risk traits and the genetic model, are possible factors accounting for non-replications of IGF2BP2 associations with T2D.
TL;DR: Recent advances in IGF research are summarized and the potential for IGF to act as a co-stimulatory factor for somatic cell reprogramming and iPS cell development is discussed, which will be instrumental in regenerative medicine.
Abstract: Recent success in reprogramming somatic cells into induced pluripotent stem cells (iPS cells) with a cluster of nuclear transcription factors, such as Oct4, Sox2, Klf4, and c-myc, opens up a new era in regenerative medicine. However, reportedly poor efficiency and slow kinetics of the reprogramming process by viral transfection of the nuclear factors may create an obstacle that hampers clinical application of the iPS cell technology. Furthermore, the viral transfection may induce mutagenesis and raises the risk for cancer development. Hence, generation of iPS cells using a non-viral approach appears to be an important prerequisite for iPS cell-based regenerative medicine. Through its receptor/phosphoinositide 3-kinase (PI3-K) signaling pathway, insulin-like growth factor (IGF) plays a critical role in promotion of survival and proliferation in a diversity of cell types, including both embryonic and adult stem cells. In addition, IGF may enhance expression of reprogramming or surviving factors in reprogramming somatic cells. This review summarizes recent advances in IGF research and discusses the potential for IGF to act as a co-stimulatory factor for somatic cell reprogramming and iPS cell development. Currently available evidence from experimental animal and human studies highly suggests that IGF may contribute to reprogramming of somatic cells into iPS cell generation, and enhancement of iPS cell survival and growth, which will be instrumental in regenerative medicine.
TL;DR: This case report describes the identification of His-tagged Long-R³-IGF-I, which is usually produced for biochemical studies, in an injection vial and the product may rather be a by-product from biochemical studies than synthesized for injection purposes.
Abstract: Objective Performance-enhancing substances are illicitly used in elite or amateur sports and may be obtained from the black market due to a cheaper and easier availability. Although various studies have shown that black market products frequently do not contain the declared substances, enormous amounts of illegally produced and/or imported drugs are confiscated from athletes or at customs with alarming results concerning the outcome of the analyses of the ingredients. This case report describes the identification of His-tagged Long-R 3 -IGF-I, which is usually produced for biochemical studies, in an injection vial. Design The ingredients were isolated by immunoaffinity purification and identified by nano-UPLC, high-resolution/high accuracy mass spectrometry of the intact and trypsinated substance and by an enzyme-linked immunosorbent assay. Results (Tandem) mass spectra characterized the protein as Long-R 3 -IGF-I with a His 6 -tag attached to the C-terminus by the linker amino acids Leu–Glu. Conclusion His-tags are commonly added to proteins during synthesis to allow a convenient and complete purification of the final product and His-tags are subsequently removed by specific enzymes when being attached to the N-terminus. The effects of His-tagged Long-R 3 -IGF-I in humans have not been elucidated or described and the product may rather be a by-product from biochemical studies than synthesized for injection purposes.
TL;DR: It is confirmed that Class 2 signal peptide is not necessary for systemic circulation of IGF-1, revealing an internal compensation system for maintaining IGF- 1 serum concentrations and uncovered a vital requirement of IGF -1 for perinatal viability, previously obscured by modifiers in heterogeneous genetic backgrounds.
Abstract: Insulin-like growth factor 1 (IGF-1) is a pleiotropic factor involved in growth, cell survival and cellular differentiation It exerts its functions through endocrine, paracrine or autocrine mechanisms Circulating IGF-1 is essential for normal fetal and postnatal growth, although the published phenotypes of IGF-1 null animals have been only partially penetrant, presumably due to mixed genetic backgrounds Molecular dissection of IGF-1 action is complicated by the existence of at least nine different IGF-1 isoforms, generated in both humans and rodents by usage of alternate promoters, differential splicing and different post-translational modifications Several lines of evidence suggest that the Class 2 IGF-1 isoform is specifically destined for circulation, supporting an endocrine role of IGF-1 in normal growth processes Using Cre/LoxP conditional gene targeting of exon 2 of the IGF-1 gene, we have generated a Class 2 IGF-1 knockout mouse line in a pure C57/Bl6 genetic background, where the specific removal of exon 2 ablated Class 2 IGF-1 isoform Class 2 IGF-1 knockout mice exhibited normal development and postnatal growth patterns and had normal IGF-1 circulating levels, due to compensatory upregulation of Class 1 transcripts In contrast, progeny of a total IGF-1 knockout line lacking exon 3 in the same genetic background were predictably smaller, displayed dramatically reduced IGF-1 receptor phosphorylation and all died perinatally, apparently due to respiratory failure These results confirm that Class 2 signal peptide is not necessary for systemic circulation of IGF-1, revealing an internal compensation system for maintaining IGF-1 serum concentrations We also uncover a vital requirement of IGF-1 for perinatal viability, previously obscured by modifiers in heterogeneous genetic backgrounds
TL;DR: Serum IGF-II/M6P-R is up-regulated in morbid obesity, down-regulated by weight loss and elevated in moderately obese T2D, indicating that the IGF- II/M 6P- R is nutritionally regulated, independently of IGF-ii.
Abstract: Objective The extracellular domain of the insulin-like growth factor II/mannose-6-phosphate receptor (IGF-II/M6P-R) is present in the circulation, but its relationship with plasma IGF-II is largely unknown. As IGF-II appears to be nutritionally regulated, we studied the impact of obesity, type 2 diabetes (T2D) and weight loss on circulating levels of IGF-II and its soluble receptor. Methods Twenty-three morbidly obese non-diabetic subjects were studied before and after gastric banding (GB), reducing their BMI from 59.3 ± 1.8 to 52.7 ± 1.6 kg/m 2 . Lean controls ( n = 10, BMI 24.2 ± 0.5 kg/m 2 ), moderately obese controls ( n = 21, BMI 31.8 ± 1.0 kg/m 2 ) and obese T2D patients ( n = 20, BMI 32.3 ± 0.8 kg/m 2 ) were studied before and after a hyperinsulinaemic euglycaemic clamp. Results Morbidly obese subjects had elevated IGF-II/M6P-R and IGF-II levels, which both decreased following GB (IGF-II/M6P-R: from 0.97 ± 0.038 to 0.87 ± 0.030 nmol/l, P = 0.001; IGF-II: from 134 ± 7 to 125 ± 6 nmol/l, P = 0.01), as did fasting plasma glucose and insulin ( P P r P r = 0.57; P r = 0.39; P Conclusion Serum IGF-II/M6P-R is up-regulated in morbid obesity, down-regulated by weight loss and elevated in moderately obese T2D. However, although plasma IGF-II was also reduced following GB, the two peptides were not statistically correlated. No acute effect of insulin was seen. These findings indicate that the IGF-II/M6P-R is nutritionally regulated, independently of IGF-II.
TL;DR: Obesity at age 18 and a weight gain of >or=21 kg since age 18 were also significantly associated with an increased risk of colorectal adenomas and both lesions, but not hyperplastic polyps.
Abstract: Objective We examined the risk of colorectal polyps in relation to body size factors and candidate polymorphisms in selected genes of insulin-like growth factor (IGF1) (rs5742612), IGF1 receptor (IGF1R) (rs2229765), IGF binding protein 3 (IGFBP3) (rs2854746) and growth hormone (GH1) (rs2665802). Design Cases with colorectal adenomas (n = 519), hyperplastic polyps (n = 691), or both lesions (n = 227), and controls (n = 772), aged 20–74 years, were recruited from patients who underwent colonoscopy between December 2004 and September 2007 at a large integrated-health plan in Washington state. Subjects participated in a 45-minute telephone interview to ascertain body size and physical activity, and provided a buccal DNA sample for genetic analysis. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable polytomous regression. Results Compared to those of normal weight, higher body mass index (BMI) was associated with elevated risk of colorectal adenomas (OR = 1.65, 95% CI 1.22-2.25 BMI ≥ 30 kg/m2, p-trend = 0.002) and both lesions (OR = 2.15, 95% CI 1.43-3.22 BMI ≥ 30 kg/m2, p-trend = 0.003), but there was no relationship with hyperplastic polyps. Obesity at age 18 and a weight gain of ≥ 21 kg since age 18 were also significantly associated with an increased risk of colorectal adenomas and both lesions, but not hyperplastic polyps. There was a reduced risk of colorectal adenomas (OR = 0.63, 95% CI 0.42-0.94) and hyperplastic polyps (OR = 0.7, 95% CI 0.5–0.9) associated with the homozygous variant genotype for GH1. Few meaningful results were evident for the other polymorphisms. Conclusions There is an increased risk of colorectal adenomas and presence of both adenomas and hyperplastic polyps in relation to increasing body size. Some genetic variation in GH1 might contribute to a reduced risk of colorectal adenomas and hyperplastic polyps.
TL;DR: Sprint exercise suppresses total ghrelin concentrations and stimulates GH release but does not alter IGF concentrations or bioactivity.
Abstract: Exercise stimulates growth hormone (GH) release, but there are conflicting reports regarding the acute effects of exercise on circulating ghrelin and insulin-like growth factor (IGF) concentrations. This investigation examined (1) the effect of a single sprint on circulating GH, ghrelin and IGF concentrations as well as a marker of IGF-I bioactivity, and (2) whether the number of muscle actions performed during a sprint influences these responses. Seven healthy men completed 3 trials in a random order. In two exercise trials they performed a single 30-s sprint on a cycle ergometer against a resistance equivalent to either 7% (FAST) or 9% (SLOW) of their body mass. In the other they rested in the laboratory (CON). Blood samples were taken pre-, immediately post-, 10 and 30 min post-exercise, and at equivalent times in the CON trial. Total ghrelin concentrations declined after the sprint and were significantly lower after 30 min of recovery than they were pre-exercise (pre-exercise vs. 30 min; FAST, 0.62 (0.19) vs. 0.49 (0.16) microg/L, P<0.001; SLOW, 0.59 (0.15) vs. 0.47 (0.13) microg/L, P<0.001). GH concentrations increased in both exercise trials and were greater in the FAST than the SLOW trial. Serum concentrations of total IGF-I, free IGF-I, total IGF-II, and IGF-I bioactivity did not change after sprinting. In conclusion, sprint exercise suppresses total ghrelin concentrations and stimulates GH release but does not alter IGF concentrations or bioactivity.
TL;DR: IG1R and IGF2R differential expression may contribute to the increased risk of malignant transformation in young AA women and to the more aggressive breast cancer phenotype observed among AA breast cancer patients and represent, along with IGF-II, potential therapeutic targets in breast cancer.
Abstract: Objective: African–American (AA) women with breast cancer are more likely to have advanced disease at diagnosis, higher risk of recurrence and poorer prognosis than Caucasian (CA) women. We have recently shown higher insulin-like growth factor II (IGF-II) expression in paired breast tissue samples from AA women as compared to CA women. IGF-II is a potent mitogen that induces cell proliferation and survival signals through activation of the IGF-I and Insulin receptors (IGF-IR, IR) while IGF-II circulating levels are regulated by cellular uptake through the IGF2 receptor. We hypothesize that differential expression of the IGF1R and IGF2R among AA and CA women potentiates IGF-II mitogenic effects, thus contributing to the health disparity observed between these ethnic groups. Design: We examined IGF-IR and IGF2R mRNA, protein expression and IGF1R phosphorylation in paired breast tissue samples from AA and CA women by Real Time-PCR, Western blot analysis, immunohistochemistry and ELISA techniques. Results: Our results showed significantly increased expression of IGF1R in AA normal tissues as compared to CA normal tissues. IGF1R expression was similar between AA normal and malignant tissues, while IGF1R, IRS-1 and Shc phosphorylation was significantly higher in AA tumor samples. Significantly higher levels of IGF2R were found in CA tumor samples as compared to AA tumor samples. Conclusions: We conclude that IGF1R and IGF2R differential expression may contribute to the increased risk of malignant transformation in young AA women and to the more aggressive breast cancer phenotype observed among AA breast cancer patients and represent, along with IGF-II, potential therapeutic targets in breast cancer.
TL;DR: Findings suggest that OC-DDTs could modulate the IGF-system in a way that is highly influenced by gender and age.
Abstract: Context Serum levels of Insulin-like growth factor I (IGF-I) play a critical role in children growth and in the pathogenesis of several diseases. In addition, recent studies suggest that DDT-derivative organochlorine pesticides (OC–DDTs) could influence IGF levels in human beings. Objective and design Because it has been suggested that IGF-I peak levels at puberty could determine IGF-I levels in adulthood, we developed a cross-sectional study of the potential association between serum levels of OC–DDTs and IGF system in 160 serum samples from young people (81 boys and 79 girls) living in the Canary Islands (Spain). Results Multivariate tests were used adjusting for confounding variables (age, height, and weight) and stratifying by gender and age: IGF-I serum levels were significantly lower in pre-pubertal male children (6–15years) who showed detectable values of p , p ′-DDE, and p , p ′-DDD than in pre-pubertal male children with undetectable levels of these OC–DDTs-metabolites ( p =0.023 and p =0.049, respectively). In addition, in this multivariate model, a non-linear dose–response curve was observed between Total DDT body burden (sum of the three DDT-derivatives measured: p , p ′-DDT, p , p ′-DDE, and p , p ′-DDD) and IGF-I in pre-pubertal male children (6–15years; p =0.043). Conclusion These findings suggest that OC–DDTs could modulate the IGF-system in a way that is highly influenced by gender and age. Improvements in our understanding of exogenous determinants of the IGF-system may provide new insights into the role played by environmental contaminants in IGF-related diseases.
TL;DR: Evidence is provided that E2F1 regulates IGF-ir gene transcription in prostate cancer cells via a mechanism that involves direct binding to specific elements in the proximal IGF-IR promoter.
Abstract: Objectives The insulin-like growth factor-I receptor (IGF-IR) plays an important role in cancer development. The E2F1 transcription factor activates S-phase promoting genes and mediates apoptosis. Microarray analyses of E2F1-induced genes revealed that genes associated with proliferation as well as apoptosis are upregulated by E2F1. Among other candidate genes, DNA microarrays identified the IGF-IR gene as a putative E2F1 target. The aim of this study was to investigate the involvement of E2F1 in regulation of IGF-IR gene transcription. Methods To examine the potential regulation of IGF-IR gene expression by E2F1, an E2F1 expression vector was transfected into P69 and M12 prostate cancer cell lines, after which IGF-IR levels were measured by Western blots. Transient transfections were used to evaluate IGF-IR promoter activity and chromatin immunoprecipitation (ChIP) assays were employed to assess E2F1-binding to the IGF-IR promoter. Results Results obtained showed that E2F1 expression induced a significant increment in endogenous IGF-IR levels. ChIP assays showed enhanced E2F1-binding to the IGF-IR promoter in E2F1-expressing cells. Transient coexpression of an E2F1 vector along with an IGF-IR promoter-luciferase reporter resulted in a ∼140-fold increase in IGF-IR promoter activity. Furthermore, deletion and bioinformatic analyses indicate that the ability of E2F1 to stimulate IGF-IR promoter activity was correlated with the number of E2F1 sites in the promoter region. Conclusions In summary, we provide evidence that E2F1 regulates IGF-IR gene transcription in prostate cancer cells via a mechanism that involves direct binding to specific elements in the proximal IGF-IR promoter.
TL;DR: It is hypothesize that the catabolism induced by HD is in part related to the observed reductions in bioactive IGF-I, which is likely a consequence of the increase in IGFBP-1, sequestering free IGF- I, and reducing bioactive FG-I.
Abstract: Objective Hemodialysis (HD) patients lose lean body mass, even when they are adequately dialysed. One reason may be a decreased activity of the IGF-system. However, data on changes in bioactive IGF-I during HD are sparse. Design Ten stable, non-diabetic HD patients were studied with 30 min intervals during a scheduled HD, with blood sampling before (−15 and 0 min), during (4 h) and after (1 h) the session. Patients were fasted for at least 6 h before and during the study. Arterial and venous blood was sampled for determination of IGF-I bioactivity, free and total IGF-I and IGF-II, IGF binding protein-1 (IGFBP-1), IGFBP-1 complexed IGF-I and IGFBP-2. Results Total IGF-I and -II decreased marginally ( Conclusion Despite marginal reductions in total IGF-I and -II, bioactive and free IGF-I declined markedly during and after HD. This is likely a consequence of the increase in IGFBP-1, sequestering free IGF-I, and reducing bioactive IGF-I. Based on the present data we hypothesize that the catabolism induced by HD is in part related to the observed reductions in bioactive IGF-I.
TL;DR: It is found that IGF-I inhibited insulin activity in the 3T3-L1 adipocytes via ROS production, which affects IRS-1 phosphorylation status, and preincubation of adipocytes with an antioxidant, N-acetyl-cysteine restored the IGF- I-induced attenuation of insulin-dependent glucose uptake.
Abstract: Objective IGF-I is known to enhance insulin sensitivity in whole body mainly via the IGF-I receptors in muscles. However, the effect of IGF-I on the regulation of insulin sensitivity in the adipose tissue is yet unclear. Insulin sensitivity was found to be higher in the IGF-I receptor-deficient adipocytes than that in wild-type adipocytes, suggesting that IGF-I signaling induces insulin resistance in adipocytes. However, the underlying mechanism has not yet been elucidated. In addition, the effect of superphysiological levels of IGF-I, as is observed in patients with acromegaly, on insulin sensitivity remains unclear. Design To clarify the role of IGF-I on insulin sensitivity in adipocytes, we determined insulin-induced glucose uptake and IRS-1 status in 3T3-L1 adipocytes treated with IGF-I. Since reactive oxygen species (ROS) are causally related to insulin resistance, we investigated the effect of IGF-I on ROS production to elucidate the molecular mechanism underlying insulin resistance. Results Preincubation of the adipocytes with IGF-I attenuated insulin-dependent glucose uptake. Interestingly, we found that IGF-I significantly stimulated ROS production. Furthermore, preincubation of adipocytes with an antioxidant, N-acetyl-cysteine (NAC) restored the IGF-I-induced attenuation of insulin-dependent glucose uptake; this indicates that IGF-I induces insulin resistance via ROS. Serine phosphorylation of IRS-1 was strongly induced and the insulin-dependent tyrosine phosphorylation of IRS-1 was suppressed by preincubating the adipocytes with IGF-I. Further, NAC restored these changes induced by IGF-I on both serine and tyrosine phosphorylation of IRS-1. Conclusions These data indicate that IGF-I inhibited insulin activity in the 3T3-L1 adipocytes via ROS production, which affects IRS-1 phosphorylation status.
TL;DR: A low IGF-I level is associated with hypercapnia presumably by reducing ventilatory drive and favouring muscle weakness, and may represent one of mechanisms involved in the OHS increased cardio-vascular risk.
Abstract: Context Obesity hypoventilation syndrome (OHS) is defined by the association between obesity and daytime arterial hypercapnia. The syndrome includes in variable proportion impaired diaphragmatic weakness, decreased central ventilatory drive and nearly systematically occurrence of sleep apnea. An increased cardio-vascular risk has been demonstrated compared to normocapnic obesity. IGF-I has a pleiotropic role in metabolism, ventilatory control, muscle function and cardiovascular protection. Objectives and design We performed a case control study comparing somatotropic axis changes including IGF-I in obese with or without OHS. Methods Patients underwent respiratory function tests, CO 2 ventilatory responses, polysomnography and somatotropic axis exploration (GH, IGF-I and IGFBP-3). Results 15 OHS (BMI: 41±5.6kg/m 2 , PaCO 2 : 6.13±0.39kPa, age: 55.6±5.9years) and 15 matched obese without hypercapnia (BMI: 42±6.7kg/m 2 , PaCO 2 : 5.13±0.27kPa, age: 55.0±7.5years) were compared. IGF-I and IGFBP-3 were significantly lowered in OHS, and negatively correlated with PaCO 2 ( r =−0.615; P r =−0.452; P =0.016, respectively). Inspiratory capacity and forced vital capacity reflecting respiratory muscle strength decreased significantly with IGF-I ( r =0.408; P =0.038). Triglycerides levels were higher in OHS (1.64±0.58 versus 1.13±0.56g/L; P r =−0.418; P =0.027). Conclusion A low IGF-I level is associated with hypercapnia presumably by reducing ventilatory drive and favouring muscle weakness. The relationship between increased triglycerides and low IGF-I may represent one of mechanisms involved in the OHS increased cardio-vascular risk.
TL;DR: Findings provide compelling evidence that PAPP-A increases bone formation primarily by increasing IGF bioavailability and that other alternative pathways may play a negligible role in mediating the anabolic effect of PAPPA in bone.
Abstract: In vivo studies have provided ubiquitous evidence that pregnancy-associated plasma protein-A (PAPP-A) functions as a potent anabolic factor. While some evidence supports the prediction that increasing IGF bioavailability contributes to the anabolic effects of PAPP-A, definitive evidence has been lacking. This important issue has been addressed in this study using a unique mouse model in which PAPP-A was overexpressed in bone either alone or together with a protease-resistant IGFBP-4 analog (PRBP-4) which serves as an IGF inhibitor. PAPP-A transgenic mice exhibited a 25% increase in skull bone mineral density (BMD) whereas PRBP-4 transgenic mice showed a 20-25% decrease in this parameter at an age of 3months. Femur/tibia size-related parameters were significantly increased in PAPP-A transgenic mice but decreased in PRBP-4 transgenic mice. This data clearly demonstrates that PAPP-A transgenic mice exhibit opposite phenotypes in both flat bone and long bone compared to PRBP-4 transgenic mice which have reduced IGF bioavailability in bone. Importantly, PRBP-4 and PRBP-4/PAPP-A double transgenic mice shared essentially identical phenotypes in both flat and long bones. Calvarial thickness, skull BMD and long bone parameters were reduced to similar degrees in PRBP-4 and PRBP-4/PAPP-A transgenic mice relative to wild-type littermates. Our findings provide compelling evidence that PAPP-A increases bone formation primarily by increasing IGF bioavailability and that other alternative pathways may play a negligible role in mediating the anabolic effect of PAPPA in bone. This clear definition of PAPP-A's mechanism of action is critical for future translational studies on the therapeutic application of PAPP-A.
TL;DR: Insulin glargine was more potent in activating the IGF-IR than HI and insulin detemir, and further research is needed to find out whether this data have implications for clinical use of insulin glargin.
Abstract: Objective To investigate whether human insulin (HI) and insulin analogues differ in their ability to activate the human IGF-I receptor (IGF-IR), the human insulin receptor A (IR-A) and the human insulin receptor B (IR-B) in vitro. Methods HI, short-acting insulin analogues (insulin aspart; insulin lispro) and long-acting insulin analogues (insulin glargine; insulin detemir) were compared by using kinase receptor activation (KIRA) bioassays specific for IGF-IR, IR-A or IR-B, respectively. These assays quantify ligand activity by measuring receptor auto-phosphorylation upon ligand binding. HI and insulin analogues were tested in a range from 0.1 to 100 nM. Results Short-acting analogues: Overall, short-acting insulin analogues did not differ substantially from HI, nor from each other. Insulin lispro was slightly more potent than HI and insulin aspart in activating the IGF-IR, only reaching statistical significance at 100 nM (p Long-acting analogues: At 1 nM (p Conclusions Insulin glargine was more potent in activating the IGF-IR than HI and insulin detemir. Since KIRA bioassays do not mimic the exact in vivo situation, further research is needed to find out whether our data have implications for clinical use of insulin glargine.
TL;DR: Serum IGF-I concentrations are associated with peak exercise capacity in healthy women, but not in men over a wide range in ages, body sizes and activity scores.
Abstract: Background Insulin-like growth factor I (IGF-I) and its binding protein 3 (IGFBP-3) are central mediators of endocrine effects of growth hormone and there is increasing evidence for an association with muscle strength and exercise capacity. The aim of the present study was to clarify the possible association of circulating IGF-I and IGFBP-3 concentrations and exercise capacity in a general adult population. Materials and methods From the Study of Health in Pomerania (SHIP) 1332 subjects aged 25 to 85 years participated in a standardised symptom limited cardiopulmonary exercise test on a bicycle. Exercise capacity was characterized by oxygen uptake at anaerobic threshold (VO 2 @AT), peak exercise (peakVO 2 ), oxygen pulse and maximum power output at peak exertion. Multivariable linear regression analyses adjusted for age, sex, body mass index, physical activity and smoking were performed. Results At peak exercise performance, in women IGF-I showed significant associations to peakVO 2 and maximum power output, IGF-I/IGFBP-3 ratio was associated with maximum power output. In men, this association was not consistently reproducible. Neither IGF-I nor IGFBP-3 did reveal any association to VO 2 @AT in both genders. Conclusion Serum IGF-I concentrations are associated with peak exercise capacity in healthy women, but not in men over a wide range in ages, body sizes and activity scores.
TL;DR: It is demonstrated that resistance training initiated in the acute post-operative phase is highly effective in increasing mean fiber area and in addition induces marked increases in the expression of IGF-I splice variants, supporting the idea that IGF- I is involved in regulating muscle hypertrophy.
Abstract: Hypertrophy of developing skeletal muscle involves stimulation by insulin-like growth factor-I (IGF-I), however, the role of IGF-I in adult muscle is less clarified. In the present study, the mRNA splice variants of IGF-I (IGF-IEa and MGF) and the changes in muscle fiber cross sectional area after 12 weeks of training were studied in elderly post-operative patients. About 28 subjects, 14 men and 14 women (age 69, range 60–86 years) were randomized to unilateral resistance training (RT: 3/week), electrical stimulation (ES: 1 h/day) or functional exercises (FE: 1 h/day). The non-operated-side served as a within subject control. Muscle biopsies were obtained from the vastus lateralis of both limbs at +2d post-operative (baseline), at 5 weeks and 12 weeks post-surgery to analyze for changes in type 1 and type 2 muscle fiber area. Changes in expression levels of IGF-I mRNA isoforms were determined using real-time RT-PCR, normalized to the ribosomal protein large protein 0 (RPLP0) mRNA and presented relative to the control-side. At baseline there was no difference between the three groups in muscle fiber area or resting levels of IGF-IEa and MGF. RT resulted in a significant increase in muscle fiber area of type 1 (+17%, p