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The article reviews the sources of scientific literature on the role of somatomedin - insulin-like growth factor-1 (IGF-1) in predicting the development of metabolic disorders in patients with hypertension, the depth of the search for a period of 10 years. It is noted that this scientific problem has been studied in different countries, the connection between IGF-1 deficiency and the occurrence of metabolic disorders in patients with hypertension (AH) is considered to be one of the predictors of cardiovascular disease. It was experimentally established that the study of the content of IGF-1 in the blood revealed a significant decrease in the level of somatomedin in groups of patients with varying degrees of hypertension. Studies have confirmed the pathogenetic role of IGF-1 deficiency in the development of left ventricular hypertrophy and heart failure in patients with hypertension in combination with type 2 diabetes mellitus (DM). It is the deficiency of IGF-1 in the blood was associated with the development of degenerative processes. Immune-modulating ability of IGF-1 has been established, antithrombotic and antiremodeling properties of somatomedin have been proved. It was found that people with normal blood pressure and people without signs of impaired glucose tolerance had significantly higher levels of IGF-1 in the blood. It is established that the study of the role of IGF-1 in the prediction of metabolic disorders in patients with hypertension is a promising scientific problem.

Growth hormone (GH) promotes growth and development in children and is the meaningful co-regulator of the metabolism in adulthood. GH may act directly, through its receptor (GHR), as well as via mediators – insulin-like growth factors: IGF-1, i.e. somatomedin C and IGF-2. Moreover, GH and two growth factors are involved in the mechanisms of cell proliferation, differentiation and survival, hence their oncogenic potential is propounded. Indeed, GH, somatomedins and their receptors are found abundantly in normal and cancer cells in several tissues. It has been shown in animal and human trials that polymorphisms and mutations that increase signal transmission from the GH and IGF-1 receptor are associated with more frequent tumors development and reduce life expectancy. Numerous epidemiological studies have confirmed a clear relationship between GH/IGF-1 level in circulation and a cancer-dependent morbidity and mortality. It dictates caution in case of treatment with use of growth hormone. Such replacement therapy is recommended in cases of GH deficiency. In the common opinion of scientific societies such treatment is generally safe, although in some cases unambiguous opinion in this field cannot be determined yet. On the other hand, on the basis of available evidence, GH cannot be recommended for use by the healthy elderly (ani-aging medicine), bearing in mind that GH decline with age may represent a beneficial adaptation to ageing. Understanding the molecular mechanisms by which GH and GH-dependent growth factors affect cell metabolism and proliferation will allow to use them in oncology in the future.

Background PrePubertal children with type 1 diabetes mellitus are shorter than their non- diabetic peers. we aimed to evaluate the role of HbA1c and IGFBP-3 in this phenomenon. Aim of the work: The aim of the study was to evaluate the effect of glycemic control on the growth and IGFBP-3, represented by height, weight, height and weight percentiles for age in a sample of prepubertal Egyptian children with T1DM. Patients and Methods This study was a cross sectional study conducted on 80 pre-pubertal Egyptian children, divided into 25 Males and 25 Females with T1DM and 30 age matched controls (15 Males and 15 Females), the participants were recruited from the Outpatient Clinic of the Pediatric Department of Ain Shams University Hospitals and the National Institute of Diabetes and Endocrinology in Cairo, Egypt during the period from July 2018 to August 2019. Anthropometric measures including height and weight were obtained and used to calculate the height and weight percentiles using the CDC calculators. HbA1c as well as IGFBP-3 levels were tested. Results The mean age (years) of the participants was (9.671±2.24) for male patients, (9.22 ± 2.19) for female patients and (8.39 ± 2.034) for controls. The height found to be lower in the children with T1DM when compared to the disease-free controls with median values of (129.287 ± 13.410) in male patients, (127.727 ±10.155) in female patients and (136.760 ± 13.431) in the controls. the height and weight percentiles (%) were found to be lower in the children with T1DM when compared to the disease-free controls, the height percentile with median values of 14.54 (IQR 27.95) in male patients, 17.93 (IQR 29.20) in female patients and 87.07 (IQR 20.48) in the controls. the weight percentile with median values of 40.68 (IQR 40.83) in male patients, 30.64(IQR 35.59) in female patients and 85.18 (IQR 20.17) in the controls. A negative correlation between HbA1c (%) and serum IGFBP-3 (ng/ml), height and height percentile were found with (0.014, 0.049 and 0.012) as well as a positive correlation between serum IGFBP-3 and height, height and weight percentiles (%), were found with (,0.004, 0.009 and 0.005 respectively). Serum IGFBP-3 levels were also found to be significantly lower in patients (P < 0.001) with a mean value of (198.6 ± 45.335) in male patients and (168.4 ± 44.317) in female patients and (285.333 ± 61.936) in the disease-free controls. Conclusion Serum IGFBP-3 levels (ng/ml) as well as growth are negatively affected in prepubertal children with T1DM in relation to the glycemic control.

Objective The neuroendocrine response to critical illness is dichotomous as it is adaptive during the acute phase then transitions to maladaptive as critical illness becomes prolonged in 25-30% of patients. Presently, monitoring all critically ill patients for endocrinopathies is not the standard of care. However, given the negative impact on patient prognosis, a need to identify those at risk for endocrinopathies, may exist. Thus, a screening tool to identify endocrinopathies along the somatotroph and gonadal axes in a cardiothoracic surgery population was developed. Methods A prospective observational pilot study was conducted in two cardiothoracic surgery intensive care units (ICU) within a multi-site healthcare system. Total testosterone and somatomedin C levels were obtained from 20 adult patients who remained in the ICU for greater than seven days after cardiothoracic surgery and were tolerating nutrition, had a risk of malnutrition and a mobility score of moderate to dependent assistance. Results Twenty patients were included for descriptive analysis (seven females). Thirteen patients tested low for total testosterone, with males more likely to have a testosterone-related endocrinopathy as compared to females (100% vs. 0 to 43%, p = 0.0072). A higher proportion of low somatomedin C levels was found in females than males (57% vs. 31%); however, the difference was not statistically significant (p = 0.251). Conclusions The screening tool used in this pilot study accurately predicted low total testosterone in all men and reasonably predicted low somatomedin C in a majority of women. However, the ability of the tool to predict low total testosterone in women and low somatomedin C in men is less certain. A gender-specific screening tool might be necessary to predict hormonal deficiencies.

The discovery of the growth hormone (GH)-mediated somatic factors (somatomedins), insulin-like growth factor (IGF)-I and -II, has elicited an enormous interest primarily among endocrinologists who study growth and metabolism. The advancement of molecular endocrinology over the past four decades enables investigators to re-examine and refine the established somatomedin hypothesis. Specifically, gene deletions, transgene overexpression or more recently, cell-specific gene-ablations, have enabled investigators to study the effects of theIgf1andIgf2genes in temporal and spatial manners. The GH/IGF axis, acting in an endocrine and autocrine/paracrine fashion, is the major axis controlling skeletal growth. Studies in rodents have clearly shown that IGFs regulate bone length of the appendicular skeleton evidenced by changes in chondrocytes of the proliferative and hypertrophic zones of the growth plate. IGFs affect radial bone growth and regulate cortical and trabecular bone properties via their effects on osteoblast, osteocyte and osteoclast function. Interactions of the IGFs with sex steroid hormones and the parathyroid hormone demonstrate the significance and complexity of the IGF axis in the skeleton. Finally, IGFs have been implicated in skeletal aging. Decreases in serum IGFs during aging have been correlated with reductions in bone mineral density and increased fracture risk. This review highlights many of the most relevant studies in the IGF research landscape, focusing in particular on IGFs effects on the skeleton.

Lesser degrees of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini/TDLU, are associated with elevated breast cancer risk. In rodent models, the insulin-like growth factor (IGF) system regulates involution of the mammary gland. We examined associations of circulating IGF measures with TDLU involution in normal breast tissues among women without precancerous lesions. Among 715 Caucasian and 283 African American (AA) women who donated normal breast tissue samples to the Komen Tissue Bank between 2009 and 2012 (75% premenopausal), serum concentrations of IGF-I and binding protein (IGFBP)-3 were quantified using enzyme-linked immunosorbent assay. Hematoxilyn and eosin-stained tissue sections were assessed for numbers of TDLUs ("TDLU count"). Zero-inflated Poisson regression models with a robust variance estimator were used to estimate relative risks (RRs) for association of IGF measures (tertiles) with TDLU count by race and menopausal status, adjusting for potential confounders. AA (vs. Caucasian) women had higher age-adjusted mean levels of serum IGF-I (137 vs. 131 ng/mL, p = 0.07) and lower levels of IGFBP-3 (4165 vs. 4684 ng/mL, p

Background and Objectives: Most athletes suffer from zinc and magnesium deficiency. Zinc and magnesium deficiency can reduce anabolic hormones and reduce performance of athletes. The aim of this study was to evaluate the effect of three months of zinc-magnesium supplementation along with intense endurance training on somatomedin C levels and endurance performance in female Wistar rats. Methods: In this experimental study, 24 mature female Wistar rats, were randomly divided into three groups of 8 each: (control, intense endurance training, and intense endurance training+zinc-magnesium supplementation(. The training protocol consisted of running on treadmill for 3 months (5day/week). In the supplement group, in addition to standard meal and water, 227 mg of zinc sulfate and 10g of magnesium sulfate, were used per liter of water. One week before the end of the period, the subjects' endurance performance, was assessed, and 24 hours after the last training session and after 8 hours of overnight fasting, blood samples were collected. Then, plasma level of somatomedin C, was measured. Data were analyzed using one-way ANOVA and Tukey's post hoc tests. Results: In this study, three months of endurance training along with supplementation, had no significant effects on serum somatomedin C levels of the groups (p=0.23), but endurance performance of the endurance training+supplementation group, significantly increased compared to the control (p=0.00) and training without supplementation group (p=0.00). Also, the endurance performance of the training without supplementation group, significantly increased compared to the control group (p=0.003). Conclusion: According to the results, zinc-magnesium supplement may be cautiously taken into account as a factor in improving endurance performance in female rats. &nbsp

As the most trait of commercial fish, increasing the growth rate of skeletal muscle is of great significance to aquaculture industry. However, the regulation of growth hormone/somatomedin (GH/IGF) growth-axis on skeletal muscle has not been effectively applied for many years, and its effect on fish and production significance for aquaculture need to be further studied. This study investigated the regulatory mechanism in sturgeon development and combined multiple organ transcriptomics revealed some common pathways emerged in the developed sturgeon including “Cytokine-cytokine receptor interaction”, “Focal adhesion”, and “Arginine and Proline Metabolism”, while many specific pathways have also been enriched in each organ. Further, all annotated GH/IGF growth-axis related genes were higher in 12 months post-fertilized sturgeon than in 24 months one, showing the potential regulation of GH/IGF growth-axis in sturgeon growth. Besides, we found that our developed hybrid F1 sturgeons with Acipenser baeri♀ and Acipenser schrenckii♂ were highly expressed in downstream of GH/IGF growth-axis than that of A. schrenckii F1 and obviously higher than A. baeri F1. The hybrid F1 with high GH/IGF growth-axis expression and high myofiber diameter also has higher growth performance. The implementation of this study proved the promotion of GH/IGF growth-axis gene on sturgeon growth, which provided a target for further development of commercial fleshy varieties in the future.

There is a growing body of evidence indicating that patients with adult GH deficiency (GHD) are characterized by a cluster of traditional and emerging cardiovascular risk factors and markers, which can significantly increase their cardiovascular morbidity and mortality possibly linked to aberrations in GH status. Patients with adult GHD present multiple different cardiovascular abnormalities. In addition, cardiovascular risk in adult GHD is increased due to altered body composition, abnormal lipid profile, insulin resistance and impaired glucose metabolism. Cardiovascular risk factors can be reversed, at least partially, after GH replacement. However, evidence on the effects of GH replacement on cardiovascular events and mortality is too limited in adult GHD patients. Aim of this review is to provide an at-a-glance overview of the role of the GH/IGF-I on the cardiovascular system and the state of art of the effects of GH replacement on cardiovascular system.

The latent variable "δ" (for "dementia") appears to be uniquely responsible for the dementing aspects of cognitive impairment. Age, depressive symptoms, gender and the apolipoprotein E (APOE) e4 allele are independently associated with δ. In this analysis, we explore serum proteins as potential mediators of age's specific association with δ in a large, ethnically diverse longitudinal cohort, the Texas Alzheimer's Research and Care Consortium (TARCC). 22 serum proteins were recognized as partial mediators of age's association with δ. These include Insulin-like Growth Factor-Binding Protein 2 (IGF-BP2), which we had previously associated with age-specific cognitive change, and both Pancreatic Polypeptide (PP) and von Willebrand Factor (vWF), previously associated with δ. Nine other δ-related proteins were not confirmed by this ethnicity adjusted analysis. Our findings suggest that age's association with the disabling fraction of cognitive performance is partially mediated by serum proteins, somatomedins and hormones. Those proteins may offer targets for the specific treatment of age-related effects on dementia severity and conversion risk.

The current understanding of human growth hormone (hGH; here GH) action is that the molecule is a 191-amino acid, single-chain polypeptide that is synthesized, stored and secreted by the somatotroph cells within the lateral wings of the anterior pituitary gland. It can be classified as a protein (comprising more than 50 amino acids) but true proteins have tertiary and quaternary chains creating a more complex structure, hence GH is usually classified as a polypeptide. GH is normally secreted at night during sleep and promotes skeletal, visceral and general body growth through the action of somatomedins or IGFs, notably IGF-1. In some tissues, GH action is directed via specific receptors GHRs; these are most abundant in liver, adipose and muscle tissues but have also been shown in granulosa cells, testicular tissues and on the oocyte, as well as in glandular cells of the luteal phase endometrium and decidua; such findings being recent and minimally researched to now. Following engagement with its receptor, the transduction process activates multiple signaling proteins. These all lead to extensive metabolic and mitogenic (growth promoting) responses. Clinically, GH is known to have an important role in pubertal development and is a key hormone for the vigor associated with adolescence and early adult life stages but has a faded presence and role for later adulthood, beyond age 30 years, and is minimally detected in advanced age, beyond 40 years. In association with the rapidly increasing trend for delaying reproduction beyond age 35 years, GH is being widely researched now as a potential adjuvant for infertility treatment in this group who, studies consistently show, have a poorer prognosis than younger females when relying on autologous oocytes. The idea that the age-related reduction in fertility prognosis is a feature of growth hormone deficiency is supported by our studies showing an elevated binding protein IGFBP-3/IGF-1 ratio and this can be reduced to a normal range (matching younger, good prognosis women) by the administration of GH as an adjuvant.

OBJECTIVES: Maternal obesity is strongly associated with offspring obesity risk. However, studies show that paternal obesity also affects offspring phenotype, especially in males. Programming of the growth hormone (GH) insulin-like growth factor (IGF) axis seems to be an important mechanism in this finding, but evidence regarding this relationship in humans is scarce. The primary purpose of this study was to evaluate associations between maternal and paternal adiposity with that of their offspring. A secondary aim was to investigate associations between paternal adiposity with GH levels in male offspring. METHODS: Parent-offspring trios (n = 209) from the Glowing study were studied. Percent body fat mass (%FM) was measured using air displacement plethysmography early in pregnancy in parents, and at age 2 weeks in the offspring. Plasma GH levels were measured at birth from umbilical cord blood (n = 31) and at age 2 years (n = 39) in male offspring. Multiple linear regression was used to model infant's %FM (dependent variable) at 2 weeks of age using parental %FM, race, age, IQ, income, delivery method, gestational weight gain, feeding mode, and gestational age (GA) as independent variables. The best fitted models were constructed for girls and boys. Spearman correlations (ρ) between paternal %FM and offspring GH levels were adjusted for maternal %FM. RESULTS: Girls (n = 94): Paternal %FM did not associate with female newborn %FM. Instead, maternal %FM (β = 0.12, P = 0.010) and C-section delivery mode (β = 2.56, P = 0.011) had the strongest associations with female newborn %FM. Boys (n = 115): Maternal %FM (β = 0.12, P = 0.006) and GA (β = 1.06, P = 0.003) were positively associated with male newborn %FM, whereas paternal %FM was negatively associated (β = −0.09, P = 0.014) with male offspring adiposity. There was no significant correlation between paternal %FM and GH measured at birth (ρ = 0.19, P = NS) in boys. However, at age 2 years, GH levels in boys decreased with increasing paternal %FM (ρ = −0.40, P = 0.015). Maternal %FM did not correlate with offspring GH level at any age. CONCLUSIONS: Parental obesity differentially associates with newborn girls’ and boys’ adiposity at age 2 weeks. In line with prior findings in animal models, this preliminary analysis points to programming of the GH/IGF axis in male offspring born to obese fathers. FUNDING SOURCES: USDA ARS # 6026-51000-010-05S, NIH 1UL1RR029884.

BACKGROUND: Rapid growth of skeletal muscle in the neonate requires the coordination of protein deposition and myonuclear accretion. During this developmental stage, muscle protein synthesis is highly sensitive to amino acid supply, especially Leu, but we do not know if this is true for satellite cells, the source of muscle fiber myonuclei. OBJECTIVE: We examined whether dietary protein restriction reduces myonuclear accretion in the neonatal pig, and if any reduction in myonuclear accretion is mitigated by restoring Leu intake. METHODS: Neonatal pigs (1.53 ± 0.2 kg) were fitted with jugular vein and gastric catheters and fed 1 of 3 isoenergetic milk replacers every 4 h for 21 d: high protein [HP; 22.5 g protein/(kg/d); n= 8]; restricted protein [RP; 11.2 g protein/(kg/d); n= 10]; or restricted protein with Leu [RPL; 12.0 g protein/(kg/d); n= 10]. Pigs were administered 5-bromo-2’-deoxyuridine (BrdU; 15 mg/kg) intravenously every 12 h from days 6 to 8. Blood was sampled on days 6 and 21 to measure plasma Leu concentrations. On day 21, pigs were killed and the longissimus dorsi (LD) muscle was collected to measure cell morphometry, satellite cell abundance, myonuclear accretion, and insulin-like growth factor (IGF) system expression. RESULTS: Compared with HP pigs, postprandial plasma Leu concentration in RP pigs was 37% and 47% lower on days 6 and 21, respectively (P

Antidepressants are among the most-prescribed class of drugs in the world and though weight gain is a common outcome of antidepressant treatment, that effect is not well understood. We employed an animal model comprised of 2 weeks of chronic restraint stress with antidepressant treatment, followed by diet-induced obesity. We showed that short-term antidepressant treatment had long-lasting effects, not only leading to weight gain, but also enhancing trabecular and cortical bone features in rats; therefore, weight gain in this model was different from that of the classic diet-induced obesity. Late in the post-restraint recovery period, antidepressant-treated animals were significantly heavier and had better bone features than saline-treated controls, when assessed in the distal femoral metaphysis. The propensity to gain weight might have influenced the rate of catch-up growth and bone allometry, as heavier animals treated with fluoxetine also had enhanced bone features when compared to non-stressed animals. Therefore, short-term antidepressant treatment ameliorated the long-term effects of stress on body growth and bone. Growth and bone structural features were associated with leptin levels, and the interaction between leptin levels and antidepressant was significant for bone mineral content, suggesting that short-term antidepressants in the context of long-term diet-induced obesity modified the role of leptin in bone formation. To our knowledge this is the first study reporting that short-term antidepressant treatment has long-lasting effects in restoring the effects of chronic stress in body weight and bone formation. Our findings may be relevant to the understanding and treatment of osteoporosis, a condition of increasing prevalence due to the aging population.

Background: Pituitary adenomas are benign and frequent tumors, some of them with tendency to be recurrent or invasive e. several pituitary tumors are positive for secretion of one or more hormones of the same adenohypophysial cell lineage. However, some cases have a subclinical course and are underestimated because they have plurihormonal secretion of different adenohypophyseal cells lineage. Clinical Case: A 38 years old women with chronic headaches, who is in fertility treatment for 12 month ago presents to the clinic with unremarkable physical examination. Her laboratory studies include: Normal campimetry. T3 (triiodothyronine) 2.15 ng/m L (NR:0.8 - 2.0), TSH (thyroid stimulating hormone) 4.4 uU/mL (NR:0.27 - 4.2), T4 (tetraiodothyronine) 13.54 ug/dl, (NR:5.1 - 14.1), Free T4 2.44 ng/d (NR:0.93 - 1.7), Estradiol 60.2 pg/ml, FSH (Follicle stimulating hormone) 4.3 mUI/ml (NR:1,7-12), Cortisol (?8 am) 9.29 ug/dl (NR:4.2 - 38.4), ACTH (Corticotrophin-releasing hormone) 13.1 pg/ml (NR: 0.0 - 46.0), Somatomedin C (IGF-1) 231 .0 ng/ml (NR for age?: 57.0-241.0). Brain MRI with pituitary protocol showed in T1 an isointense lesion and slightly heterogeneous in T2 in the anterior and left aspect of the turkish saddle, of 1 x 1.1 x 1.1 cm of anteroposterior, transverse and cephalocaudal diameter, suggestive of a macroadenoma. The tumor pathology showed, possitive for a pituitary adenoma. Immunohistochemistry results were negative for: ACTH:, positive for GH, TSH: (+++) and for Prolactin:. Her post-operative findings showed a residual pituitary gland without significant findings. Her post operative pituitary axis include: Sodium 139.2 mmol/l (NR”135.0 - 145.0), Chloride 100.8 mmol/l (NR95.0 - 115.0), Potassium 3.71 mmol/l (NR3.5 - 5.1), ACTH 4.1 pg/ml(NR0.0 - 46.0), Cortisol (am) 11.11 ug/dl (NR4.2 - 38.4), Estradiol 106.5 pg/ml, FSH 5.1 mUI/ml, LH (Luteinizing Hormone) 13.53 mIU/ml, Somatomedin C (IGF-1) 134 .0 ng/m, Free T32.4 pg/ml, TSH 0.9 uU/mL Free T4 0.99 ng/dl, and Prolactin 23.4ng/ml. Patient had a satisfactory clinical course after surgery, she maintained normal pituitary function without requirement of hormonal replacement therapy. Conclusion: We present a a prolactin, TSH and GH secreting pituitary adenoma case, which is very unusual. It i is important to make a proper pituitary evaluation, and offer effective treatment to prevent complications

Regulation of final organ size is a complex developmental process that involves the integration of systemic and organ-specific processes. Previously, we have shown that in developing Drosophila, perturbing the growth of one imaginal disc - the parts of a holometabolous larva that become the external adult organs - retards growth of other discs and delays development, resulting in tight inter-organ growth coordination and the generation of a correctly proportioned adult. Whether different parts of the same imaginal disc similarly coordinate their growth to generate a functioning adult organ is, however, unclear. In this study, we use the wing imaginal disc in Drosophila to study and identify mechanisms of intra-organ growth coordination. We generate larvae in which the two compartments of the wing imaginal disc have ostensibly different growth rates (wild-type or growth-perturbed). We find that there is tightly coordinated growth between the wild-type and growth-perturbed compartments, where growth of the wild-type compartment is retarded to match that of the growth-perturbed compartment. Crucially, this coordination is disrupted by application of exogenous 20-hydroxyecdysone (20E), which accelerates growth of the wild-type compartment. We further elucidate the role of 20E signaling in growth coordination by showing that in wild-type discs, compartment-autonomous up-regulation of 20E signaling accelerates compartment growth and disrupts coordination. Interestingly, growth acceleration through exogenous application of 20E is inhibited with suppression of the Insulin/Insulin-like Growth Factor Signaling (IIS) pathway. This suggests that an active IIS pathway is necessary for ecdysone to accelerate compartment growth. Collectively, our data indicate that discs utilize systemic mechanisms, specifically ecdysone signaling, to coordinate intra-organ growth.

Leptin is an anorexigenic peptide hormone that circulates as an indicator of adiposity in mammals, and functions to maintain energy homeostasis by balancing feeding and energy expenditure. In fish, leptin tends to be predominantly expressed in the liver, another important energy storing tissue, rather than in fat depots as it is in mammals. The liver also produces the majority of circulating insulin-like growth factors (IGFs), which comprise the mitogenic component of the growth hormone (GH)-IGF endocrine growth axis. Based on similar regulatory patterns of leptin and IGFs that we have documented in previous studies on hybrid striped bass (HSB: Morone saxatilis×Morone chrysops), and considering the co-localization of these peptides in the liver, we hypothesized that leptin might regulate the endocrine growth axis in a manner that helps coordinate somatic growth with energy availability. Using a HSB hepatocyte culture system to simulate autocrine or paracrine exposure that might occur within the liver, this study examines the potential for leptin to modulate metabolism and growth through regulation of IGF gene expression directly, or indirectly through the regulation of GH receptors (GHR), which mediate GH-induced IGF expression. First, we verified that GH (50nM) has a classical stimulatory effect on IGF-1 and additionally show it stimulates IGF-2 transcription in hepatocytes. Leptin (5 and/or 50nM) directly stimulated in vitro GHR2 gene expression within 8h of exposure, and both GHR1 and GHR2 as well as IGF-1 and IGF-2 gene expression after 24h. Cells were then co-incubated with submaximal concentrations of leptin and GH (25nM each) to test if they had a synergistic effect on IGF gene expression, possibly through increased GH sensitivity following GHR upregulation by leptin. In combination, however, the treatments only had an additive effect on stimulating IGF-1 mRNA despite their capacity to increase GHR mRNA abundance. This suggests that leptin's stimulatory effect on GHRs may be limited to enhancing transcription or mRNA stability rather than inducing full translation of functional receptors, at least within a 24-h time frame. Finally, leptin was injected IP (100ng/g and 1μg/gBW) to test the in vivo regulation of hepatic IGF-1 and GHR1 gene expression. The 100ng/g BW leptin dose significantly upregulated in vivo IGF-1 mRNA levels relative to controls after 24h of fasting, but neither dosage was effective at regulating GHR1 gene expression. These studies suggest that stimulation of growth axis component transcripts by leptin may be an important mechanism for coordinating somatic growth with nutritional state in these and perhaps other fish or vertebrates, and represent the first evidence of leptin regulating GHRs in vertebrates.

BACKGROUND: Chronic undernutrition, a condition currently affecting more than 17 millions of children under five years of age, has severe long-term consequences including stunting. Epidemiologic studies have emphasized that undernutrition cannot be ascribed to food insecurity alone and gut microbiota has been shown to play an active role in disease aetiology. In mammals, post-natal growth is controlled by the activity of the somatotropic axis. Undernutrition leads to a decrease of the Insulin like Growth Factor 1 (IGF-1) and a state of Growth Hormon (GH) resistance. AIMS: Previously we have shown the capacity of selected Lactobacillus plantarum strain to maintain growth in infant mono-colonized mice during chronic undernutrition. Here we show that L. plantarum retains its growth promoting capabilities also in a conventional mouse model. METHODS: C57BL6 male mice were weaned at 21 days and bred on a standard or an experimental (isocaloric, hypoprotidic and hypolipidic) diet until young adulthood. One group of mice on experimental diet received an Lp(WJL) oral supplementation (2*10^8 CFU/day; 5 days per week) and the other group received placebo. Length and weight were measured weekly. Mice were sacrificed at day 56 to study the impact of the Lp(WJL) oral supplementation on IGF-1 levels and organ growth. Somatotropic axis activity was tested at Day 28 by injecting the mice with GH and measured by the STAT5 phosphorylation level. RESULTS: At D56, mice fed with the experimental diet were smaller than the standard diet group (7.7 vs 8.9 cm; p< 0.01). Undernourished mice had a lower hepatic level of IGF-1 (113 ± 39 vs 174 ± 35 pg/mg tissues; p

The purpose of the present study was to determine the response of glucose (G), insulin (In) and insulin-like growth factor (IGF)-I to eccentric (ECC) vs. concentric (CON) resistance exercise in healthy trained and untrained subjects. Venous blood samples were drawn before and immediately after the test, and during 1-hour recovery for the determinations of hormonal and somatomedin concentrations. As compared to resting values, the maximal eccentric (ECC) resistance exercise test caused a significant decrease in G level (p

Non-islet cell tumor hypoglycemia (NICTH) is a paraneoplastic syndrome characterized by persistent, severe hypoglycemia with a wide variety of solid tumors. It is considered to cause hypoglycemia by increasing the insulin-like bioactivity of the circulating insulin-like growth factor (IGF) system, however, the precise mechanism of hypoglycemia remains unclear. In this manuscript, we report on a patient suffering from NICTH caused by a small cell carcinoma of the colon. This is the first report focusing on the role of bioactive IGFs for this pathological condition. First, we demonstrated that the IGF signal pathway has been activated in this tumor in an autocrine and/or paracrine manner using immunohistochemical analysis. Second, we confirmed that bioactive IGFs in the patient's serum were increased using a modified kinase receptor activation assay, thus bioactive IGFs (mainly IGF-2) could be considered to play a major pathogenic role in enhanced hypoglycemic insulin-like activity. Third, increased IGF bioactivity in the patient's serum was completely inhibited by an anti-IGF neutralizing antibody in vitro. These results suggest that neutralization of bioactive IGFs might become a novel therapeutic strategy for NICTH to relieve the hypoglycemic symptoms together with the tumor suppressive effect.

Sleep and sleep disordered breathing (obstructive sleep apnea [OSA]) are known to affect the growth hormone/insulin-like growth factor (GH/IGF) axis. There are few relevant population studies in this area, particularly in the elderly. We conducted this study to investigate the relationship between sleep (architecture and OSA) and circulating IGF-I (insulin-like growth factor-1), IGFBP-1 (insulin-like growth factor binding protein-1), and IGFBP-3 (insulin-like growth factor binding protein-3) levels in an elderly population.Cross-sectional analysis of participants from the year 9 visit of the Cardiovascular Health Study (CHS) who were enrolled in the Sleep Heart Health Study (SHHS).1,233 elderly participants from the CHS and SHHS.The mean age of males (n = 526) and females (n = 697) was 77 years. The mean value of IGF-I (ng/mL) in males was 112.4 vs. 97.1 in females (p0.01). Mean IGFBP-1 and IGFBP-3 levels were higher in females than males (p0.01). As expected, slow wave sleep was better preserved in females compared to males (22% total sleep time vs. 9% total sleep time, p0.01). Furthermore, as expected, OSA (apneahypopnea index [AHI] ≥ 5/h) was more prevalent in males compared to females (60% vs. 46%, p0.01). Multivariable linear regression was used to determine the relationship between objective sleep parameters and circulating IGF-I, IGFBP-1, and IGFBP-3 levels, with adjustment for age, sex, race, BMI, diabetes, estrogen use, progestin use, and physical activity. We did not detect a significant association between slow wave sleep (SWS) (per 5 min) and IGF-I, IGFBP-1, and IGFBP-3 levels (ng/mL). We found no significant linear association between OSA (AHI ≥ 5/h) and IGF-I, IGFBP-1, and IGFBP-3 levels. Gender-stratification of the entire cohort did not alter these findings. Sensitivity analyses excluding diabetics revealed that moderate OSA (AHI ≥ 5 and15) is inversely associated with IGFBP-3 levels in women. Conclusions The relationship between SWS and GH/IGF system is not significant in the elderly. Furthermore, OSA does not appear to adversely influence the GH/IGF axis, as reported in younger individuals. Whether our study findings are due to diminished GH/IGF-I axis activity in elderly needs further investigation by replication in other large population based elderly cohorts.

Colorectal cancer (CRC) is one of the most prevalent cancers worldwide and also the one with the highest mortality rate. Tumor growth is assisted by various growth factors, and insulin-like growth factors (IGFs) are among the most important. A majority of the IGFs are bound to IGF-binding proteins (IGFBPs) and their release is dependent on the rate of IGFBP proteolysis. The action of free IGFs is exerted and controlled by binding to cell membrane receptors (IGF-Rs). The objective of this work was to connect two determinants of the CRC pathology: oxidation as a process that underlies tumor development and the members of the IGF system that control it. Carbonyl groups (CO) on IGFBP-2, IGFBP-3, IGF-1R, and IGF-2R were determined in samples obtained from patients with CRC, and IGF-binding properties of these proteins were analyzed. According to our results, IGFBP-2 and IGFBP-3 in serum had increased content of CO groups due to CRC. Oxidation of IGFBP-2 increased its affinity for IGF molecules, whereas oxidation of IGFBP-3 reduced it. As for receptors, only intact CO-IGF-2R was detected on solubilized colon membranes, whereas CO-IGF-1R was degraded into fragments. Oxidative changes in the IGF axis may be regarded as part of the mechanism of its action. IGFs bound to IGFBP-3 remain in the circulation, whereas those bound to IGFBP-2 freely reach target tissues. Therefore, oxidation supports IGF distribution toward tissues and, consequently, promotes tumor growth.

Reduced signaling through the IGF type 1 (IGF-1) receptor increases life span in multiple invertebrate organisms. Studies on mammalian longevity suggest that reducing levels of IGF-1 may also increase life span. However, the data are conflicting and complicated by the physiology of the mammalian neuroendocrine system. We have performed life-span analysis on mice homozygous for an insertion in the Igf1 gene. These mice produce reduced levels of IGF-1 and display a phenotype consistent with a significant decrease in IGF-1. Life-span analysis was carried out at three independent locations. Although the life-span data varied between sites, the maximum life span of the IGF-1-deficient mice was significantly increased and age-specific mortality rates were reduced in the IGF-1-deficient mice; however, mean life span did not differ except at one site, where mean life span was increased in female IGF-1-deficient animals. Early life mortality was noted in one cohort of IGF-1-deficient mice. The results are consistent with a significant role for IGF-1 in the modulation of life span but contrast with the published life-span data for the hypopituitary Ames and Snell dwarf mice and growth hormone receptor null mice, indicating that a reduction in IGF-1 alone is insufficient to increase both mean and maximal life span in mice.

BackgroundAcromegaly is an illness usually defined by excessively high growth hormone (GH) and insulin like growth factor 1 (IGF-1) levels, the latter mainly reflecting GH action on the liver. IGF-1, also known as somatomedin C, mediates several actions of GH. The diagnosis and management of acromegaly is relatively straight forward, but long-term follow-up of patients can be difficult, as elevated IGF-1 levels can occur in the presence of apparently normalised GH levels and late recurrence of acromegaly may arise despite previous suppression on oral glucose tolerance testing. Data suggest this applies especially to patients in whom the GH receptor lacks exon 3. In such patients, GH may not always be a useful marker of disease, and traditional GH cut-offs may be misleading. Recent data suggest that soluble Klotho (sKlotho), besides and in addition to IGF-1, may help monitor the activity of GH-producing adenomas (presumably reflecting GH action on the kidneys) and may be a useful supplementary tool.MethodsGHR genotyping was performed in 112 patients with acromegaly. IGF-1 and sKlotho levels were measured in the sera of patients before and after transsphenoidal surgery, with emphasis on patients judged inconclusively cured by surgery or with small residual tumour masses shortly after surgery. Patients were assessed for recurrence of acromegaly with GH levels (random or nadir during an oGTT).ResultsOf the 48 patients who underwent surgery between 2000 and 2009 and who had well-documented longer term follow-up at our institution, 29 had no biochemical evidence of residual disease activity after transsphenoidal surgery (marked reduction in IGF-1 and sKlotho levels, GH suppressible to

Calorie restriction (CR) inhibits prostate cancer progression, partially through modulation of the IGF axis. IGF-1 receptor (IGF-1R) blockade reduces prostate cancer xenograft growth. We hypothesized that combining calorie restriction with IGF-1R blockade would have an additive effect on prostate cancer growth. Severe combined immunodeficient mice were subcutaneously injected with 22Rv1 cells and randomized to: (1) Ad libitum feeding/intraperitoneal saline (Ad-lib); (2) Ad-lib/20 mg/kg twice weekly, intraperitoneal ganitumab [anti-IGF-1R antibody (Ad-lib/Ab)]; (3) 40% calorie restriction/intraperitoneal saline (CR); (4) CR/ intraperitoneal ganitumab, (CR/Ab). CR and ganitumab treatment were initiated one week after tumor injection. Euthanasia occurred 19 days post treatment. Results showed that CR alone decreased final tumor weight, plasma insulin and IGF-1 levels, and increased apoptosis. Ganitumab therapy alone reduced tumor growth but had no effect on final tumor weight. The combination therapy (CR/Ab) further decreased final tumor weight and proliferation, increased apoptosis in comparison to the Ad-lib group, and lowered plasma insulin levels relative to the Ad-lib and Ad-lib/Ab groups. Tumor AKT activation directly correlated with plasma IGF-1 levels. In conclusion, whereas ganitumab therapy modestly affected 22Rv1 tumor growth, combining IGF-1R blockade with calorie restriction resulted in a significant decrease in final tumor weight and improved metabolic profile.

OBJECTIVE: To investigate possible mechanisms of growth impairment in children with juvenile rheumatoid arthritis (JRA). METHODS: Eighteen prepubertal children with JRA and growth retardation received recombinant human growth hormone (rHuGH) for 1 year. Growth hormone profiles over 24 hours were obtained before treatment in 12 patients; the levels did not differ from those in "short normal" children. Levels of insulin-like growth factor 1 (IGF-1), IGF binding proteins (IGFBPs) 1 and 3, insulin, osteocalcin, and C-reactive protein (CRP), as well as the erythrocyte sedimentation rate were measured serially. Pretreatment levels were compared with control levels. RESULTS: In JRA patients, IGF-1, IGFBP-3, and osteocalcin levels were significantly lower and insulin levels significantly higher than those in controls, but there was no significant difference in the level of IGFBP-1. With rHuGH treatment, height velocity and mean levels of IGF-1, osteocalcin, and insulin increased significantly, while mean levels of IGFBP-1 fell significantly. Levels of IGFBP-3 correlated with those of IGF-1. The height velocity correlated positively with IGF-1 and osteocalcin, and negatively with IGFBP-1. Levels of IGFBP-1 were inversely related to those of insulin and IGF-1. There was a significant negative correlation between the CRP and height velocity, IGF-1 level, and osteocalcin level. CONCLUSION: IGF-1 production is impaired in children with active JRA. Treatment with a therapeutic dose of rHuGH can rectify the IGF-1 deficiency within 4 days, but its effect is adversely influenced by the acute-phase response, as reflected by an elevated CRP level.

Plasma somatomedin activity was measured in 12 patients who had sustained non-fatal musculo-skeletal injuries. It was depressed for 2-3 d after injury, but this depression bore no relationship to the catabolic response to injury which, as judged by urinary nitrogen excretion, was maximal at about one week. The depression of somatomedin activity may have been related to the high plasma cortisol concentrations observed during the first few days after injury. Plasma growth hormone concentrations were high acutely after injury but rapidly returned to normal. The changes in plasma somatomedin activity were thus unrelated to those in growth hormone, but were very similar to those in plasma insulin concentrations. A marked positive relationship was observed between plasma insulin concentrations and urinary nitrogen excretion, indicating unresponsiveness of protein metabolism to the normal anabolic effects of insulin. The study showed, however, that this was not as a result of low somatomedin activity.

In Drosophila, the fat body, functionally equivalent to the mammalian liver and adipocytes, plays a central role in regulating systemic growth in response to nutrition. The fat body senses intracellular amino acids through Target of Rapamycin (TOR) signaling, and produces an unidentified humoral factor(s) to regulate insulin-like peptide (ILP) synthesis and/or secretion in the insulin-producing cells. Here, we find that two peptides, Growth-Blocking Peptide (GBP1) and CG11395 (GBP2), are produced in the fat body in response to amino acids and TOR signaling. Reducing the expression of GBP1 and GBP2 (GBPs) specifically in the fat body results in smaller body size due to reduced growth rate. In addition, we found that GBPs stimulate ILP secretion from the insulin-producing cells, either directly or indirectly, thereby increasing insulin and insulin-like growth factor signaling activity throughout the body. Our findings fill an important gap in our understanding of how the fat body transmits nutritional information to the insulin producing cells to control body size., The insect fat body transmits nutritional information to control body growth by producing and secreting two peptides, GBP1 and GBP2, in response to dietary amino acids. These two peptides stimulate insulin-like peptide secretion, increasing insulin-signaling activity throughout the body and inducing systemic growth., Author Summary Organisms adjust their development in response to environmental conditions to maximize important life history traits such as body size and survival. From work in the fruit fly, Drosophila melanogaster, we are beginning to resolve some of the molecular mechanisms through which environmental conditions, specifically nutrition, modify developmental processes. The insect fat body is functionally equivalent to the mammalian liver and adipocytes. In response to the concentration of dietary amino acids, the fat body secretes a peptide signal into the insect bloodstream that regulates the systemic release of important growth-regulating peptides, the insulin-like peptides. The nature of this peptide signal was previously unknown. Here we found that two peptides, Growth-Blocking Peptide (GBP1) and CG11395 (GBP2), are produced in the fat body in response to amino acids. Once secreted from the fat body, these two peptides stimulate secretion of insulin-like peptides, which results in elevating insulin-signaling activity in the rest of the body to stimulate body growth.

We hypothesized that stimulatory and superovulatory treatments, using equine chorionic gonadotropin (eCG), modulate the expression of genes related to insulin, cellular modelling and angiogenesis signaling pathways in the bovine corpus luteum (CL). Therefore, we investigated: 1-the effect of these treatments on circulating insulin and somatomedin C concentrations and on gene and protein expression of INSR, IGF1 and IGFR1, as well as other insulin signaling molecules; 2-the effects of eCG on gene and protein expression of INSR, IGF1, GLUT4 and NFKB1A in bovine luteal cells; and 3-the effect of stimulatory and superovulatory treatments on gene and protein expression of ANG, ANGPT1, NOS2, ADM, PRSS2, MMP9 and PLAU. Serum insulin did not differ among groups (P = 0.96). However, serum somatomedin C levels were higher in both stimulated and superovulated groups compared to the control (P = 0.01). In stimulated cows, lower expression of INSR mRNA and higher expression of NFKB1A mRNA and IGF1 protein were observed. In superovulated cows, lower INSR mRNA expression, but higher INSR protein expression and higher IGF1, IGFR1 and NFKB1A gene and protein expression were observed. Expression of angiogenesis and cellular modelling pathway-related factors were as follows: ANGPT1 and PLAU protein expression were higher and MMP9 gene and protein expression were lower in stimulated animals. In superovulated cows, ANGPT1 mRNA expression was higher and ANG mRNA expression was lower. PRSS2 gene and protein expression were lower in both stimulated and superovulated animals related to the control. In vitro, eCG stimulated luteal cells P4 production as well as INSR and GLUT4 protein expression. In summary, our results suggest that superovulatory treatment induced ovarian proliferative changes accompanied by increased expression of genes providing the CL more energy substrate, whereas stimulatory treatment increased lipogenic activity, angiogenesis and plasticity of the extracellular matrix (ECM).

Growth regulation in adult Atlantic salmon (1.6 kg) was investigated during 45 days in seawater at 13, 15, 17, and 19 °C. We focused on feed intake, nutrient uptake, nutrient utilization, and endocrine regulation through growth hormone (GH), insulin-like growth factors (IGF), and IGF-binding proteins (IGFBP). During prolonged thermal exposure, salmon reduced feed intake and growth. Feed utilization was reduced at 19 °C after 45 days compared with fish at lower temperatures, and body lipid storage was depleted with increasing water temperature. Although plasma IGF-1 concentrations did not change, 32-Da and 43-kDa IGFBP increased in fish reared at ≤17 °C, and dropped in fish reared at 19 °C. Muscle igf1 mRNA levels were reduced at 15 and 45 days in fish reared at 15, 17, and 19 °C. Muscle igf2 mRNA levels did not change after 15 days in response to increasing temperature, but were reduced after 45 days. Although liver igf2 mRNA levels were reduced with increasing temperatures after 15 and 45 days, temperature had no effect on igf1 mRNA levels. The liver igfbp2b mRNA level, which corresponds to circulating 43-kDa IGFBP, exhibited similar responses after 45 days. IGFBP of 23 kDa was only detected in plasma in fish reared at 17 °C, and up-regulation of the corresponding igfbp1b gene indicated a time-dependent catabolic response, which was not observed in fish reared at 19 °C. However, higher muscle ghr mRNA levels were detected in fish at 17 and 19 °C than in fish at lower temperatures, indicating lipolytic regulation in muscle. These results show that the reduction of muscle growth in large salmon is mediated by decreased igf1 and igf2 mRNA levels in addition to GH-associated lipolytic action to cope with prolonged thermal exposure. Accordingly, 13 °C appears to be a more optimal temperature for the growth of adult Atlantic salmon at sea.

The liver is a major source of insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) that are present in the circulation and have important endocrine activities relating to energy metabolism, body size, carcinogenesis, and various organ-specific functions. Although IGFs have only minor effects on the normal liver itself, production of IGFs and IGFBPs in a tissue-specific manner in the gastrointestinal tract exert important regulatory effects on cellular proliferation, survival, and apoptosis. IGFs and IGFBPs play important regulatory roles in the response of both the liver and the gastrointestinal tract to inflammation and in the development of neoplasia.

Growth hormone (GH) and insulin-like growth factor-I (IGF-I) exert powerful influences on somatic growth, metabolism, and tissue repair, and have been implicated in aging and carcinogenesis. Since the formulation of the somatomedin hypothesis over 50 years ago, GH and IGF-I have been linked intimately to one another. Recent studies have established that GH potently stimulates IGF-I gene transcription, and through this mechanism controls production of IGF-I. A key mediator of the GH - IGF-I biosynthetic pathway is the latent transcription factor Stat5b. This review summarizes the potentially complex mechanistic relationship among GH action, Stat5b, and IGF-I gene activation, and suggests that Stat5b may have a broad role in mediating IGF-I gene regulation in response to diverse physiological inputs.

Meniscus had two areas with different vascular supply. Cells of the two areas and the synovium were monolayer cultivated. We analyzed the expression of genes of Col1, Col 2A, MMP-2, MMP-13, and aggrecan in a baseline state and after incubation with VEGF, TGF-β, FGF, and IGF. We found that the growth factors used produced a major increase in the MMP-13 in all three areas. In the vascular area, the stimulation of MMP-3 was produced by FGF, while in the synovial and avascular areas, it was caused by TGF-β. MMP-2 was only stimulated in the synovial area by IGF. Col 2A was stimulated in the synovial area by VEGF, and in the avascular area by TGF-β, FGF, and IGF, whereas Col 1 was stimulated in the avascular area by IGF, FGF, and VEGF. The vascular or avascular areas of the meniscus, behave differently in terms of repair, and their cells express different factors. The growth factors act in a different way in each meniscal area.

Naked mole-rats (Heterocephalus glaber) (NMRs) are the longest living rodents known. They show negligible senescence, and are resistant to cancers and certain damaging effects associated with aging. The insulin-like growth factors (IGFs) have pluripotent actions, influencing growth processes in virtually every system of the body. They are established contributors to the aging process, confirmed by the demonstration that decreased IGF signaling results in life-extending effects in a variety of species. The IGFs are likewise involved in progression of cancers by mediating survival signals in malignant cells. This report presents a full characterization of the IGF system in the NMR: ligands, receptors, IGF binding proteins (IGFBPs), and IGFBP proteases. A particular emphasis was placed on the IGFBP protease, pregnancy-associated plasma protein-A (PAPP-A), shown to be an important lifespan modulator in mice. Comparisons of IGF-related genes in the NMR with human and murine sequences indicated no major differences in essential parts of the IGF system, including PAPP-A. The protease was shown to possess an intact active site despite the report of a contradictory genome sequence. Furthermore, PAPP-A was expressed and translated in NMRs cells and retained IGF-dependent proteolytic activity towards IGFBP-4 and IGF-independent activity towards IGFBP-5. However, experimental data suggest differential regulatory mechanisms for PAPP-A expression in NMRs than those described in humans and mice. This overall description of the IGF system in the NMR represents an initial step towards elucidating the complex molecular mechanisms underlying longevity, and how these animals have evolved to ensure a delayed and healthy aging process.

Protein hormones from the anterior pituitary gland have well-established endocrine roles in their peripheral target glands. It is, however, now known that these proteins are also produced within many of their target tissues, in which they act as local autocrine or paracrine factors, with physiological and/or pathophysiological significance. This emerging concept is the focus of this brief review.

Oxidative stress plays a pathological role in the development of heart failure. This study examined telomere biology in heart/muscle-specific manganese superoxide dismutase-deficient mice (H/M-SOD2^), which develop progressive congestive heart failure and exhibit pathology typical of dilated cardiomyopathy. EUK-8 (25 mg/kg/day), a superoxide dismutase and catalase mimetic, was administered to H/M-SOD2^ mice for four weeks beginning at 8 weeks of age. Telomere length, telomerase activity, telomere-associated proteins, and cell death signals were assessed in hearts from control wild-type mice (H/M-Sod2^) and H/M-SOD2^ mice either treated or untreated with EUK-8. While cardiac function was unchanged in these experimental mice, the end-diastolic dimension in H/M-SOD2^ mice was notably dilated and could be significantly reduced by EUK-8 treatment. At the end of the study, no shortening of telomere length was observed in heart tissues from all mice tested, but telomerase activity was decreased in heart tissue from H/M-SOD2^ mice compared to control mice. Protein expression for telomerase reverse transcriptase and telomere repeat binding factor 2 was also downregulated in H/M-SOD2^ heart tissue as was expression of phospho-Akt, insulin-like growth factor, and endothelial nitric oxide synthase. Expression levels of Sirt1, a lifespan modulator, were enhanced while FoxO3a was depressed in H/M-SOD2^ hearts. All of the changes seen in H/M-SOD2^ heart tissue could be inhibited by EUK-8 treatment. Taken together, the results suggest that oxidant stress might affect myocardial telomerase activity and telomere-associated proteins. Telomerase may therefore play a pivotal role in antioxidant defense mechanisms, and may be useful as a novel therapeutic tool for treating human heart failure.2010 Elsevier Ltd.

The insulin-like growth factor (IGF) system plays essential role in the regulation of cell growth, proliferation and survival and affects nearly every organ system in the body. IGF-I, which has a high structural similarity to insulin, exerts growth-promoting effects, influences glucose metabolism and has neuroprotective and cardioprotective effects, partly because of its cell-proliferative and antiapoptotic properties. Aberrations in the IGF system may associate with various pathological conditions, including cancer. Insulin and its synthetic analogs are known to possess IGF-IR binding affinity, and concern has been raised about their mitogenic potential in humans. The present review summarizes the main aspects of the IGF system biology and the interactions among IGF-I, insulin, insulin analogs and their receptors.

Aims: To study the effect of in-utero alcohol exposure on the insulin-like growth factor axis (IGF) and leptin during infancy and childhood, considering that exposed children may exhibit pre- and postnatal growth retardation. Methods: We prospectively identified heavily drinking pregnant women who consumed on average 4 or more drinks of ethanol per day (≧48 g/day) and assessed growth in 69 of their offspring and an unexposed control group of 83 children, measuring serum IGF-I (radioimmunoassay), IGF-II (immunoradiometric assay, IRMA), insulin-like growth factor-binding protein 3 (IGFBP-3) (IRMA) and leptin (IRMA) at 1 month and 1, 2, 3, 4, and 5 years of age. Results: IGF-II levels increased with age in both groups, but the rate of increase was significantly higher in exposed children, and levels were significantly higher in ethanol-exposed children at 3, 4, and 5 years of age. In exposed children, IGF-I levels were higher at 3 and 4 years and leptin levels were significantly lower at 1 and 2 years. Exposed subjects showed a much lower correlation between IGF-I and growth parameters than unexposed subjects. Conclusion: Exposure to ethanol during pregnancy increases IGF-I and IGF-II and decreases leptin during early childhood. The increase in serum IGF-II concentrations in ethanol-exposed children suggests that this hormone should be explored as a potential marker for prenatal alcohol exposure.

Expression of insulin-like growth factor I (IGF-I) was studied during time in the callus formed after tibial fracture in rats. Levels of IGF-I mRNA in callus peaked on the day 8 postfracture, showing a 10- to 15-fold induction compared to control bone. Levels of IGF-I mRNA tended also to be increased in the fracture-adjacent musculus tibialis anterior. IGF-I immunoreactivity was found in cartilaginous cells, osteoblasts, and myocytes 6 and 8 days after fracture. No obvious differences were found between hypophysectomized animals and control animals with regard to IGF-I immunoreactivity. Administration of the antiinflammatory drug indomethacin decreased the IGF-I mRNA expression in the tibial fracture model. Previous findings have shown that IGF-I is activated during in vivo muscle regeneration, and also in this model indomethacin administration reduces the expression of IGF-I. The finding that indomethacin administration reduces IGF-I expression could indicate that an inflammatory response may be important for activation of IGF-I during tissue regeneration.

The mechanism of action of thyroid hormones on bone is still not clear. At low concentrations, they stimulate bone formation; at high concentrations, they elicit bone resorption in vitro and in vivo. In the present study we investigated the effect of T3 and T4 as well as their active and inactive analogs (TRIAC, SKF L-94901, rT3, and DIT) on the IGF-I and TNF-α content in the medium of UMR-106 rat osteoblastic cells and fetal rat limb bones. In the dose-response studies, a biphasic increase in medium IGF-I was observed in both cells and limb bones, with peak stimulatory concentrations of 10−8 M for T3 and 10−7 M for T4 in both systems. At higher concentrations, at which thyroid hormones elicit bone resorption, the stimulatory effect diminished and finally was no longer detectable. The active analogs TRIAC and SKF L-94901 also enhanced IGF-I release in UMR-106 cells. The inactive compounds rT3 and DIT failed to increase IGF-I in these cultures. The protein content of the cell culture wells exposed to high concentrations of thyroid hormones was similar to those containing low concentrations, indicating that the decrease in IGF-I content at high doses was not due to toxic effects. This was also confirmed by trypan blue exclusion. Time course studies with UMR-106 cells revealed a significant increase in medium IGF-I after 2 days of incubation. No significant further increase was observed after this up to 5 days of culture. In contrast, the medium of limb bone cultures showed a linear increase in IGF-I content up to 7 days of culture. No TNF-α production was observed in either UMR-106 cells or fetal limb bones. Also, no increase in medium TNF-α levels was seen in response to thyroid hormones. Based on our results, we conclude that IGF-I may be responsible for some of the anabolic effects of thyroid hormones in bone tissue, but TNF-α, at least in the models we used, does not play a role in the mediation of thyroid hormone action.

The effects of tissue maturation on the cellular composition and biochemical characteristics of bone were studied in neonatal, young adult, and aging mice. Osteoblast subclasses were isolated on Percoll density gradients. Neonatal calvariae consisted almost exclusively of cells banding at low and intermediate buoyant density. High buoyant density cells constituted 5–10% of total cells at 10 days of age but increased to 50–60% by 5 weeks of age. These latter cells were released late during collagenase digestion. This indicates that they arise from the deeper layer of bone. For this reason, we consider them putative osteocytes. We established that constitutive secretion of IGF-I and TGF-β and activities of cellular alkaline phosphatase paralleled those of the tissue of origin in all cell groups and was highest in cells of intermediate buoyant density. These activities declined rapidly after cessation of growth at 5 weeks of age in both bone and isolated cells. Between 5 and 8 weeks of age, the hormonal response to PTH also declined dramatically. The maximum cAMP induced by PTH declined by about 70% in highly responsive cells of intermediate buoyant density and fell to insignificant levels in cells of high buoyant density. We found that a cyclic AMP response to PTH was positively correlated with stimulated secretion of IGF-I by this hormone in cells from animals of all ages. Despite their inability to respond to PTH with increases in cAMP and IGF-I, adult bone cells of high buoyant density continued to respond to PTH with increases in the secretion of TGF-β. The stimulatory effect of PTH on the secretion of TGF-β could not be mimicked by dibutyryl-cAMP or forskolin in any subclass of osteoblasts, in contrast to IGF-I, which was increased in the presence of these compounds. In summary, we show that PTH increases secretion of TGF-β by bone cells. In addition, separation of bone cells from mature mice on the basis of buoyant density permits separation of specific osteoblastic subclasses whose numbers and biochemistry change with maturity. Furthermore, these data suggest that osteocytic cells (1) accumulate in mature bone, (2) undergo loss of selective PTH responses, including cAMP and IGF-I, and (3) retain cAMP-independent PTH responsiveness as shown by increased secretion of TGF-β.

The effects of recombinant human growth hormone (rhGH) on biochemical markers of bone turnover and bone mineral content (BMC) were investigated in 20 normal male volunteers (aged 22-31 years) randomized to treatment for 7 days with either rhGH (0.1 IU/kg subcutaneously twice a day) or placebo. Serum somatomedin C rose during treatment (p less than 0.001) but was not significantly different from baseline at day 14. The fasting urinary hydroxyproline/creatinine (p less than 0.001) and calcium/creatinine ratios (p less than 0.01) increased during treatment and remained elevated for 4 and 2 weeks, respectively. Serum bone gamma-carboxyglutamic acid-containing protein (BGP) increased during treatment (p less than 0.001) and remained elevated for 6 months (p less than 0.02). Serum bone alkaline phosphatase (B-AP), after an initial fall in the treatment period (p less than 0.001), increased slightly in the following months (p less than 0.01). In the rhGH group BMC was significantly higher than the prestudy value at day 14 (p less than 0.05) but was unaltered at the end of study. The simultaneous increase in markers of bone resorption and formation during rhGH treatment followed by a decline in resorption parameters within a few weeks and the prolonged effect on BGP and B-AP demonstrate that rhGH treatment stimulates osteoblasts and activates bone remodeling.

SummaryMembers of the insulin family of peptides have conserved roles in the regulation of growth and metabolism in a wide variety of metazoans. Here we show that Drosophila insulin-like peptide 6 (DILP6), which is structurally similar to vertebrate insulin-like growth factor (IGF), is predominantly expressed in the fat body, a functional equivalent of the vertebrate liver and adipocytes. This expression occurs during the postfeeding stage under the direct regulation of ecdysteroid. We further reveal that dilp6 mutants show growth defects during the postfeeding stage, which results in reduced adult body size through a decrease in cell number. This phenotype is rescued by fat body-specific expression of dilp6. These data indicate that DILP6 is a functional, as well as a structural, counterpart of vertebrate IGFs. Our data provide in vivo evidence for a role of ILPs in determining adult body size through the regulation of postfeeding growth.

Growing pigs were given 8% rape seed meal (RSM), which was offered without or with different iodine-supplements and further trace elements. RSM without I-supplementation reduced food intake and weight gains by more than 50%, thyroid weight increased by the factor 6, T4 declined below the detectable limit, T3 by two thirds and somatomedin activity by 50% compared to the control group (soy bean meal). In spite of supplementation with iodine and further trace elements the T3-level reached the level of the control group in no variant due to nutrient deficiency (reduced food intake) and the conversion-impeding effect of goitrogenic substances. The same is true for Sm-activity and weight gains, whereas the T4-level increased even above the level of control animals due to I-supplementation. There are significant correlations (correlation coefficients 0.77 and 0.64 resp.; p less than 0.001) between food intake and T3-concentration resp. and Sm-activity. This study demonstrate that the reduced growth in case of the intake of phytogenic substances with thyreostatic effects is directed by the diminished food consumption and the peripheral hypothyroid situation via decreased Sm-synthesis. The high content of thyreostatic substances in tissues of rape seed fed animals is a potential danger for the human consumer.

The effect of body weight excess and hyperlipidemia on stimulated growth hormone (GH) secretion and serum somatomedin activity (SSA) has been investigated. Among 40 obese men gradually impairment of GH secretory response during the insulin hypoglycemia test was shown. Propranolol-L-DOPA administration elicited satisfactory GH secretory response only in the subgroup of patients with the mild weight excess. SSA was found to be in the normal range among the whole group of obese patients, however, it was significantly depressed in subjects with average weight excess higher than 100%. Obese men with hypertriglyceridemia and hypercholesterolemia presented low SSA even when their weight excess was relatively moderate, i.e., 52% and 57%, respectively.

By means of 3 endurance exercises, the effect of a several-hour intensive somatic stress on the changes of the Sm-C/IGF-I concentration was tested during, immediately after and on the day following the exercise. Exp. 1: Marathon with 17 male sportsmen in 2 groups with different glucose supply. Exp. 2: 45-km crosscountry run with 41 males. Exp. 3: Three 20-km runs with 8 young females at intervals of 3 months. In the marathon, no significant changes of the Sm-C/IGF-I concentration were found between the start, half distance and final values. The exogenous glucose supply (continuous or discontinuous) had also no effect. The tendency of a slight decrease of the Sm-C/IGF-I concentration by 0.14 U/ml (p greater than 0.05) was observed between start and finish in the 45 km crosscountry run lasting one hour longer. In the three 20-km runs, reproducible, slightly increased levels were measured at the end, whereas a decrease to the initial value or even below was detected on the following day (p greater than 0.05). The insignificant alterations of the Sm-C/IGF-I concentration measured in the 3 variants of races show that neither the hormonal changes stimulating the Sm-C/IGF-I synthesis (e.g. increase of GH and prolactin) nor inhibiting factors (energy deficiency) clearly dominate during strenuous exercises. The binding of carrier protein prevents great variations of the Sm-C/IGF-I level even under the condition of 3- to 4-hour extreme endurance exercises.

Sm-C concentrations in serum were found significantly different in either active acromegaly or following successful treatment with pituitary adenomectomy. Although after normalization of serum GH the Sm-C levels sometimes exceeded the normal range no overlap was found between both groups. Exceptionally two acromegalic patients showed elevated Sm-C levels in spite of normal GH values. Likewise, a high Sm-C concentration was found in one patient suspective of ectopic GH secretion with only moderately elevated serum GH. Sm-C determinations are judged as a good adjunct to usual diagnostic methods which in special cases of acromegaly can be even superior to measurements of serum GH.

To clarify the pathogenesis of growth retardation in patients with Ullrich-Turner's syndrome (TS) we have investigated basal SmC/IGF-I, insulin and prolactin concentrations. Compared with 56 age matched healthy controls basal SmC/IGF-I concentration in 51 patients with TS older than 9-11 years was significantly lower (age group 13-14 years; TS 273 +/- 47 and controls 479 +/- 114 ng/ml). Mean basal prolactin level in 43 patients with TS (406 +/- 211 microU/ml) was significantly higher (p less than 0.01) than in 192 female controls (age 3-11 years; 264 +/- 176 microU/ml). Basal insulin concentration in 28 TS patients in comparison to 20 healthy children of a control group was significant higher (TS 18 +/- 8 microU/ml; controls 9 +/- 4 microU/ml; p less than 0.01). It seems that neither insulin nor prolactin are relevant stimulators of Smc/IGF-I in man, especially in patients with gonadal dysgenesis. Considering these results we speculate that despite higher prolactin and higher insulin levels in TS, the lower SmC/IGF-I concentrations may be predominantly related to the abnormal sex steroid secretion.