Insulin-like growth factor-I (IGF-I) signalling plays a key role in learning and memory processes. While the effects of IGF-I on neurons have been studied extensively, the involvement of astrocytes in IGF-I signalling and the consequences on synaptic plasticity and animal behavior remain unknown. We have found that IGF-I induces long-term potentiation (LTP, here called LTP_IGFI) of the postsynaptic potentials that is caused by a long-term depression (LTD) of inhibitory synaptic transmission in mice. We have demonstrated that this long-lasting decrease in the inhibitory transmission is evoked by astrocytic activation through its IGF-IRs. We show that LTP_IGFI not only increases the output of pyramidal neurons, but also favours the N-methyl-D-aspartate (NMDAR) dependent LTP, resulting in the crucial information processing at the Barrel cortex since specific deletion of IGF-IR in cortical astrocytes (IGF-IR^-/-) impairs the whisker discrimination task. Our work reveals a novel mechanism and functional consequences of IGF-I signalling on cortical inhibitory synaptic plasticity and animal behavior, revealing that astrocytes are key elements in these processes.SIGNIFICANCE STATEMENTInsulin-like growth factor-I (IGF-I) signaling plays key regulatory roles in multiple processes of brain physiology, such as learning and memory. Yet, the underlying mechanisms remain largely undefined. Here we demonstrate that astrocytes respond to IGF-I signaling, elevating their intracellular Ca²⁺ and stimulating the release of ATP/adenosine, which triggers the LTD of cortical inhibitory synapses, thus regulating the behavioral task performance related to cortical sensory information processing. Thus, the present work represents a major conceptual advance in our knowledge of the cellular basis of IGF-I signaling in brain function, by including for the first time astrocytes as key mediators of IGF-I actions on synaptic plasticity, cortical sensory information discrimination and animal behavior.

The clinical and biological presentation of idiopathic growth hormone (GH) deficiency (GHD) varies greatly, demonstrating the variety of its pathogenic features and explaining why it is difficult to diagnose. We examined 48 patients (26 males) with certain idiopathic GHD diagnosed at 4.8 +/- 0.7 yr. The symptoms that led to the diagnosis of GHD were low growth rate (33 cases), hypoglycemia (12 cases), microphallus (1 case) and in 2 cases the GHD was diagnosed from magnetic resonance imaging (MRI) performed for delayed mental development (1 case), or congenital blindness (1 case). The 2 other cases were diagnosed from routine GH evaluation performed at birth because of idiopathic GHD in siblings. Thirteen had congenital malformation. Twenty three cases (48%) had features suggesting that the GHD was of antenatal origin. Six of them were born by breech delivery. Twenty one cases (44%) had features suggesting a hypothalamic origin. The decrease in growth rate occurred before 0.5 year in 21 (55%), before 1 year in 27 (71%) and before 2 years in 30 (79%): 8 patients (21%) maintained a normal growth rate after this age. Among these 8 patients, 5 had signs suggesting an antenatal origin and 4 had severe episodes of hypoglycemia from birth. The mean GH peak after the pharmacological stimulation test was 3.6 +/- 0.5 micrograms/l. The mean plasma insulin-like growth factor 1 (IGFI) was 0.1 +/- 0.02 U/ml. The GH deficiency was associated with deficiencies of thyrotropin in 26 (54%) and of adrenocorticotrophic hormone in 17 (35%) patients. Among the 15 patients of pubertal age, 9 (60%) had gonadotrophin deficiency. No patient had diabetes insipidus. The MRI showed pituitary stalk interruption syndrome in 39 patients and normal pituitary anatomy in 6 patients. GH treatment reduced the difference between target and actual heights from 3.5 SD (before) to I SD (after 3 years) in the 39 more recently seen patients given 0.5-0.6 U/kg/w GH in 6 or 7 weekly injections. Height gain during the first year and cumulative height gain over 3 years (SD) was correlated negatively with height (SD) at the start of treatment (p < 0.01). We conclude that most of the patients with GHD have features suggesting an antenatal origin. Despite this early origin, the decreased growth rate may occur after 2 years.

Osteocalcin is one of the major proteins in the osseous matrix. To evaluate the determinants and thus the physiological control of osteocalcin production in normal and osteoporotic subjects, the serum levels of osteocalcin, 25-hydroxycholecalciferol (25-OH-D3), and insulin-like growth factor I (IGFI) were measured by radioimmunoassay in 44 subjects over 60 years old. Circulating osteocalcin, 25-OH-D3, and IGFI were 0.28 +/- 0.10 nmol/L (1.65 +/- 0.96 ng/mL), 70.5 +/- 25.1 nmol/L (28.3 +/- 10.1 ng/mL), and 23.8 +/- 12.0 nmol/L in 27 healthy controls respectively, as compared with 0.09 +/- 0.09 nmol/L (0.52 +/- 0.52 ng/mL), 48.2 +/- 19.9 nmol/L (19.35 +/- 7.91 ng/mL), and 16.56 +/- 6.96 nmol/L in 17 patients with spinal fractures. Significant correlation was found between osteocalcin and 25-OH-D3 level, as well as between osteocalcin and IGFI. The results show that IGFI and 25-OH-D3 are important determinants for serum concentration of osteocalcin in elderly subjects with and without spinal fractures.

Based on previous observations of the presence of both insulin-like growth factors I and II (IGF-I and IGF-II) in murine saliva (kerr et al., Biochem Pharmacol 49: 1521-1531, 1995), the saliva from BALB/c and Non-obese diabetic (NOD) mice was examined for the presence of insulin-like growth factor binding proteins (IGFBPs). Using a western-blot type ligand binding assay with 125I-labeled IGF-I, a series of binding proteins with molecular masses (M), between 25 and 45 kDa were detected in the sera, but not saliva, from both BALB/c and diabetic NOD mice. In the diabetic NOD mice, there were detectable changes in the concentrations of several of the IGFBPs relative to BALB/c mice. Using specific antibody to the binding proteins, one of these was identified as IGFBP-2. Gavage administration of [125I]IGFI indicated substantial uptake from the gastrointestinal tract and significant tissue distribution. There was an increase in serum concentrations of radiolabeled IGF-I in diabetic NOD mice over that in BALB/c mice but less recovered from most of the tissues. Intact 125I-labeled IGF-I was extracted and purified from various tissues, following gavage, and shown to retain biological activity. Thus, the uptake of biologically active IGFs from saliva would appear to take place independently of specific binding proteins.

BACKGROUND

Obesity is associated with various changes in cardiac geometry and this process involves both hemodynamic and non-hemodynamic factors, among which adipocitokines and growth factors may play an important role. The aim of this study was to identify the extent and pattern of cardiac remodeling in a group of severely obese patients and analyze the relationship between adiponectin, IGFI and cardiac parameters reflecting obesity-associated structural changes.

METHODS

Our study included 344 patients (104 men) with severe obesity [mean body mass index (BMI)= 45.7 ± 8.5 kg/m(2)], extensively evaluated clinically and biologically (complete metabolic tests, serum adiponectin, and IGF-I measurements). Left ventricular (LV) mass index (LVMI), left atrium (LA) size, and LV geometry were determined by means of cardiac ultrasound.

RESULTS

The most prevalent pattern of LV geometry was eccentric hypertrophy (28.7% of patients). In a gender-, age-, BMI-, diabetes- and hypertension-adjusted general linear model, patients with concentric or eccentric hypertrophy had significantly lower values of adiponectin than those with normal geometry (6.75 ± 0.41, 6.96 ± 0.53, vs 9.04 ± 0.42 mg/l, p<0.05). In multivariate analysis, independent determinants for LVMI were BMI (β=0.364, p<0.001), systolic blood pressure (BP) (β=0.187, p=0.004), age (β=0.246, p<0.001), adiponectin (β=-0.151, p=0.012), and IGF-I z-score (β=0.134, p=0.025) while factors independently related to LA size were systolic BP (β=0.218, p<0.001), BMI (β=0.194, p<0.001), age (β=0.273, p<0.001), gender (β=-0.195, p<0.001), and adiponectin (β=-0.180, p=0.005).

CONCLUSIONS

In patients with severe obesity, IGF-I z score and adiponectin correlate with parameters of cardiac remodeling independently of anthropometric, hemodynamic or metabolic factors.

Substantial cellular proliferative activity is necessary to produce a mature hair follicle. Therefore, it is likely that cytokines and their receptors play an important controlling role. To provide an understanding of the mechanisms involved during hair growth, we investigated the expression of cytokines in rat anagen hair follicles. A new technique was developed that allowed the rapid isolation of large numbers of intact, viable, anagen, rat pelage hair follicles. Total RNA was isolated from these follicles using an acid-phenol-chloroform extraction and analyzed for cytokine expression. Using the conventional technique of Northern blotting, it was only possible to detect transcripts for transforming growth factor beta (TGF beta) and insulin-like growth factor I (IGFI). Polymerase chain reaction amplification of reverse-transcribed mRNA detected cDNA fragments for TGF beta, IGF I, IGF II, nerve growth factor beta (NGF beta), and interleukin-1 alpha (IL-1 alpha). The amplified products were confirmed by digestion with restriction endonucleases. The proteins themselves for TGF beta and IGF I have been shown to be present within the anagen hair follicle using immunogold antibody labeling. This study has provided the first reported cytokine expression profile of rat anagen hair follicles. It is likely that the analysis of the pattern and timing of expression of these cytokines in the follicle will provide valuable insights into hair growth regulation.

We report a boy with pseudohypoparathyroidism (PHP), hypothyroidism and low growth hormone (GH) values with no response to growth hormone releasing hormone (GHRH). He presented at age 17 mo because of developmental delay. He had the typical features (short stature, obesity, round face, brachydactyly) of Albright's hereditary osteodystrophy (AHO) and the biochemical profile of PHP; low serum calcium and high phosphate, raised parathormone (PTH) values and lack of response of urinary phosphate and cyclic AMP to PTH administration. The serum total thyroxine value (T4) was 37.32 nmol/L and the thyroid stimulating hormone (TSH) 29 mU/L. Peak GH values during two provocative tests (Glucagon, L-Dopa) were <2.5 microg/L and <1.7 microg/L, respectively, while following GHRH administration the maximum GH value was 0.2 microg/L. The IGFI value was 65 ng/ml and rose to 253 ng/ml after GH administration for three days. This boy had PTH and TSH receptor defect and we speculate that he also has GHRH receptor defect.

This study was intended to examine whether serum IGF-I concentration is appropriate for use as a physiological predictor for genetic improvement of meat production and meat quality traits in pigs. Heritabilities and genetic correlations were estimated for these traits. The Duroc breed used in this study was selected for seven generations for average daily BW gain (DG) from 30 to 105 kg of BW, loin-eye muscle area (EM), backfat thickness (BF), and intramuscular fat (IMF) content. Serum IGF-I concentration of boars and gilts at the fourth generation of selection and that of boars, gilts, and barrows from the fifth to seventh generations of selection were measured at 8 wk (IGFI-8W) for 832 animals and again at the time they reached 105 kg of BW (IGFI-105KG) for 834 animals. A multivariate REML procedure was used to estimate genetic parameters with a model incorporating generation of selection, sex, common environmental effect of litter, and individual additive genetic effects. Heritability estimates for IGFI-8W and IGFI-105KG were 0.23 +/- 0.02 and 0.26 +/- 0.03, respectively. The estimates of common environmental effect for IGFI-8W and IGFI-105KG were 0.20 +/- 0.02 and 0.03 +/- 0.01, respectively. Positive genetic correlations were estimated between IGFI-8W and DG (0.26 +/- 0.08), EM (0.22 +/- 0.10), and IMF (0.32 +/- 0.10). Moreover, the positive genetic correlation between IGFI-105KG and EM was 0.42 +/- 0.08. These results indicate that serum IGF-I concentration at an early stage of growth was effective for prediction of IMF, but it was not a reliable physiological predictor of genetic merit of meat production traits.

This review will discuss the uses of avian models, particularly the chicken, to examine nutrition-endocrine interactions. The chicken has been employed extensively to examine nutritional effects. The effects of fasting, protein deficiency and calcium deficiency on endocrine status have been the subject of intense investigation in young chicks and adult female chickens. The ratio of circulating concentrations of triiodothyronine (T3) and thyroxine (T4) is substantially changed by fasting or protein deficiency. Similarly, protein deficiency reduces circulating concentrations of insulin-like growth factor I (IGFI) while protein deficiency increases growth hormone (GH). Moreover, protein deficiency increases the sensitivity and responsiveness of adrenocortical cells. The chicken also as advantages for studying diabetes, endocrine pancreatic functioning due to the splenic lobe of the pancreas being predominantly endocrine in nature, and the cellular mechanism of GH on chicken adipose tissue. The adult female chicken with its high calcium requirement is a unique system for examining nutritional effects on reproduction.

Is increased synthesis of proteins responsible for the hypertrophy of kidney cells in diabetes mellitus? Does the lack of insulin, and/or the effect of insulin-like growth factor I (IGFI) on renal tubule protein synthesis play a role in diabetic renal hypertrophy? To answer these questions, we determined the rates of 3H-valine incorporation into tubule proteins and the valine-tRNA specific activity, in the presence or absence of insulin and/or IGFI, in proximal tubule suspension isolated from kidneys of streptozotocin diabetic and control rats. The rate of protein synthesis increased, while the stimulatory effects of insulin and IGFI on tubule protein synthesis were reduced, early (96 hours) after induction of experimental diabetes. Thus, hypertrophy of the kidneys in experimental diabetes mellitus is associated with increases in protein synthesis, rather than with decreases in protein degradation. Factor(s) other than the lack of insulin, or the effects of IGFI, must be responsible for the high rate of protein synthesis present in the hypertrophying tubules of diabetic rats.

The production of somatomedin C/insulin-like growth factor I (Sm-C/IGFI) by human fetal lung tissue maintained in vitro was examined in the present study. We have shown that epithelial cells in human fetal lung explants maintained in vitro differentiate into type II cells within 4-6 days. During the first 24 h of culture, the fetal lung explants released 2.74 +/- 0.14 ng Sm-C/IGFI/mg tissue protein into the culture medium. At this time the explants contained 0.24 +/- 0.02 ng Sm-C/IGFI/mg tissue protein. During the next 4 days of culture, explant Sm-C/IGFI content and the rate of Sm-C/IGFI secretion into the medium declined by approximately 50%. Sm-C/IGFI secretion was inhibited significantly when fetal lung explants were cultured in media that contained cortisol (10(-7) M), a hormone that is known to stimulate fetal lung type II cell differentiation. The effect of cortisol was both concentration- and time-dependent. While insulin, bovine prolactin, and human growth hormone had no apparent effect on Sm-C/IGFI production by the explants, human prolactin and human placental lactogen both decreased Sm-C/IGFI production. These findings are unprecedented and are suggestive that Sm-C/IGFI synthesis may be regulated in a unique fashion in the fetal lung. The decline in Sm-C/IGFI production by fetal lung tissue temporally correlates with the initiation of fetal lung type II cell differentiation in the human fetal lung explants.

BACKGROUND

In our work we asked ourselves whether it would be possible to use growth factors for a quick orientation in the clinical status of patients prior to biopsy and histological examination.

METHODS

Our patient group included 82 patients with breast cancer. Serum samples were collected preoperatively. Histological examination findings were available for each patient. Our set was divided into three groups based on the disease stage. The values of analytes in different tumor stages were statistically evaluated and statistical comparisons of Stage I and II, and then of Stage II and III were performed.

RESULTS

Tumor markers CEA, CA 15-3, TK, TPA-M and MonoTotal correlate with the disease severity. Serum levels of the growth factor IGFI negatively correlated with the severity of cancer. There was aa statistically significant increase in the EGF growth factor serum levels between Stage I and II. No statistically significant differences between Stage I vs. II and Stage II vs. III were detected when HGF and VEGF growth factor serum levels were assessed.

CONCLUSIONS

The growth factor EGF is one of the candidates to become a tumor growth marker in early disease stages. The IGFI, HGF and VEGF growth factors can not be used for quick and correct orientation in the clinical condition of patients in the early stages of tumor growth.

The present study was aimed at determining the influence of nutrients supplied by a milk diet (glucose, amino acids, triglycerides) on hepatic somatomedin C (IGFi) production in vivo in four 30-d-old milk-fed calves fitted with chronically indwelling catheters in hepatic (HV), portal (PV) and mesenteric veins and in the hepatic artery (HA), and with electromagnetic flow-meters on HA and PV. Fasting for 16 h induced a decrease (P less than 0.01) in hepatic IGF1 production (nmol/kg body-weight (BW) for 6 h) (1.1 (SE 0.2) v. 6.6 (SE 0.7) in control animals). Infusion of glucose (1.8 g/kg BW for 4 h) or a mixture of amino acids (Azonutril; R. Bellon, Neuilly sur Seine; 62.5 mg nitrogen/kg BW for 3 h) in a mesenteric vein led to no significant effect on hepatic IGF1 production for 6 h (1.2 (SE 0.3) and 0.7 (SE 0.3) nmol/kg BW respectively) compared with fasted calves. Infusion of chylomicrons purified from milk-fed calves (10.5 mg/h per kg BW, i.e. 0.16 mg triglycerides/kg BW per min) enhanced significantly (P less than 0.01) the hepatic production of IGF1 (mean value for 6 h: 5.3 (SE 0.8) nmol/kg BW). Infusion of Intralipid (7 mg triglycerides/kg BW per min) induced a slight but significant hepatic IGF1 production which amounted to 3.5 (SE 0.4) nmol/kg BW (P less than 0.1 compared with chylomicron treatment) and it began only 5 h after starting the infusion. Neither triglyceride nor chylomicron infusion significantly modified hepatic blood flow. Thus, these results demonstrate for the first time the role of lipids in the regulation of hepatic IGF1 production in vivo.

Hypercholesterolemia is a well established risk factor for cardiac cell apoptosis. The purpose of this study is to evaluate the effects of garlic oil on cardiac apoptosis induced by a hypercholesterol diet. Twenty-four male Golden-Syrian hamsters at 3 months of age were randomly divided into three groups, control, cholesterol and garlic oil groups received a chow diet, chow diet with 2% cholesterol, and chow diet with 2% cholesterol and 1% garlic oil for 8 weeks, respectively. The TUNEL-positive apoptotic cells, and several apoptotic proteins were significantly induced in the excised left ventricle in cholesterol group, whereas significant reduction was observed in cholesterol plus garlic oil group. The IGFI receptor dependent survival pathway was inhibited in cholesterol group whereas it was obviously reversed in cholesterol plus garlic oil group. Our results suggest that administration of garlic oil shows protective effects on cardiac apoptosis in rats with high cholesterol intake.

The decrease in adult height of children who have been given cranial irradiation (24 Gy) for acute lymphoblastic leukaemia is attributed to chemotherapy, growth hormone (GH) deficiency and early puberty. This study evaluates the factors involved in the height loss between irradiation and adult height and its markers in 43 patients irradiated at 5.8 +/- 0.4 (SEM) years. The mean height loss was 0.9 +/- 0.2 SD in the children with a normal GH peak (n = 11), 1.7 +/- 0.2 SD in those with a low GH peak and untreated (n = 15) and 0.6 +/- 0.2 SD in those treated with GH (n = 17). The adult height was significantly lower than target height in all three groups. The height loss correlated negatively with the GH peak (p < 0.02) and with the age at onset of puberty (p < 0.05) in the first two groups with spontaneous growth, but not with the chemotherapy regimen or its duration, or the plasma insulin-like growth factor I (IGFI) and its GH-dependent binding protein (BP-3). Early puberty (onset at 8-10 years) occurred in 6 girls from the first two groups. At the first evaluation, 5.6 +/- 0.4 years after irradiation, the GH peak values after arginine-insulin stimulation correlated with the age at irradiation (p < 0.03), taking into account the time since irradiation. The plasma IGFI and BP-3 values were correlated with each other, but not with the GH peak. In conclusion, this study demonstrates the impact of GH deficiency and GH replacement therapy on adult height in children given cranial irradiation for leukaemia. They therefore should be evaluated for their GH secretion 1-2 years after the end of chemotherapy. GH therapy is indicated for those with low GH peak and decreased growth rate or no increase in growth rate despite puberty.

Aging involves numerous changes in body composition that include a decrease in skeletal muscle mass. The gradual reduction in muscle mass is associated with a simultaneous decrease in muscle strength, which leads to reduced mobility, fragility and loss of independence. This process called sarcopenia is secondary to several factors such as sedentary lifestyle, inadequate nutrition, chronic inflammatory state and neurological alterations. However, the endocrine changes associated with aging seem to be of special importance in the development of sarcopenia. On one hand, advancing age is associated with a decreased secretion of the main hormones that stimulate skeletal muscle mass and function (growth hormone, insulin-like growth factor 1 (IGFI), testosterone and estradiol). On the other hand, the alteration of the IGF-I signaling along with decreased insulin sensitivity also have an important impact on myogenesis. Other hormones that decline with aging such as the adrenal-derived dehydroepiandrosterone, thyroid hormones and vitamin D seem to also be involved in sarcopenia. Adipokines released by adipose tissue show important changes during aging and can affect muscle physiology and metabolism. In addition, catabolic hormones such as cortisol and angiotensin II can accelerate aged-induced muscle atrophy, as they are involved in muscle wasting and their levels increase with age. The role played by all of these hormones and the possible use of some of them as therapeutic tools for treating sarcopenia will be discussed.

Keywords: Adiponectin; Angiotensin II; Cortisol; Estrogens; IGF-I; Insulin; Leptin; Sarcopenia; Skeletal muscle atrophy; Testosterone.

Heart failure represents the endpoint of a variety of cardiovascular diseases. It is a growing health burden and a leading cause of death worldwide. To date, limited treatment options exist for the treatment of heart failure, but exercise has been well established as one of the few safe and effective interventions, leading to improved outcomes in patients. However, a lack of patient adherence remains a significant barrier in the implementation of exercise-based therapy for the treatment of heart failure. The insulin-like growth factor 1 (IGF1)- phosphoinositide 3-kinase (PI3K) pathway has been recognized as perhaps the most critical pathway for mediating exercised-induced heart growth and protection. Here, we discuss how modulating activity of the IGF1-PI3K pathway may be a valuable approach for the development of therapies that mimic the protective effects of exercise on the heart. We outline some of the promising approaches being investigated that utilize PI3K based therapy for the treatment of heart failure. We discuss the implications for cardiac pathology and cardiotoxicity that arise in a setting of reduced PI3K activity. Finally, we discuss the use of animal models of cardiac health and disease, and genetic mice with increased or decreased cardiac PI3K activity for the discovery of novel drug targets and biomarkers of cardiovascular disease.

Keywords: Cardiac protection; Cardiotoxicity; Exercise; Heart failure; IGFI, PI3K, Therapies.

Polymerase chain reaction amplification of a cDNA derived from dog left ventricular myocardium, using primers specific for rat insulin-like growth factor I (IGFI), exons 3 and 6, yielded the dog clone, IGFIIGFI and the C-terminal extension sequence. By analogy with the organization of the rat and human IGFI genes which encode two extension peptides, we have termed this cDNA, dog IGFIa. The deduced amino acid sequence of mature dog IGFI is identical to that of human IGFI.

BACKGROUND

In patients with acromegaly, sleep apnea-related hypoxemia results in considerable morbidity and mortality.

OBJECTIVE

To evaluate the relative weight of pathogenic factors in predicting such hypoxemia.

METHODS

In this cross-sectional study, 34 acromegaly patients were submitted to clinical evaluation, nocturnal oximetry, and nasolaryngeal airway tomography. GH, IGF-I, and its upper limit normal value were measured. Nocturnal hypoxemia was defined as >5 episodes of desaturation/h of sleep. Craniofacial abnormalities were expressed using a linear parameter index (LPI). Nocturnal hypoxemia was predicted using logistic regression, including the variables markers of craniofacial abnormality, hormonal alteration, and obesity. Coefficients were standardized in order to determine their effect magnitudes relative to the outcome. The best model included the variables gender, age, LPI, body mass index (BMI), and IGFI upper limit normal value.

RESULTS

In the absence of the age and gender variables, the odds ratio for the LPI (1.60) was slightly higher than those found for BMI (1.49) and upper limit normal value (1.40). When the data were adjusted for age, the hormone upper limit normal value presented little alteration (1.49), although the decrease in the LPI was considerable (1.21), as was the increase in the BMI (2.18). The relative weight of the LPI was age-dependent. The gender variable did not alter the relevance of the others.

CONCLUSIONS

The effects that craniofacial aspect, obesity, and hormonal alterations have on nocturnal hypoxemia are of similar magnitude.

Physical fitness is a trait determined by multiple genes, and its genetic basis is modified by numerous environmental factors. The present study examines the effects of the (CA)n tandem repeats polymorphism in IGFI gene and SNP Alw21I restriction site -202 A>C polymorphism in IGF1BP3 on VO2max--a physiological index of aerobic capacity of high heritability. The study sample consisted of 239 (154 male and 85 female) students of the University School of Physical Education in Poznań and athletes practicing various sports, including members of the Polish national team. An association was found between -202 A/C polymorphism of IGFBP3 gene with VO2max in men. Higher VO2max values were attained by men with CC genotype, especially male athletes practicing endurance sports and sports featuring energy metabolism of aerobic/anaerobic character. A statistically significant influence of allele 188 and genotype 188/188 of tandem repeats (CA)n polymorphism of IGF1 gene on VO2max was found in women. Also, lower values of maximal oxygen uptake were noted in individuals with allele 186 or genotype 186/186, and higher VO2max values in athletes with allele 194.

The Ecuadorian cohort of subjects with LS has taught us valuable lessons since the late 80's. We have learned about migration of Sephardic Jews to our country, their isolation in remote hamlets and further inbreeding. These geographical, historical and social determinants induced dissemination of a growth hormone (GH) receptor mutation which widely occurred in those almost inaccessible villages. Consequently, the world's largest Laron syndrome (LS) cohort emerged in Loja and El Oro, two of the southern provinces of Ecuador. We have been fortunate to study these patients since 1987. New clinical features derived from GH insensitivity, their growth patterns as well as treatment with exogenous insulin-like growth factor I (IGF-I) have been reported. Novel biochemical characteristics in the field of GH insensitivity, IGFs, IGF binding proteins (BP) and their clinical correlates have also been described. In the last few years, studies on the morbidity and mortality of Ecuadorian LS adults surprisingly demonstrated that despite obesity, they had lower incidence of diabetes and cancer than their relatives. These events were linked to their metabolic phenotype of elevated but ineffective GH concentrations and low circulating IGF-I and IGFBP-3. It was also noted that absent GH counter-regulation induces a decrease in insulin resistance (IR), which results in low but highly efficient insulin levels which properly handle metabolic substrates. We propose that the combination of low IGF-I signaling, decreased IR, and efficient serum insulin concentrations are reasonable explanations for the diminished incidence of diabetes and cancer in these subjects.

Keywords: Diabetes-cancer-insulin-IGFI-Ecuadorian Laron syndrome.

Growth hormone (GH) and insulin like growth factor-I (IGFI) are key bone trophic hormones, whose rising levels during puberty are critical for pubertal bone accrual. Conditions of GH deficiency and genetic resistance impact cortical and trabecular bone deleteriously with reduced estimates of bone strength. In humans, conditions of undernutrition (as in anorexia nervosa (AN), or subsequent to chronic illnesses) are associated with low IGF-I levels, which correlate with disease severity, and also with lower bone mineral density (BMD), impaired bone structure and lower strength estimates. In adolescents and adults with AN, studies have demonstrated a nutritionally acquired GH resistance with low IGF-I levels despite high concentrations of GH. IGF-I levels go up with increasing body weight, and are associated with rising levels of bone turnover markers. In short-term studies lasting 6-10 days, recombinant human IGF-I (rhIGF-I) administration in physiologic replacement doses normalized IGF-I levels and increased levels of bone formation markers in both adults and adolescents with AN. In a randomized controlled trial in adults with AN in which participants were randomized to one of four arms: (i) rhIGF-I with oral estrogen-progesterone (EP), (ii) rhIGF-I alone, (iii) EP alone, or (iv) neither for 9 months, a significant increase in bone formation markers was noted in the groups that received rhIGF-I, and a significant decrease in bone resorption markers in the groups that received EP. The group that received both rhIGF-I and EP had a significant increase in bone density at the spine and hip compared to the group that received neither. Side effects were minimal, with no documented fingerstick glucose of <50 mg/dl. These data thus suggest a potential role for rhIGF-I administration in optimizing bone accrual in states of undernutrition associated with low IGF-I.

Proline and arginine-rich end leucine-rich repeat protein (PRELP) is a member of the small leucine-rich repeat proteoglycans (SLRPs) family. Levels of PRELP mRNA are down-regulated in many types of cancer, and PRELP has been reported to have suppressive effects on tumor cell growth, although the molecular mechanism has yet to be fully elucidated. Given that other SLRPs regulate signaling pathways through interactions with various membrane proteins, we reasoned that PRELP likely interacts with membrane proteins to maintain cellular homeostasis. To identify membrane proteins that interact with PRELP, we carried out co-immunoprecipitation coupled with mass spectrometry (CoIP-MS). We prepared membrane fractions from Expi293 cells transfected to overexpress FLAG-tagged PRELP or control cells and analyzed samples precipitated with anti-FLAG antibody by mass spectrometry. Comparison of membrane proteins in each sample identified several that seem to interact with PRELP; among them, we noted two growth factor receptors, insulin-like growth factor I receptor (IGFI-R) and low-affinity nerve growth factor receptor (p75NTR), interactions with which might help to explain PRELP's links to cancer. We demonstrated that PRELP directly binds to extracellular domains of these two growth factor receptors with low micromolar affinities by surface plasmon resonance analysis using recombinant proteins. Furthermore, cell-based analysis using recombinant PRELP protein showed that PRELP suppressed cell growth and affected cell morphology of A549 lung carcinoma cells, also at micromolar concentration. These results suggest that PRELP regulates cellular functions through interactions with IGFI-R and p75NTR, and provide a broader set of candidate partners for further exploration.

Keywords: PRELP; co-immunoprecipitation; growth factor receptor; membrane protein; protein‐protein interaction; proteomics; small leucine‐rich proteoglycan (SLRP); surface plasmon resonance (SPR).