Higher IGF-I Research Articles

Abstract P3-10-05: Normal breast biopsies reveal an "active" transcriptome associating with higher breast cancer risk (Gail) scores and increased IGF-1 growth factor expression

Abstract Background: Recent studies have identified at least two different transcriptional subtypes of benign human breast tissue (Haakensen et al., 2011), including an “active” subtype associated with increased risk of later life mortality from breast cancer (Troester et al., 2016). However, previous studies used "normal" breast samples from cosmetic surgery, biopsies from abnormal mammograms, or cancer-adjacent tissue. The present study evaluates normal breast transcriptome phenotypes from healthy women who donated for this study purpose only. Methods: 200 formalin-fixed paraffin-embedded (FFPE) breast tissue biopsy samples were analyzed from healthy, parous non-Hispanic white women ranging in age from 27–66 (median = 45) with no prior history of breast cancer (<16% had prior breast biopsies), who donated to the Komen Tissue Bank (KTB) and provided questionnaire data enabling calculation of breast cancer risk (Gail) scores. Extractable RNA from FFPE sections sufficient for RNA sequencing (˜100ng) was obtained from 145/200 donor samples; digitized H&E analysis confirmed normal breast histology. Transcript levels were quantified using RSEM and normalized; 2558 genes were used for unsupervised hierarchical clustering to identify “active” vs. “inactive” normal transcriptome subtypes as previously described (Roman-Perez et al., 2012), and these subtypes were compared for risk scores and IGF1R and IGF-1 gene expression levels and their respective signatures (Creighton et al., 2008; Mu et al., 2012). Results: As expected, the normal histologic composition of these KTB samples varied considerably with mean % adipose area twice that of fibrous area, and epithelial content averaging <5%. Unsupervised gene expression analysis produced two primary clusters, with 31% of donor samples showing the “active” transcriptome phenotype. These “active” breast samples came from women with significantly higher Gail scores (Wilcoxon rank sum p=0.007) and showed significantly different expression levels in 12 of 17 IGF-1/IGF1R pathway genes (FDR-corrected p values) including higher IGF-1, IGF-2, IRS1, IRS2, IGF2R, IGFBP3, IGFBP5, IGFBP6, and IGF2BP3 levels, and lower IGF1R, IGFBP2, and IGFBP3 transcript levels. A multigene signature associated with IGF-1 induction was consistent with the 2-fold significant increase in mean IGF-1 mRNA levels seen in this “active” subset; likewise, an independent multigene signature associated with IGF1R activation was consistent with the 0.84-fold significant reduction in mean IGF1R mRNA levels observed in this same subset. Conclusion: Over 30% of healthy adult women with histologically normal breast tissue carry an “active” breast transcriptome phenotype previously linked to co-existent breast cancer and now shown to be associated with increased future risk of developing breast cancer assessed by Gail score. This “active” transcriptome phenotype is characterized by increased endogenous IGF-1 activity, a known breast cancer promoting growth factor, along with an inverse reduction in IGF1R expression and activity as previously seen in some breast cancers. Further morphologic and molecular characterization of this risk-associated subset of normal breast tissues is underway. Citation Format: Benz C, Yau C, Benz S, Krings G, Powell M. Normal breast biopsies reveal an "active" transcriptome associating with higher breast cancer risk (Gail) scores and increased IGF-1 growth factor expression [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-10-05.

IGF-1 Levels Among Adolescent Girls Living In Jakarta and It's relation to Nutritional Status

Background and Objective:Insulin-like growth factor (IGF)-1 is one of the hormones that plays a role in the growth of adolescent girls. Its level will rise at puberty and begin to decline at the end of puberty. High IGF-1 levels in adult is associated with the incidence of breast cancer. This study aims to know the level of IGF-1 and investigates its relationship with dietary intake, nutritional status, and physical activity of adolescent girls aged 13-15 in Jakarta.Methods and Study Design:This cross-sectional study used secondary data from a previous study (titled "Determinant Factor Levels of Estradiol, IGF-1, and Early Menarche in Adolescent Girls Aged 13-15 in Jakarta: Nutritional Epidemiology Study Related to Breast Cancer Risk Factors") and primary data from stored blood serum to measure IGF-1 levels by colorimetric method. The secondary data such as dietary intake, anthropometric data, and physical activities were obtained from 178 subjects with a total population sampling method.Results and Conclusions:There was a positive correlation between IGF-1 levels and carbohydrate intake (p=0.041, r=0.153) and a negative correlation between IGF-1 levels and fat intake (p=0.042, r=-0.152). No correlation between IGF-1 and body mass index was found, but there was a tendency that IGF-1 values would increase in overweight and decrease in obesity. IGF-1 levels have nonlinear pattern by carbohydrates intake, fat intake and nutritional status. In conclusion, the adolescent girls should maintain their nutritional status by maintaining diet, choosing the right and balanced foods, as well as increasing physical activities.

Insulin-Like Growth Factor-1 at Diagnosis and during Subsequent Years in Adolescents with Type 1 Diabetes.

Background Type 1 diabetes (T1D) in adolescents is associated with alterations in the insulin-like factor system probably caused both by a deranged metabolism and insulinopenia in the portal vein. Objective To study how the circulating IGF-1 is affected at diagnosis and during subsequent years in adolescents with T1D. Methods Ten girls and ten boys with type 1 diabetes (T1D), aged 13.0 ± 1.4 (mean ± SD) years at diagnosis, took part in the study. Blood samples were drawn at diagnosis and after 3, 9, 18, and 48 months. HbA1c, total IGF-1, and C-peptide were measured. Results At diagnosis, the patients had high HbA1c, low IGF-1, and measurable C-peptide. After the start of insulin treatment, maximal improvement in glycemic control and IGF-1 occurred within 3 months and then both tended to deteriorate, that is, HbA1c to increase and IGF-1 to decrease. C-peptide decreased with time, and after 4 years, half of the patients were C-peptide negative. At diagnosis, C-peptide correlated positively to IGF-1 (r = 0.50; p < 0.03). C-peptide correlated negatively with insulin dose (U/kg) after 18 and 48 months from diagnosis (r = −0.48; p < 0.03 and r = −0.72; p < 0.001, resp.). Conclusions In conclusion, our results show that in newly diagnosed adolescents with type 1 diabetes and deranged metabolism, the IGF-1 level is low and rapidly improves with insulin treatment but later tends to decrease concomitantly with declining endogenous insulin secretion.

Circulating concentrations of insulin like growth factor-1 in female dogs with spontane-ous mammary tumours

The aim of this study was the investigation of the circulating concentration of IGF-1 in female dogs with spontaneous mammary tumours. The study was performed on 34 female dogs undergoing surgery due to spontaneously occurring mammary gland tumours (24 malignant and 10 benign) and 10 clinically healthy fe-male dogs. The serum concentrations of IGF-1 were determined by specific ELISA Kit assay. The mean con-centrations of IGF-1 were significantly higher (P &lt; 0.05) both in dogs with malignant (173.35 ± 120.45 ng/ml) and benign (130.58 ± 59.0 ng/ml) mammary tumours than in healthy controls (117.45±71.0 ng/ml). In the group of female dogs with mammary carcinomas, the mean concentration of IGF-1 gradually increased from 132.85 ± 65.64 ng/ml in dogs with grade 1 tumours to 317.74 ± 119.25 ng/ml in those with grade 3 tumours, and significant differences (P &lt; 0.05) were found among dogs with various grade tumours. These findings suggest that circulating IGF-1 may play an important role in the pathogenesis of canine mammary tumour. Moreover, high IGF-1 levels may reflect tumour cell differentiation into a more aggressive phenotype. .

Association of maternal breast milk and serum levels of macronutrients, hormones, and maternal body composition with infant's body weight.

This study was aimed to investigate the association of maternal serum and breast-milk levels of macronutrients, hormones, growth factors, and maternal body composition with infant's body weight. Eighty mother-infant pairs comprised 40 with overweight or obese infant and 40 with normal-weight infant were enrolled in this study. The level of ghrelin, Leptin, adiponectin, EGF, and IGF1 in plasma and breast milk were assessed. Daily breast milk intake and macronutrient concentration along with anthropometric indices of mother-infant pairs were also assessed. No significant differences were observed in concentrations of serum hormones between two groups (p > 0.05). However, hormones levels in maternal serum were higher than those in breast milk. A significant positive correlation was found between serum EGF and ghrelin (r = 0.57, p = 0 < 0001). Higher IGF1 in serum showed a significant association with its milk counterpart (r = 0.37). Current mother's weight was associated with infant's weight at the 2nd and 6th month (B = 0.023 p = 0.04, B = 0.055 p = 0.005). The breast-milk macronutrient content was not comparable between two groups. However, the average daily breast milk consumption in obese infants was higher than normals (p = 0.001). Milk EGF and leptin were related to a decrease of 59% and 46% the odds of obese infant development, respectively. There was a significant association of milk EGF and ghrelin with birth weight (B = -0.19, p = 0.04 and B = -0.2, p = 0.04, respectively), and also serum leptin with infant's body weight at the 6th month. Our findings provide a positive association of maternal weight, daily breast milk intake, EGF, and ghrelin with infant's body weight.

The IGF1R/INSR Inhibitor BI 885578 Selectively Inhibits Growth of IGF2-Overexpressing Colorectal Cancer Tumors and Potentiates the Efficacy of Anti-VEGF Therapy.

Clinical studies of pharmacologic agents targeting the insulin-like growth factor (IGF) pathway in unselected cancer patients have so far demonstrated modest efficacy outcomes, with objective responses being rare. As such, the identification of selection biomarkers for enrichment of potential responders represents a high priority for future trials of these agents. Several reports have described high IGF2 expression in a subset of colorectal cancers, with focal IGF2 amplification being responsible for some of these cases. We defined a novel cut-off value for IGF2 overexpression based on differential expression between colorectal tumors and normal tissue samples. Analysis of two independent colorectal cancer datasets revealed IGF2 to be overexpressed at a frequency of 13% to 22%. An in vitro screen of 34 colorectal cancer cell lines revealed IGF2 expression to significantly correlate with sensitivity to the IGF1R/INSR inhibitor BI 885578. Furthermore, autocrine IGF2 constitutively activated IGF1R and Akt phosphorylation, which was inhibited by BI 885578 treatment. BI 885578 significantly delayed the growth of IGF2-high colorectal cancer xenograft tumors in mice, while combination with a VEGF-A antibody increased efficacy and induced tumor regression. Besides colorectal cancer, IGF2 overexpression was detected in more than 10% of bladder carcinoma, hepatocellular carcinoma and non-small cell lung cancer patient samples. Meanwhile, IGF2-high non-colorectal cancer cells lines displayed constitutive IGF1R phosphorylation and were sensitive to BI 885578. Our findings suggest that IGF2 may represent an attractive patient selection biomarker for IGF pathway inhibitors and that combination with VEGF-targeting agents may further improve clinical outcomes. Mol Cancer Ther; 16(10); 2223-33. ©2017 AACR.

Methylation status of IGF2 DMR and LINE1 in leukocyte DNA provides distinct clinicopathological features of gastric cancer patients.

DNA methylation of leukocyte DNA has been proposed to be a biomarker for cancer that can be used to target patients for appropriate clinical implementation. We investigated IGF2 DMR and LINE1 methylation in the leukocyte DNA and their association with clinicopathological features and prognosis of gastric cancer (GC) patients. Methylation status of IGF2 DMR and LINE1 in the leukocyte DNA was quantified using bisulfite pyrosequencing in 207 GC patients. Methylation of both IGF2 DMR and the LINE1 was significantly higher in the undifferentiated histologic type compared to the differentiated histologic type (both P=0.0002). Hypermethylation of both the IGF2 DMR and the LINE1 was associated with more aggressive features of GC such as advanced stage (IGF2 DMR, P=0.0002; LINE1, P<0.0001), lymphatic invasion positive (IGF2 DMR, P=0.004; LINE1, P=0.002), venous invasion positive (IGF2 DMR, LINE1, both P=0.03), lymph node metastasis positive (IGF2 DMR, P=0.01; LINE1, P=0.001), peritoneal dissemination positive (IGF2 DMR, P=0.04; LINE1, P=0.002), liver metastasis positive (IGF2 DMR, P=0.008; LINE1, P=0.001), and other distant metastasis positive (IGF2 DMR, P=0.04). Our data suggest that high LINE1 and IGF2 DMR methylation status would be a phenomenon that is observed with the progression of GC, supporting their potential utility as a biomarker in GC patients.

IGFBP3 Modulates Lung Tumorigenesis and Cell Growth through IGF1 Signaling.

Insulin-like growth factor binding protein 3 (IGFBP3) modulates cell growth through IGF-dependent and -independent mechanisms. Reports suggest that the serum levels of IGFBP3 are associated with various cancers and that IGFBP3 expression is significantly decreased in cisplatin (CDDP)-resistant lung cancer cells. Based on these findings, we investigated whether Igfbp3 deficiency accelerates mouse lung tumorigenesis and if expression of IGFBP3 enhances CDDP response by focusing on the IGF1 signaling cascade. To this end, an Igfbp3-null mouse model was generated in combination with KrasG12D to compare the tumor burden. Then, IGF-dependent signaling was assessed after expressing wild-type or a mutant IGFBP3 without IGF binding capacity in non-small cell lung cancer (NSCLC) cells. Finally, the treatment response to CDDP chemotherapy was evaluated under conditions of IGFBP3 overexpression. Igfbp3-null mice had increased lung tumor burden (>2-fold) and only half of human lung cancer cells survived after expression of IGFBP3, which corresponded to increased cleaved caspase-3 (10-fold), inactivation of IGF1 and MAPK signaling. In addition, overexpression of IGFBP3 increased susceptibility to CDDP treatment in lung cancer cells. These results, for the first time, demonstrate that IGFBP3 mediates lung cancer progression in a KrasG12D mouse model. Furthermore, overexpression of IGFBP3 induced apoptosis and enhanced cisplatin response in vitro and confirmed that the suppression is in part by blocking IGF1 signaling.Implications: These findings reveal that IGFBP3 is effective in lung cancer cells with high IGF1 signaling activity and imply that relevant biomarkers are essential in selecting lung cancer patients for IGF1-targeted therapy. Mol Cancer Res; 15(7); 896-904. ©2017 AACR.

Association of IGF-1 with coronary collateral circulation in stable coronary artery disease.

The aim of the present study is to evaluate the relationship between coronary collateral circulation (CCC) grade and serum IGF-1 levels in patients diagnosed with stable coronary artery disease. Totally, 190 consecutive patients with stable coronary artery disease who underwent coronary angiography were included in this study. The patients with good CCC had significantly higher IGF-1 levels compared with the poor ones. On the contrary, hs-CRP was significantly lower in the good CCC group. We also demonstrated that IGF-1 level was significantly related with the grade of CCC. We believe that measurement of IGF-1 level may help clinicians for predicting CCC development.

Insulin-like growth factor 1 receptor affects the survival of primary prostate cancer patients depending on TMPRSS2-ERG status

BackgroundProstate cancer (PCa) is characterized by clinical and biological heterogeneity and has differential outcomes and mortality rates. Therefore, it is necessary to identify molecular alterations to define new therapeutic strategies based on the risk of progression. In this study, the prognostic relevance of the insulin-like growth factor (IGF) system was examined in molecular subtypes defined by TMPRSS2-ERG (T2E) gene fusion within a series of patients with primary localized PCa.MethodsA cohort of 270 formalin-fixed and paraffin-embedded (FFPE) primary PCa samples from patients with more than 5 years’ follow-up was collected. IGF-1R, IGF-1, IGFBP-3 and INSR expression was analyzed using quantitative RT-PCR. The T2E status and immunohistochemical ERG findings were considered in the analyses. The association with both biochemical and clinical progression-free survival (BPFS and PFS, respectively) was evaluated for the different molecular subtypes using the Kaplan-Meier proportional risk log-rank test and the Cox proportional hazards model.ResultsAn association between IGF-1R overexpression and better BPFS was found in T2E-negative patients (35.3% BPFS, p-value = 0.016). Multivariate analysis demonstrated that IGF-1R expression constitutes an independent variable in T2E-negative patients [HR: 0.41. CI 95% (0.2–0.82), p = 0.013]. These data were confirmed using immunohistochemistry of ERG as subrogate of T2E. High IGF-1 expression correlated with prolonged BPFS and PFS independent of the T2E status.ConclusionsIGF-1R, a reported target of T2E, constitutes an independent factor for good prognosis in T2E-negative PCa. Quantitative evaluation of IGF-1/IGF-1R expression combined with molecular assessment of T2E status or ERG protein expression represents a useful marker for tumor progression in localized PCa.

Classification of Patients With GH Disorders May Vary According to the IGF-I Assay.

Insulinlike growth factor I (IGF-I) measurement is essential for the diagnosis and management of growth hormone (GH) disorders. However, patient classification may vary substantially according to the assay technique. We compared individual patient data and classifications obtained with six different IGF-I assay kits in a group of patients with various GH disorders. In this cross-sectional study, we measured IGF-I with six immunoassays in 102 patients with active or treated acromegaly or GH deficiency. IGF-I normative data previously established for the same six assay kits were used to classify the patients (high, low, or normal IGF-I levels), using both raw data and standard deviation scores (SDSs). Pairwise concordance between assays was assessed with Bland-Altman plots and with the percentage of observed agreement and the weighted κ coefficient for categorized IGF-I SDS. We observed marked variability both across each individual's IGF-I raw data and across IGF-I SDS values obtained with each of the six immunoassays. Pairwise concordance between assay values, as assessed with the weighted κ coefficient, ranged from 0.50 (moderate) to 0.81 (excellent). Even when using normative data obtained in the same large population of healthy subjects and when using calculated IGF-I SDSs, agreement among IGF-I assay methods is only moderate to good. Differences in assay performance must be taken into account when evaluating and monitoring patients with GH disorders. This argues for the use of the same IGF-I assay for a given patient throughout follow-up.

Extreme Hypoglycaemia in Anaplastic Large Cell Lymphoma.

IntroductionHypoglycaemia associated with non-islet cell tumours (NICTH) is a rare entity in patients with extra-pancreatic malignancies, mostly attributed to large mesenchymal or epithelial tumours. Anaplastic large cell lymphoma has not previously been associated with NICTH, making this the first publication of such a report.Patient and methodsA 22-year-old, non-diabetic patient was admitted to our department with malaise, itching, night sweats and weight loss. Serum glucose levels at presentation were extremely low, reaching 3 mg/dl at the lowest. Further investigations revealed undetectable blood insulin and C-peptide levels, together with low IGF-1 (34 ng/ml) levels. Inguinal lymph node biopsy showed anaplastic large cell lymphoma, and bone marrow biopsy along with supporting blood tests revealed haemophagocytic lymphohistiocytosis.DiscussionIn conjunction with an adequate hyperglycaemic response to intravenous glucagon, all of the above findings indicate hypoglycaemia as a result of overproduction of high molecular weight IGF-2 precursor protein, generally referred to as ‘Big IGF-2’. Large solid tumours can occasionally produce loosely bound or free Big IGF-2 molecules which circulate throughout the plasma and bind to insulin as well as IGF receptors, thus increasing glucose intake by body tissues, decreasing the release of glucose to the bloodstream by the liver and causing feedback suppression of insulin, IGF-1 and growth hormone production. Therefore, it is exceptional to find Big IGF-2-related hypoglycaemia in non-solid tumours. Our case shows that, although extremely uncommon, rare instances of NICTH can be attributed to the production of Big IGF-2 in non-solid malignancies including anaplastic large cell lymphoma.LEARNING POINTSAlthough extremely rarely, haematological malignancies can produce non-islet cell tumours (NICTH) as a result of IGF-2 and Big IGF-2 secretion.Insulin, C-peptide and IGF-1 levels may be sufficient to diagnose NICTH.

Exercise increases leptin levels correlated with IGF-1 in hippocampus and prefrontal cortex of adolescent male and female rats

It is known that regular aerobic exercise has positive effects on hippocampus and prefrontal cortex. We have previously have been able to demonstrate that aerobic exercise increased IGF-1 in hippocampus. Leptin, which is associated with cognitive functions, is also involved in fat metabolism and stimulates energy consumption. While it is known that leptin stimulates IGF-1 production in hepatocytes, little known is on the link between IGF-1 and leptin in brain during aerobic exercise.In this study, we investigated the effects of regular aerobic exercise on leptin, leptin receptor expression levels in hippocampus and prefrontal cortex. Additionally, we investigated the correlation of IGF-1 levels with leptin and leptin receptor expression. During the experiment, exercise group was run on a treadmill for 30min per session at a speed of 8m/min and 0° slope, five times a week for 6 weeks. Leptin, leptin expression, IGF-1 levels and cell numbers increased in prefrontal cortex and hippocampus of exercise groups. Blood leptin levels increased in female rats in exercise group; whereas it did not change in male rats; blood IGF-1 levels were found to be increased in exercised male rats. There was a strong positive correlation between hippocampal leptin levels and hippocampal IGF-1 levels; also a strong positive correlation between hippocampal leptin receptor expression and hippocampal IGF-1.These results indicate that, increased leptin and leptin receptor expression are correlated with IGF-1 in regular aerobic exercised rats. Blood leptin and IGF-1 levels were also found to be associated with gender. Females had high blood leptin levels and males had high blood IGF-1 levels in the exercise groups.

First and second trimester gestational weight gains are most strongly associated with cord blood levels of hormones at delivery important for glycemic control and somatic growth

BackgroundExcessive gestational weight gain (GWG) during pregnancy is associated with adverse outcomes for mothers and offspring. Early, mid, and late pregnancy GWGs have different associations with fetal growth and later life adiposity, but associations with cord blood hormones, which might predict later health, are not well studied. MethodsIn 978 pregnant women from the pre-birth Project Viva cohort, we calculated trimester-specific GWG using clinically recorded prenatal weights. Outcomes were levels of umbilical cord blood hormones related to fetal and postnatal growth. We used linear regression models adjusted for maternal race/ethnicity, pre-pregnancy BMI, parity, education, pregnancy smoking status and child sex; 2nd and 3rd trimester models were additionally adjusted for GWG in prior trimesters. ResultsMean±SD pre-pregnancy BMI was 24.9±5.5kg/m2, 30% were non-white, and 63% were college graduates. Mean±SD cord blood hormone levels were insulin-like growth factor [IGF]-1 (56.4±24.3ng/mL), IGF-2 (408.5±92.7ng/mL), IGFBP-3 (1084±318ng/mL), insulin (6.5±7.2 uU/mL), C-peptide (1.0±0.6ng/mL), leptin (9.0±6.6ng/mL) and adiponectin (28.7±6.8μg/mL). Mean±SD 1st, 2nd and 3rd trimester GWG rates were 0.22±0.22, 0.49±0.19 and 0.46±0.22kg/wk. Greater 1st trimester GWG (per 0.2kg/wk) was associated with higher insulin (0.5 uU/mL; 95% CI 0.1, 0.9) and C-peptide (0.06ng/mL; 95% CI 0.02, 0.09) and lower adiponectin (−0.4μg/mL; 95% CI −0.9, 0.0). Greater 2nd trimester GWG (per 0.2kg/wk) was associated with higher IGF-1 (2.3ng/mL; 95% CI 0.6, 4.0), IGF-2 (7.9ng/mL; 95% CI 1.2, 14.6), IGFBP-3 (41.6ng/mL; 95% CI 19.4, 63.7) and leptin (0.9ng/mL; 0.4, 1.4). 3rd trimester GWG was not associated with cord blood hormones. Conclusion1st trimester weight gain appears to matter more for cord blood hormones related to offspring glucose/insulin regulation, whereas 2nd trimester gain matters more for hormones related to growth and adiposity.

Bone material strength index as measured by impact microindentation is altered in patients with acromegaly.

Acromegaly is a rare disease caused by excess growth hormone (GH) production by the pituitary adenoma. The skeletal complications of GH and IGF-1 excess include increased bone turnover, increased cortical bone mass and deteriorated microarchitecture of trabecular bone, associated with a high risk of vertebral fractures in the presence of relatively normal bone mineral density (BMD). We aimed to evaluate tissue-level properties of bone using impact microindentation (IMI) in well-controlled patients with acromegaly aged ≥18 years compared to 44 controls from the outpatient clinic of the Centre for Bone Quality. In this cross-sectional study, bone material strength index (BMSi) was measured in 48 acromegaly patients and 44 controls with impact microindentation using the osteoprobe. Mean age of acromegaly patients (54% male) was 60.2 years (range 37.9-76.5), and 60.5 years (range 39.8-78.6) in controls (50% male). Patients with acromegaly and control patients had comparable BMI (28.2 kg/m2 ± 4.7 vs 26.6 kg/m2 ± 4.3, P = 0.087) and comparable BMD at the lumbar spine (1.04 g/cm2 ± 0.21 vs 1.03 g/cm2 ± 0.13, P = 0.850) and at the femoral neck (0.84 g/cm2 ± 0.16 vs 0.80 g/cm2 ± 0.09, P = 0.246). BMSi was significantly lower in acromegaly patients than that in controls (79.4 ± 0.7 vs 83.2 ± 0.7; P < 0.001). Our data indicates that tissue-level properties of cortical bone are significantly altered in patients with controlled acromegaly after reversal of long-term exposure to pathologically high GH and IGF-1 levels. Our findings also suggest that methods other than DXA should be considered to evaluate bone fragility in patients with acromegaly.

Seminal plasma hormonal profile of Arabian stallions that are classified ‘good’ or ‘poor’ for semen freezing

ObjectiveTo relate seminal plasma reproductive and metabolic hormone profile to both semen freezability and post-thaw semen characteristics. MethodsSemen was collected from each Arabian stallion (N = 16) for five consecutive weeks and evaluated before conducting this study. Seminal plasma was collected during semen processing for measuring leptin, insulin, Insulin like growth factor-I (IGF-1), cortisol, testosterone, estradiol and thyroid hormones. Stallions were classified into good (N = 10) and poor freezer (N = 6). Semen post-thaw motility (%), viability index, membrane and acrosome integrity (%) were also evaluated. ResultsGood freezer stallions had significantly (P = 0.0001) high cortisol, estradiol, insulin, IGF-1, T3 and T4, but significantly low leptin (P = 0.003). Post-thaw sperm viability index (P = 0.0001), membrane integrity (%) (P = 0.002) and motility (%) (P = 0.0001) at 0, 1, 2 and 3 h of good freezer stallions was significantly high compared to poor freezers. Testosterone, insulin and IGF-1 in seminal plasma of good freezer stallions had significant (P < 0.01) positive correlation with sperm post-thaw viability index but estradiol and insulin in seminal plasma of poor freezers correlated with sperm post-thaw viability index. Within good freezer stallions, testosterone in seminal plasma correlated positively with both viability and acrosome integrity but within poor freezer stallions it had a negative correlation with both of them. Individual variation existed between animals and significantly affected seminal plasma hormones and semen post-thaw characteristics. ConclusionGood freezer stallions could be selected depending on assaying seminal plasma hormones. Both estradiol and IGF-1 could be used as semen extender supplementation to improve sperm post-thaw motility, viability and acrosome integrity.

Equine Chorionic Gonadotropin Modulates the Expression of Genes Related to the Structure and Function of the Bovine Corpus Luteum.

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).

Hormonal regulation of postnatal growth from birth to age six months in Small-for-Gestational - Age children

This article is devoted to the investigation hormonal mechanisms of postnatal growth from birth to age six months in small for gestational age children (SGA) with asymmetrical and asymmetrical IUGR. The IGF-1 and GH levels, insulin sensitivity (by homeostasis model assessment (HOMA-IR)) were measured blood at 3 and 6 months of age. The prospective study includes 40 SGA infants (group 1) - 24 - with asymmetrical (1a) and 16 with symmetrical IUGR babies (1b) and 17 appropriate for gestational age (AGA) infants (group 2). Most SGA infants showed rapid, or “catch-up” postnatal growth. Symmetrical IUGR infants with “catch-up” growth had higher IGF-1 and growth GH levels at 3 month of age than asymmetrical IUGR with “catch-up” growth (p &lt; 0,05). From 3 to 6 months of age 77 % of infants with “catch-up” growth showed retardation of growth velocity. At 6 month of age SGA infants with “catch-up” growth had lower IGF-1, GH blood levels and HOMA-IR than at 3 months of age (p &lt; 0,05). Infants without “catch-up” growth had similar hormone levels at 3 and 6 months of age. We suppose, that these changes of “GH - IGF-1” axis and insulin sensitivity at age 3 and 6 months in SGA infants are the mechanisms, which promote the postnatal growth. It can be assumed that the same mechanisms may underlie metabolic disorders in later life.

Combined administration of mesenchymal stem cells overexpressing IGF-1 and HGF enhances neovascularization but moderately improves cardiac regeneration in a porcine model

BackgroundInsulin-like growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) are among the most promising growth factors for promoting cardiorepair. Here, we evaluated the combination of cell- and gene-based therapy using mesenchymal stem cells (MSC) genetically modified to overexpress IGF-1 or HGF to treat acute myocardial infarction (AMI) in a porcine model.MethodsPig MSC from adipose tissue (paMSC) were genetically modified for evaluation of different therapeutic strategies to improve AMI treatment. Three groups of infarcted Large White pigs were compared (I, control, non-transplanted; II, transplanted with paMSC-GFP (green fluorescent protein); III, transplanted with paMSC-IGF-1/HGF). Cardiac function was evaluated non-invasively using magnetic resonance imaging (MRI) for 1 month. After euthanasia and sampling of the animal, infarcted areas were studied by histology and immunohistochemistry.ResultsIntramyocardial transplant in a porcine infarct model demonstrated the safety of paMSC in short-term treatments. Treatment with paMSC-IGF-1/HGF (1:1) compared with the other groups showed a clear reduction in inflammation in some sections analyzed and promoted angiogenic processes in ischemic tissue. Although cardiac function parameters were not significantly improved, cell retention and IGF-1 overexpression was confirmed within the myocardium.ConclusionsThe simultaneous administration of IGF-1- and HGF-overexpressing paMSC appears not to promote a synergistic effect or effective repair. The combined enhancement of neovascularization and fibrosis in paMSC-IGF-1/HGF-treated animals nonetheless suggests that sustained exposure to high IGF-1 + HGF levels promotes beneficial as well as deleterious effects that do not improve overall cardiac regeneration.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0350-z) contains supplementary material, which is available to authorized users.

Overproduction of IGF-2 drives a subset of colorectal cancer cells, which specifically respond to an anti-IGF therapeutic antibody and combination therapies

Colorectal cancer (CRC) is a heterogeneous disease with a broad spectrum of genetic and epigenetic changes. A comprehensive molecular characterization of CRC by The Cancer Genome Atlas Network detected the overexpression of the insulin-like growth factor 2 (IGF2) gene, encoding a ligand for the insulin-like growth factor 1 receptor (IGF-1R), in a subset of CRC tumors. In this study, we investigated the oncogenic potential of IGF-2 in IGF2-overexpressing CRC models and the efficacy of MEDI-573, an IGF-1/2-neutralizing antibody. We found that a subset of CRC cell lines express high IGF-2 levels owing to an increased DNA copy number and hypermethylation in the H19 promoter of the IGF2 gene. MEDI-573 efficiently neutralized IGF-2 and induced apoptosis, which resulted in significant tumor growth inhibition in CRC mouse models that express high levels of IGF-2. These effects were specific to CRCs overexpressing IGF-2, as MEDI-573 did not affect the growth CRC cell lines with normal levels. Moreover, blockade of IGF-2 by MEDI-573 modulated other signaling pathways, suggesting combination therapies with inhibitors of these pathways. Indeed, in vivo efficacy was significantly enhanced when MEDI-573 was used in combination with trastuzumab, AZD2014 (dual mTORC1/2i), AZD5363 (AKTi) and selumetinib (AZD6244/ARRY-142886, MEK1/2i) or cetuximab. These results demonstrate that overexpressed IGF-2 is the major tumorigenic driver in a subset of CRCs and encourage testing of MEDI-573, alone and in combinations, in IGF2-overexpressing CRC patients.