Growth hormone-releasing hormone (GHRH) regulates growth hormone release from the pituitary. However, in addition to this neuroendocrine action, much evidence implies an additional role for GHRH in carcinogenesis in non-pituitary tissues. This role of GHRH in cancer development appears to be due to the operation of several mechanisms, which involve the regulation of the growth hormone-dependent hepatic insulin-like growth factor I (IGFI) production, tumoural IGF-I and IGF-II secretion and direct action of GHRH on tumour cells by autocrine and/or paracrine pathways. This review summarises the available information regarding the role of GHRH in tumorigenesis with special emphasis on the direct action of GHRH in primary and experimental cancers.

MEDI-573 is a human antibody that neutralizes insulin-like growth factor (IGF) I and IGFII. IGFs are overexpressed in multiple types of cancer; their overexpression is a potential mechanism for resistance to IGFI receptor (IGFIR)-targeting therapy. Effects of IGF on cell proliferation, differentiation, and survival are mediated through its binding to and activation of IGFIR or insulin receptor A (IR-A). In this study, we measured the mRNA levels of IGFI, IGFII, and IGFIR in human pediatric sarcoma xenografts, and protein levels in sarcoma cell lines. MEDI-573 potently inhibited in vitro proliferation of sarcoma cell lines, with Ewing sarcoma cell lines being the most sensitive. In addition, MEDI-573 inhibited IGFI- and IGFII-induced sarcoma cell proliferation in vitro. The effect of MEDI-573 on IGF signaling was also examined. Treatment with MEDI-573 markedly reduced levels of pIGFIR, pIR-A, and pAKT and significantly blocked IGFI- and IGFII-induced activation of the IGFIR and AKT pathways. MEDI-573 inhibited the growth of sarcoma xenografts in vivo and inhibition correlated with neutralization of IGFI and IGFII. Combination of MEDI-573 with either rapamycin or AZD2014, another mTOR inhibitor (mTORi), significantly enhanced the antitumor activity of MEDI-573, and this response correlated with modulation of AKT and mTOR signaling. In summary, sarcoma cells respond to autocrine or paracrine growth stimulation by IGFI and IGFII, and inhibition of IGFI and IGFII by MEDI-573 results in significant slowing of tumor growth rate in sarcoma models, particularly in Ewing sarcoma. These data provide evidence for the potential benefits of MEDI-573 and mTORi combinations in patients with Ewing sarcoma.

OBJECTIVE

Levels of IGFI have been shown to be low in transfusion-dependent thalassaemia and there is preliminary evidence to suggest that this may be reversed by GH treatment. In this further study we have evaluated serum growth hormone (GH) binding protein (GHBP), IGF-I and IGFBP-3 in patients with beta-thalassaemia major and the effects of GH treatment on these various parameters.

METHODS

Fifty-six transfusion dependent patients with beta-thalassaemia major without GH deficiency between 2 and 20 years of age were studied. Thirteen non-GH deficient patients with heights of -1.5 SD or more were treated with GH at a dose of 0.14 IU/kg/day subcutaneously for 1 year.

METHODS

Serum GHBP, IGF-I and IGFBP-3 were measured in all the patients. In the 13 patients treated with GH, these serum parameters were measured before and after 3, 6 and 12 months of treatment.

RESULTS

The mean serum GHBP concentrations were normal in both prepubertal and pubertal children but the serum IGF-I and IGFBP-3 concentrations were low throughout childhood and adolescence. There was a significant correlation between serum IGF-I and IGFBP-3 concentrations (r = 0.79; P = 0.0001) but there was no correlation between the height SDS of the patients with serum GHBP, IGF-I or IGFBP-3 levels. GH treatment in the 13 patients resulted in significant growth acceleration associated with a significant rise in the serum IGF-I and IGFBP-3 and a significant fall in serum GHBP concentrations.

CONCLUSIONS

The low serum concentrations of IGF-I and IGFBP-3 in the presence of normal GH reserve and serum GHBP concentrations in patients with beta-thalassaemia suggest a state of partial GH insensitivity at the post-receptor level. This partial GH insensitivity state can be overcome by supraphysiological doses of exogenous GH. The lack of correlation of IGF-I, IGFBP-3 and GHBP with height SDS of the patients imply that the growth failure commonly observed in patients with beta-thalassaemia major may not be specifically related to dysregulation of the GH-IGF-I axis. GH therapy resulted in significant increase in serum IGF-I and IGFBP-3 but a significant fall in GHBP.

Pure and partial agonist antioestrogens, exemplified by ICI 164,384 and tamoxifen or 4-hydroxytamoxifen (4'-OHT) respectively, differ in their capacity to inhibit the growth of MCF-7 human breast cancer cells. Under basal conditions which maintain but do not permit proliferation of MCF-7 cells, growth rate was enhanced by oestradiol, Phenol Red, insulin and 4'-OHT but not by ICI 164,384. Oestradiol and insulin together enhanced cell growth rate synergistically. 4'-OHT, but not ICI 164,384, similarly increased insulin-stimulated cell growth in the absence of oestradiol. ICI 164,384 blocked the stimulatory action of 4'-OHT. The stimulatory effect of the peptide growth factors TGF-alpha and IGFI on MCF-7 cells were attenuated by ICI 164,384 and 4'-OHT; ICI 164,384 was more effective than 4'-OHT. The antiproliferative action of ICI 164,384 on oestradiol or growth factor stimulated MCF-7 cells was only weakly inhibited by TGF-beta antibodies.

Recent evidence implicates the insulin-like growth factor (IGF) pathway in development of Ewing sarcoma, a highly malignant bone and soft-tissue tumor that primarily affects children and young adults. Despite promising results from preclinical studies of therapies that target this pathway, early-phase clinical trials have shown that a significant fraction of patients do not benefit, suggesting that cellular factors determine tumor sensitivity. Using FAIRE-seq, a chromosomal deletion of the PTEN locus in a Ewing sarcoma cell line was identified. In primary tumors, PTEN deficiency was observed in a large subset of cases, although not mediated by large chromosomal deletions. PTEN loss resulted in hyperactivation of the AKT signaling pathway. PTEN rescue led to decreased proliferation, inhibition of colony formation, and increased apoptosis. Strikingly, PTEN loss decreased sensitivity to IGF1R inhibitors but increased responsiveness to temsirolimus, a potent mTOR inhibitor, as marked by induction of autophagy. These results suggest that PTEN is lost in a significant fraction of primary tumors, and this deficiency may have therapeutic consequences by concurrently attenuating responsiveness to IGF1R inhibition while increasing activity of mTOR inhibitors. The identification of PTEN status in the tumors of patients with recurrent disease could help guide the selection of therapies.

CONCLUSIONS

PTEN status in Ewing sarcoma affects cellular responses to IGFI and mTOR-directed therapy, thus justifying its consideration as a biomarker in future clinical trials.

As the consumption of probiotics increases worldwide, scientists focus on identifying bacterial strains able to improve human life quality and evidence the biological pathways affected by probiotic treatment. In this review, some recent observations on the effects of changes of microbiota on zebrafish metabolism were discussed. In addition, the effects of Lactobacillus rhamnosus - a component of the human gut microflora - as a diet supplement on Danio rerio were presented. When administered chronically, L. rhamnosus may affect larval development and the physiology of reproductive system in the zebrafish model. It was hypothesized exogenous L. rhamnosus accelerates larval growth and backbone development by acting on insulin-like growth factors-I (igfI) and -II (igfII), peroxisome proliferator activated receptors-α and -β, (pparα,β) vitamin D receptor-α (vdrα) and retinoic acid receptor-γ (rarγ). Gonadal differentiation was anticipated at 6weeks together with a higher expression of gnrh3 at the larval stage when L. rhamnosus was administered throughout development. Moreover, brood stock alimented with a L. rhamnosus-supplemented diet showed better reproductive performances as per follicles development, ovulated oocytes quantification and embryos quality. A plausible involvement of factors such as leptin, and kiss1 and 2 in the improvements was concluded. The observations made on the physiology of female reproduction were correlated with the gene expression of a gigantic number of factors as the aromatase cytochrome p 19 (cyp19a), the vitellogenin (vtg) and the α isoform of the E2 receptor (erα), luteinizing hormone receptor (lhr), 20-β hydroxysteroid dehydrogenase (20β-hsd), membrane progesterone receptors α and β, cyclin B, activinβA1, smad2, transforming growth factor β1 (tgfβ1), growth differentiation factor9 (gdf9) and bone morphogenetic protein15 (bmp15.) A model in which the exogenous L. rhamnosus in the digestive tract of zebrafish from the first days of life through sexual maturation positively influences the physiological performances of zebrafish was evidenced and a number of pathways that might be influenced by the presence of this human probiotic strain were proposed.

Here, we describe a child, born from consanguineous parents, with clinical features of SHORT syndrome, high IGF1 levels, developmental delay, CNS defects, and marked progeroid appearance. By exome sequencing, we identified a new homozygous c.2201G>T missense mutation in the IGF1R gene. Proband's parents and other relatives, all heterozygous carriers of the mutation, presented with milder phenotype including high IGFI levels, short stature, and type 2 diabetes. Functional studies using patient's cell lines showed a lower IGF1R expression that leads to the alteration of IGF1R-mediated PI3K/AKT/mTOR downstream pathways, including autophagy. This study defines a clinically recognizable incomplete dominant form of SHORT syndrome, and provides relevant insights into the pathophysiological and phenotypical consequences of IGF1R mutations.

OBJECTIVE

To develop classification models of demographic/clinical factors and biomarker data from spontaneous preterm birth in African Americans and Caucasians.

METHODS

Secondary analysis of biomarker data using multivariate adaptive regression splines (MARS), a supervised machine learning algorithm method.

METHODS

Analysis of data on 36 biomarkers from 191 women was reduced by MARS to develop predictive models for preterm birth in African Americans and Caucasians.

METHODS

Maternal plasma, cord plasma collected at admission for preterm or term labor and amniotic fluid at delivery.

METHODS

Data were partitioned into training and testing sets. Variable importance, a relative indicator (0-100%) and area under the receiver operating characteristic curve (AUC) characterized results.

RESULTS

Multivariate adaptive regression splines generated models for combined and racially stratified biomarker data. Clinical and demographic data did not contribute to the model. Racial stratification of data produced distinct models in all three compartments. In African Americans maternal plasma samples IL-1RA, TNF-α, angiopoietin 2, TNFRI, IL-5, MIP1α, IL-1β and TGF-α modeled preterm birth (AUC train: 0.98, AUC test: 0.86). In Caucasians TNFR1, ICAM-1 and IL-1RA contributed to the model (AUC train: 0.84, AUC test: 0.68). African Americans cord plasma samples produced IL-12P70, IL-8 (AUC train: 0.82, AUC test: 0.66). Cord plasma in Caucasians modeled IGFII, PDGFBB, TGF-β1 , IL-12P70, and TIMP1 (AUC train: 0.99, AUC test: 0.82). Amniotic fluid in African Americans modeled FasL, TNFRII, RANTES, KGF, IGFI (AUC train: 0.95, AUC test: 0.89) and in Caucasians, TNF-α, MCP3, TGF-β3 , TNFR1 and angiopoietin 2 (AUC train: 0.94 AUC test: 0.79).

CONCLUSIONS

Multivariate adaptive regression splines models multiple biomarkers associated with preterm birth and demonstrated racial disparity.

Recent studies of the growth hormone insulinlike growth factor I (IGFI) axis suggest that these hormones are involved in several physiologic processes, in addition to growth. Thus, several lines of evidence indicate an increasingly important role for recombinant human growth hormone as a part of the modern therapeutic armamentarium. In addition to the treatment of children with growth hormone deficiency, administration of growth hormone appears to be of considerable benefit to girls with Turner syndrome, children with chronic renal failure, and adults with growth hormone deficiency or human immunodeficiency virus (HIV) wasting syndrome. Moreover, its therapeutic use is being investigated in other conditions, such as children with idiopathic short stature, the healthy elderly, and the critically ill. However, long-term surveillance among growth hormone recipients is needed to fully evaluate its risk-benefit profile.

A synthetic gene coding for human-insulin-like growth factor I (IGFI) was fused to the leader sequence of yeast prepro-alpha-factor and expressed in Saccharomyces cerevisiae under the control of a glyceraldehyde-3-phosphate dehydrogenase promoter fragment. Recombinant IGFI was found inside yeast cells and secreted into the medium. The secreted IGFI migrated on SDS gels with the same electrophoretic mobility as authentic IGFI, i.e. at about 7.5 kDa. HPLC analysis of secreted IGFI revealed the presence of the correctly folded, genuine molecule as well as an isomeric byproduct of equal molecular mass but with two of the three disulfide bonds interchanged. Inside exponentially growing cells the 7.5-kDa IGFI was also found, along with up to four additional IGFI-related polypeptides of higher molecular mass. By endoglycosidase F treatment the three polypeptides between 19-26 kDa were converted to a single peptide of 17 kDa. Since this peptide also reacted with an anti-alpha-factor antibody, it represents most likely the unglycosylated alpha-factor--IGFI fusion precursor. Pulse-chase experiments established the precursor nature of the intracellular higher-molecular-mass IGFI species. Conversion of the primary translation product to the differently glycosylated IGFI precursor proteins and into the mature form occurred very rapidly, within 2 min. Rapid maturation was, however, not followed by an equally rapid secretion of the mature form into the medium: only after 30-40 min did IGFI appear outside the cells. We therefore postulate the presence of an as yet undefined Golgi or post-Golgi bottleneck representing a major obstacle in secretion of recombinant IGFI from S. cerevisiae cells.

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder caused by damage of motoneurons leading to paralysis state and long term disability. Riluzole is currently the only FDA-approved drug for the treatment of ALS. The proposed mechanisms of ALS include glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, protein aggregation, SOD1 accumulations, and neuronal death. In this review, we discuss potential biomarkers for the identification of patients with ALS. We further emphasize potential therapy involving the uses of neurotrophic factors such as IGFI, GDNF, VEGF, ADNF-9, colivelin and angiogenin in the treatment of ALS. Moreover, we described several existing drugs such as talampanel, ceftriaxone, pramipexole, dexpramipexole and arimoclomol potential compounds for the treatment of ALS. Interestingly, the uses of stem cell therapy and immunotherapy are promising for the treatment of ALS.

OBJECTIVE

This study was done to determine whether the use of reference values obtained in children with idiopathic short stature (ISS) improved the clinical value of serum insulin-like growth factor I (IGF-1) as a tool for diagnosing GH deficiency (GHD) in prepubertal children.

METHODS

Serum IGF-1 was measured with a new IRMA kit (IGFI-RIA CT, Cis Bio, Gif sur Yvette, France) in 168 prepubertal normal children and in prepubertal children with ISS (n = 68), organic GHD due to a craniopharyngioma (oGHD, n = 15) and permanent idiopathic GHD (iGHD, n = 28).

RESULTS

IGF-1 was lower (P < 0.001) in iGHD than in either ISS or oGHD and was below the fifth percentile of the normal range in 29/68 ISS (43%), 8/15 oGHD (53%) and 28/28 (100%) iGHD patients. Three oGHD (20%) and two iGHD (7%) patients had a serum IGF-1 below the fifth percentile of the normal group but above the fifth percentile of the ISS group. Thus, a serum IGF-1 below the fifth percentile of the normal group distinguished between normal children and iGHD with 100% sensitivity, between normal and oGHD with 53% sensitivity and between normal and all GHD (idiopathic + organic) with 84% sensitivity; the overall specificity was only 57%. Conversely, a serum IGF-1 below the fifth percentile of the ISS population distinguished between ISS and iGHD with 93% sensitivity, between ISS and oGHD with 33% sensitivity and between ISS and all GHD with 72% sensitivity; the overall specificity was then 95%.

CONCLUSIONS

A serum IGF-1 within the normal range virtually excludes idiopathic GHD but does not rule out organic GHD, whereas an IGF-1 below the ISS range is strongly in favour of GHD, after exclusion of poor nutritional status and/or liver disease. An IGF-1 below the normal range but in the idiopathic short stature range gives no definitive conclusion even when it is associated with a low GH peak. Thus, whereas reference values obtained in normal children must be used to interpret serum IGF-1 in short prepubertal children, reference data obtained in idiopathic short stature children should also be taken into account.

The most updated guidelines for the diagnosis of adult GH deficiency (GHD) come from the GH Research Society Consensus Workshop held in Sydney, Australia, in 2007. Regarding who to test for GHD, advice should be extended from primitive hypothalamic- pituitary diseases and cranial irradiation to include brain injuries (Traumatic Brain Injury in particular). Regarding how to test for GHD, the insulin tolerance test (ITT) remains a provocative test of reference; among classical provocative test, glucagon test has also been validated. Above all, GHRH + arginine and GHRH + GH-secretagogues are now considered, at least, as reliable as ITT for the diagnosis of adult GHD. Interestingly, it is now accepted that very low IGF-I represents definite evidence of severe GHD in congenital forms of GHD and also in patients with acquired multiple hypopituitarism. These patients would skip provocative test; however, as normal IGFI levels do not rule out severe GHD, patients suspected for hypopituitarism showing normal IGF-I levels must undergo a provocative test of GH secretion. Retesting the GH status in the transition age is of major relevance in order to decide about continuing or not recombinant human GH replacement in adult life.

Patients operated on for craniopharyngioma frequently suffer from hyperphagia and are obese, but their statural growth is normal despite growth hormone (GH) deficiency. We have evaluated the hormonal factors influencing changes in weight and growth in 17 children before and 1, 3-6, 12, and/or 24 months after surgical resection of a craniopharyngioma performed at 7.7 +/- (SE) 1 years of age. Of these, 15 patients had a GH deficiency before surgery, and all had complete pituitary deficiency after it. The plasma fasting insulin concentrations before surgery were positively correlated with body mass index (BMI, kg/m(2); p < 0.05), plasma insulin-like growth factors (IGFI, p = 0.03, and IGFII, p = 0.04), and leptin (p = 0.03). They increased significantly 1 month after surgery and continued to increase thereafter, whereas leptin increased significantly only 3-6 months after surgery, paralleling changes in BMI. The plasma fasting insulin concentrations before surgery were also positively correlated with the weight changes (12.3 +/- 2.3 kg, p < 0.01) during the 12 months after surgery, but not with changes in BMI SDS (3.1 +/- 0.5, p = 0.07). Both expressions of weight change were correlated with the concomitant growth rates (4.8 +/- 0.7 cm, p < 0.01). IGFI was above the 10th percentile for children with idiopathic short stature in 10 of 15 patients with craniopharyngioma-induced GH deficiency and IGF-binding protein 3 in 14 of 15 patients. Craniopharyngioma itself modified the control of insulin secretion, and surgery increased the insulin secretion which continued in the same way in a given patient after surgery. The increased insulin secretion in turn increases weight and keeps IGFI nearly normal. This may explain the normal growth rate despite the complete lack of GH.

OBJECTIVE

Abnormalities of the melanocortin system produce obesity and increased linear growth. While the obesity phenotype is well characterised, the mechanism responsible for increased linear growth is unclear. The somatotrophic axis was studied in the obese agouti (A(y)/a) mouse as a model of a perturbed melanocortin system.

METHODS

Adult obese A(y)/a mice were compared to age- and sex-matched wild-type (WT) controls. Weight and body length (nose-anus) were recorded. Plasma growth hormone (GH), insulin-like growth factor-I (IGFI), insulin and leptin were measured using radioimmunoassay. Since ghrelin is a potent GH secretagogue, plasma ghrelin, stomach ghrelin peptide and stomach ghrelin mRNA expression were studied. Hypothalamic periventricular (PeVN) somatostatin neurones and arcuate (Arc) neuropeptide Y (NPY) neurones inhibit the growth axis, whereas Arc growth hormone-releasing hormone (GHRH) neurones are stimulatory. Therefore, specific hypothalamic expression of somatostatin, NPY and GHRH was measured using quantitative in situ hybridisation.

RESULTS

Obese A(y)/a mice were significantly heavier and longer than WT controls. Plasma IGFI concentrations were 30% greater in obese A(y)/a mice. Obese A(y) /a mice were hyperinsulinaemic and hyperleptinaemic, yet plasma ghrelin, and stomach ghrelin peptide and mRNA were significantly reduced. In obese A(y)/a mice, PeVN somatostatin and Arc NPY mRNA expression were reduced by 50% compared to WT controls, whereas Arc GHRH mRNA expression was unchanged.

CONCLUSIONS

Increased body length in adult obese A(y)/a mice may result from reduced Arc NPY and PeVN somatostatin mRNA expression, which in turn, may increase plasma IGFI concentrations and upregulate the somatotrophic axis.

We assessed the effect of chronic hyperglycemia on bone mineral density (BMD) and bone remodeling in patients with type 2 diabetes mellitus. We investigated 42 patients with type 2 diabetes under stable control for at least 1 year, 22 of them with good metabolic control (GMC: mean age = 48.8 +/- 1.5 years, 11 females) and 20 with poor metabolic control (PMC: mean age = 50.2 +/- 1.2 years, 8 females), and 24 normal control individuals (CG: mean age = 46.5 +/- 1.1 years, 14 females). We determined BMD in the femoral neck and at the L2-L4 level (DEXA) and serum levels of glucose, total glycated hemoglobin (HbA1), total and ionic calcium, phosphorus, alkaline phosphatase, follicle-stimulating hormone, intact parathyroid hormone (iPTH), 25-hydroxyvitamin D (25-OH-D), insulin-like growth factor I (IGFI), osteocalcin, procollagen type I C propeptide, as well as urinary levels of deoxypyridinoline and creatinine. HbA1 levels were significantly higher in PMC patients (12.5 +/- 0.6 vs 7.45 +/- 0.2% for GMC and 6.3 +/- 0.9% for CG; P < 0.05). There was no difference in 25-OH-D, iPTH or IGFI levels between the three groups. BMD values at L2-L4 (CG = 1.068 +/- 0.02 vs GMC = 1.170 +/- 0.03 vs PMC = 1.084 +/- 0.02 g/cm(2)) and in the femoral neck (CG = 0.898 +/- 0.03 vs GMC = 0.929 +/- 0.03 vs PMC = 0.914 +/- 0.03 g/cm(2)) were similar for all groups. PMC presented significantly lower osteocalcin levels than the other two groups, whereas no significant difference in urinary deoxypyridine was observed between groups. The present results demonstrate that hyperglycemia is not associated with increased bone resorption in type 2 diabetes mellitus and that BMD is not altered in type 2 diabetes mellitus.

BACKGROUND

The insulin-like growth factor-I (IGFI) receptor is a potential target for breast cancer treatment and may be influenced by dietary intake.

METHODS

Nested, case-control study of 265 postmenopausal breast cancer survivors; primary breast cancer tissue was stained to determine IGFI receptor status. Change in carbohydrate intake from baseline to year 1 of study was estimated from 24-hour dietary recalls. Breast cancer recurrence cases (91) were matched to two controls (n = 174) on disease and study characteristics and counter matched on change in carbohydrate intake. Weighted conditional logistic regression models fit the risk of recurrence on IGFI receptor status and dietary change.

RESULTS

Half of the tumors were IGFI receptor positive. Increased risk of recurrence was associated with IGFI receptor-positive status [HR 1.7; 95% confidence interval (CI), 1.2-2.5] and, separately, with a stable/increased intake of carbohydrates (HR 2.0; 95% CI, 1.3-5.0). There was a borderline significant interaction between those two variables (P = 0.11). Specifically, carbohydrate intake had no significant impact on risk of recurrence among women who were receptor negative, yet increased the risk of recurrence by more than 5-fold among women who were receptor positive (HR 5.5; 95% CI, 1.8-16.3).

CONCLUSIONS

Among women whose tumor tissue is positive for the IGFI receptor, reducing carbohydrate intake after diagnosis could reduce the risk of breast cancer recurrence. These findings need replication in a larger sample.

CONCLUSIONS

This is the first study to suggest that it may be possible to personalize dietary recommendations for breast cancer survivors based on molecular characteristics of their primary tumor tissue. .

The use of ultrasonic vocalizations as an experimental tool for studying emotional states in rodents has led to an increased understanding of the basic science of affect as well as the development of novel diagnostics and therapeutics for the treatment of affective disorders. At the behavioral level, the rules that govern the generation of affective 'feeling' states are similar to those of the psychophysics of sensory perception. Emotions are elicited primarily in response to active social stimuli. A linear increase in affective response requires a logarithmic increase in stimulation and habituation of a given affective response allows for transition across the cycle of emotional/affective states (approach→consummatory phase→avoidance). At the neuronal level, the coordinated expression of affective responses in the medial prefrontal cortex is orchestrated by rhythmic activity, which is initiated and maintained by a variety of short-term and long-term synaptic plasticity processes. An objective measure of affective states may emerge from these psychophysical and neuronal properties of emotion. Enhancing synaptic plasticity with pharmacological agents that modulate NMDA receptor activity as well as IGFI receptor activity may have therapeutic potential for the treatment of affective disorders.

Binding of human GH (hGH) and insulin-like growth factors I and II (IGFI and II) to isolated human adipocytes from adult subjects was studied. Binding equilibrium for hGH at 24 degrees C was reached at 120 min and half-maximal specific binding at 6-8 ng/ml. Apparent Ka was 2.1 X 10(9) M-1 and Bmax 7.3 X 10(-11) M/10(6) cells. The human fat cell growth hormone receptor recognized neither bovine, ovine or rat GH nor human prolactin or placental lactogen. No specific receptors for human IGFII could be demonstrated. Thus, human adipocytes do not possess IGF receptors but have specific GH receptors which recognize hGH but not GH from lower species.

BACKGROUND

Somatostatin (SST) and its receptors (SSTR1-5) may have a role in prostate cancer by influencing the IGFI hormone axis or through direct effects on prostate epithelia. We have investigated if genetic variation in the SST and SSTR1-5 genes influences prostate cancer risk and/or circulating IGFI and IGFBP3 hormone levels.

METHODS

We analyzed 28 haplotype tagging single nucleotide polymorphisms in the SST and SSTR1-5 genes in a case-control/genetic association study to investigate the association between genetic variation and prostate cancer risk. The study included 2863 cases and 1737 controls from the Cancer Prostate in Sweden (CAPS) study. To investigate the genetic influence on circulating hormone levels, plasma concentrations of IGFI and IGFBP3 were analyzed in 874 controls of the CAPS study and 550 male subjects from the Northern Sweden Health and Disease Cohort (NSHDC).

RESULTS

No clear association between prostate cancer risk and genetic variation of the SST and SSTR1-5 genes was identified. The SSTR5 missense single nucleotide polymorphism rs4988483 was associated with circulating IGFI (P = 0.002) and IGFBP3 (P = 0.0003) hormone levels in CAPS controls, with a per allele decrease of approximately 11%. This decrease was replicated in NSHDC for circulating IGFBP3 (P = 0.01) but not for IGFI (P = 0.09). Combining CAPS and NSHDC subjects indicated evidence of association between rs4988483 and both IGFBP3 (P = 2 x 10(-5)) and IGFI (P = 0.0004) hormone levels.

CONCLUSIONS

Our results suggest that genetic variation in the SSTR5 gene and, particularly, the rs4988483 single nucleotide polymorphism influence circulating IGFI and IGFBP3 hormone levels with no measurable effect on prostate cancer risk.

In the polycystic ovary syndrome, hyperinsulinaemia is commonly found in women with hirsutism, oligomenorrhoea and acanthosis nigricans and this subset of patients possess adverse risk factors for coronary artery disease, particularly reduced HDL2 concentrations. Conversely, raised serum insulin concentrations are not common in women with PCOS in whom raised serum LH concentrations or regular menstrual cycles are present. We postulate that both direct ovarian and indirect actions of insulin (through changes in IGFI-I, IGFBP-I and SHBG concentrations) play important roles in determining androgen concentrations in women. Many intriguing questions follow from this link between the control of nutrition and reproduction and many old observations required re-examination in this new light. Vital to our understanding in this field will be the cause of moderate hyperinsulinaemia, the action of insulin on the normal ovary, and the importance of adverse surrogate risk factors for heart disease in hyperinsulinaemic women.

Locally produced growth hormone (GH) and IGF-I are key factors in the regulation of mammary gland (MG) development and may be important in breast cancer development/progression. Somatostatin (SST) and cortistatin (CORT) regulate GH/IGF-I axis at various levels, but their role in regulating GH/IGF-I in MGs remains unknown. Since obesity alters the expression of these systems in different tissues and is associated to MG (patho) physiology, we sought to investigate the role of SST/CORT in regulating GH/IGF-I system in the MGs of lean and obese mice. Therefore, we analyzed GH/IGF-I as well as SST/CORT and ghrelin systems expression in the mammary fat pads (MFPs) of SST- or CORT-knockout (KO) mice and their respective littermate-controls fed a low-fat (LF) or a high-fat (HF) diet for 16 wks. Our results demonstrate that the majority of the components of GH/IGF-I, SST/CORT and ghrelin systems are locally expressed in mouse MFP. Expression of elements of the GH/IGF-I axis was significantly increased in MFPs of HF-fed control mice while lack of endogenous SST partially suppressed, and lack of CORT completely blunted, the up-regulation observed in obese WT-controls. Since SST/CORT are known to exert an inhibitory role on the GH/IGFI axis, the increase in SST/CORT-receptor sst2 expression in MFPs of HF-fed CORT- and SST-KOs together with an elevation on circulating SST in CORT-KOs could explain the differences observed. These results offer new information on the factors (GH/IGF-I axis) involved in the endocrine/metabolic dysregulation of MFPs in obesity, and suggest that CORT is not a mere SST sibling in regulating MG physiology.

Consumption of fructose has been linked to the development of metabolic syndrome, whereas the cardiomyopathic changes and cardiac apoptosis of dietary high-fructose intake have not yet been clarified. The purpose of this study was to evaluate the effects of high-fructose on cardiac apoptotic and survival pathways. Thirty-two Wistar rats were randomly divided into a control group (CON), which received a standard chow diet, and a fructose-induced metabolic syndrome group (FIMS), which received a 50% fructose-content diet for 13 weeks. Histopathological analysis, TUNEL assays and Western blotting were performed on the excised hearts from both groups. The blood pressure, glucose, insulin, triglyceride and cholesterol levels were significantly increased in the FIMS group, compared with the CON group. The abnormal myocardial architecture, enlarged interstitial space and increased cardiac TUNEL-positive apoptotic cells were observed in the FIMS group. The TNF-α, TNF receptor 1, Fas ligand, Fas receptor, FADD, and activated caspase-3 and 8 protein levels (Fas pathway) and the Bax, Bak, Bax/Bcl-2, Bak/Bcl-xL, cytosolic cytochrome c, and activated caspase-3 and nine protein levels (mitochondria pathway) were increased in the FIMS group compared with those in the CON group. The IGFI, IGFI-R, p-PI3K, p-Akt, Bcl-2 and Bcl-xL protein levels (survival pathway) were all significantly decreased in the FIMS group compared with those in the CON group. High-fructose intake elevated blood pressure and glucose levels; moreover, high-fructose diet activated cardiac Fas-dependent and mitochondria-dependent apoptotic pathways and suppressed the survival pathway, which might provide one possible mechanism for developing heart failure in patients with metabolic syndrome.

Lead is known to reduce linear and ponderal growth in children, even at levels of exposure common in the general population. The mechanism involved is not known. The present study was conducted in order to establish the role of food consumption and insulin-like growth factor (IGFI), also commonly known as somatomedin C (SmC), in lead-induced reduction in growth in weanling rats. A further purpose was to test the hypothesis that depressed growth could be prevented by administration of growth hormone and thyroxine, a procedure which prevents arrested growth due to hypophysectomy. Treatment with growth hormone in combination with thyroxine had no effect on depressed growth or food consumption. The reduction in linear and ponderal growth due to lead (approximately 17%) could be largely though not completely accounted for on the basis of reduced food consumption, apparently by a mechanism not involving growth hormone or thyroxine (see above). Plasma SmC was reduced in proportion to reduced food intake, regardless of whether due to Pb or to restriction of food intake in a pair-feeding experiment thereby ruling out an effect of lead on SmC synthesis or activity other than through reduced food consumption. The experiments leading to these conclusions all involved administration of lead in the drinking water, suggesting the possibility that reduced food consumption was peripherally mediated as a result of contact of lead with appetite-depressant receptors in the gastrointestinal tract, e.g., taste receptors. An additional experiment therefore was conducted comparing food consumption and growth resulting from oral lead administration to subcutaneous administration. Similar depressant effects on food consumption and growth resulted at similar concentrations of lead and zinc protoporphyrin in blood. These effects were significantly greater following oral administration, however, suggesting that lead depresses appetite by both a systemic mechanism and one operating at the level of the gastrointestinal tract.