Low Insulin-like Growth Factor Binding Research Articles

Malnutrition in children associated with low insulin-like growth factor binding protein-3 (IGFBP-3) levels

ObjectiveThis study aimed to compare serum levels of Insulin-like Growth Factor Binding Protein-3 in children with malnutrition and good nutritional status. MethodThis cross-sectional study included 41 participants consisting of 31 malnourished, 10 well-nourished children aged between 36 and 60 months. Demographic data of participants were obtained utilizing a questionnaire. Nutritional status was determined by calculating the Z-score of body weight for age, height for age, and body weight for height indices using the WHO classification. IGFBP-3 levels were determined by the Enzyme-Linked Immunosorbent Assay (ELISA) method. ResultMedian serum IGFBP-3 levels in malnourished children were found to be lower i.e. 0.35mcg/mL (minimum–maximum: 0.04–1.52mcg/mL) compared to well-nourished children 1.52ng/mL (minimum–maximum 0.47–3.17mcg/mL). ConclusionSerum IGFBP-3 levels can be used as indicators to assess nutritional status.

Gonadotropin versus Follicle-Stimulating Hormone for Ovarian Response in Patients Undergoing in vitro Fertilization: A Retrospective Cohort Comparison

Poor ovarian responders generally refer to patients who respond poorly to ovarian stimulation for assisted reproductive techniques (ART) such as in-vitro fertilization (IVF) and hence experience low live birth rate. Various controlled ovarian stimulation (COS) protocols have been developed during the past 3 decades for IVF/ICSI to improve oocyte quality and ultimately live birth rate, to increase ovarian response in POR patients, and to reduce the risk of ovarian hyperstimulation syndrome. Both highly puri?ed human menopausal gonadotropin (hp-hMG) and recombinant follicle-stimulating hormone (rFSH) have been widely used for COS during IVF/ICSI. Their in?uence on treatment outcome in women undergoing IVF/ICSI hasbeen actively debated. To compare highly purified human menopausal gonadotropin (hp-hMG) and recombinant follicle-stimulating hormone (rFSH) in patients with poor ovarian response undergoing in vitro fertilization/intracytoplasmic sperm injection with a gonadotropin-releasing hormone antagonist protocol. This retrospective cohort study included 60 patients with poor ovarian response (30 received hp-hMG and 30 received rFSH) undergoing in vitro fertilization/intracytoplasmic sperm injection with a gonadotropin-releasing hormone antagonist protocol. Pregnancy-related outcomes, ovarian response, oocyte, and embryo parameters were compared between the 2 groups. Additionally, serum insulin-like growth factor-1 and insulin-like growth factor binding protein-1 levels on the day of oocyte retrieval were compared between the 2 groups. The 2 treatments resulted in comparable numbers of oocytes retrieved and embryos, comparable oocyte retrieval rate, mature oocyte rate, and fertilization rate, and also comparable clinical pregnancy rates, implantation rates, and miscarriage rate. However, hp-hMG led to statistically insignificant higher viable embryo rate (54.0% vs 44.8%; P = 0.174) and live birth rate per pregnancy (16.7% vs 10%) versus rFSH. Finally, statistically significantly higher serum insulin-like growth factor-1 level (178.53 [13.70] ng/mL vs 164.93 [12.17] ng/mL; P = 0.01) and statistically insignificantly lower serum insulin-like growth factor binding protein-1 level (19.53 [3.56] ng/mL vs the lower insulin-like growth factor binding protein-1 level SD is (2.76 [20.83] ng/mL; P > 0.05) on the day of oocyte retrieval were associated with hp-hMG versus rFSH. hp-HMG and rFSH did not lead to significantly different treatment outcomes in patients with poor ovarian response undergoing in vitro fertilization/intracytoplasmic sperm injection with a gonadotropin-releasing hormone antagonist protocol, although significantly higher serum insulin-like growth factor-1 level and insignificantly lower serum insulin-like growth factor binding protein-1 level on the day of oocyte retrieval associated with hp-HMG might suggest a beneficial endocrine environment. (Curr Ther Res Clin Exp. 2020; 81:XXX-XXX).

Response to inhibition of smoothened in diverse epithelial cancer cells that lack smoothened or patched 1 mutations

Hedgehog (HH) pathway Smoothened (Smo) inhibitors are active against Gorlin syndrome-associated basal cell carcinoma (BCC) and medulloblastoma where Patched (Ptch) mutations occur. We interrogated 705 epithelial cancer cell lines for growth response to the Smo inhibitor cyclopamine and for expressed HH pathway-regulated species in a linked genetic database. Ptch and Smo mutations that respectively conferred Smo inhibitor response or resistance were undetected. Previous studies revealed HH pathway activation in lung cancers. Therefore, findings were validated using lung cancer cell lines, transgenic and transplantable murine lung cancer models, and human normal-malignant lung tissue arrays in addition to testing other Smo inhibitors. Cyclopamine sensitivity most significantly correlated with high cyclin E (P=0.000009) and low insulin-like growth factor binding protein 6 (IGFBP6) (P=0.000004) levels. Gli family members were associated with response. Cyclopamine resistance occurred with high GILZ (P=0.002) expression. Newer Smo inhibitors exhibited a pattern of sensitivity similar to cyclopamine. Gain of cyclin E or loss of IGFBP6 in lung cancer cells significantly increased Smo inhibitor response. Cyclin E-driven transgenic lung cancers expressed a gene profile implicating HH pathway activation. Cyclopamine treatment significantly reduced proliferation of murine and human lung cancers. Smo inhibition reduced lung cancer formation in a syngeneic mouse model. In human normal-malignant lung tissue arrays cyclin E, IGFBP6, Gli1 and GILZ were each differentially expressed. Together, these findings indicate that Smo inhibitors should be considered in cancers beyond those with activating HH pathway mutations. This includes tumors that express genes indicating basal HH pathway activation.

Abstract 1615: Gene expression profile predicts response to smoothened inhibitors in epithelial cancers

Abstract The hedgehog (HH) signaling pathway is important for embryonic development as it controls cell fate and proliferation. Deregulation of the HH pathway is linked to the onset and maintenance of multiple cancers. Clinical trials revealed promising effects of targeting the HH pathway with smoothened (Smo) inhibitors, particularly in basal cell carcinomas and medulloblastomas where HH pathway activation occurs. This study sought to uncover a gene signature that would predict response to Smo inhibitors, such as cyclopamine or SANT-1. A panel of 705 human cancer cell lines from diverse epithelial cancers was interrogated for sensitivity to cyclopamine. A subset of cancer cell lines exhibited substantial growth inhibition across a broad array of epithelial cancers. Sensitivity was significantly linked to high Gli1, high cyclin E, and low insulin-like growth factor binding protein 6 (IGFBP6) expression levels (P < 0.05). Cyclin E overexpression and IGFBP6 knockdown conferred increased sensitivity to either cyclopamine or SANT-1 Smo inhibitors in lung cancer cell lines. This functionally validated the importance of this gene signature. To ascertain the biological impact of this profile, cyclin E transgenic mice that spontaneously developed premalignant and malignant lung lesions were studied. These lung cancers expressed the gene signature profile that predicts sensitivity to Smo inhibitors. As expected, cyclopamine treatment of these transgenic mice caused substantial immunohistochemical repression of cyclin D1 and Ki-67 in both premalignant and malignant lung lesions. To confirm and extend these findings, cyclopamine antineoplastic effects were examined using a previously described murine syngeneic and transplantable lung cancer model. Cyclopamine treatment significantly repressed lung cancer formation in these mice (P < 0.01). Notably, a subset of examined human lung cancers was found to express the same gene signature that predicted response to Smo inhibitors. Taken together, these findings reveal a gene expression profile that predicts response of diverse epithelial cancers to Smo inhibitors. Future work should discern whether this same gene signature also predicts response to HH inhibitors in epithelial cancers of patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1615. doi:10.1158/1538-7445.AM2011-1615

Celiac Autoimmunity in Children with Type 1 Diabetes: A Two-Year Follow-Up

To determine the benefits of screening for celiac autoimmunity via immunoglobulin A transglutaminase autoantibodies (TG) in children with type 1 diabetes (T1D). We followed up 79 screening-identified TG+ and 56 matched TG- children with T1D for 2 years to evaluate growth, bone mineral density, nutritional status, and diabetes control. TG+ subjects self-selected to gluten-free or gluten-containing diet. Of the initial cohort, 80% were available for reexamination after 2 years. TG+ subjects had consistently lower weight z-scores and higher urine N-telopeptides than TG- subjects, but similar measures of bone density and diabetes outcomes. TG+ children who remained on a gluten-containing diet had lower insulin-like growth factor binding protein 3 z-scores compared with TG+ subjects who reported following a gluten-free diet. Children who continued with high TG index throughout the study had lower bone mineral density z-scores, ferritin, and vitamin D 25OH levels, compared with the TG- group. No significant adverse outcomes were identified in children with T1D with screening-identified TG+ who delay therapy with a gluten-free diet for 2 years. Children with persistently high levels of TG may be at greater risk. The optimal timing of screening and treatment for celiac disease in children with T1D requires further investigation.

Low Insulin-Like Growth Factor Binding Protein-2 Expression Is Responsible for Increased Insulin Receptor Substrate-1 Phosphorylation in Mesangial Cells from Mice Susceptible to Glomerulosclerosis

Mesangial cells (MC) isolated from glomerulosclerosis-prone ragged, olygosyndactilism, pintail (ROP) mice retain a stable phenotype after exposure to elevated glucose concentrations, whereas MC from glomerulosclerosis-resistant C57BL/6 (C) mice do not. In NOD and db/db mice, the stable phenotype induced by diabetes consists of autocrine activation of the IGF-I signaling pathway. We hypothesized that high ambient glucose activates the IGF-I pathway in ROP but not in C MC. MC were propagated in either 6 or 25 mm glucose. Isolated murine glomeruli were used to confirm in vitro experiments. 25 mm glucose induced increased insulin receptor substrate (IRS)-1 phosphorylation in ROP but not C MC. However, IGF-I, IGF-I receptor, and IRS-1 protein levels were induced by exposure to 25 mm glucose in both cell lines. This occurred without a change in IGF-I binding sites, suggesting a role for IGF binding protein (IGFBP). ROP MC and glomeruli expressed less IGFBP-2 than C MC and glomeruli. Addition of exogenous IGFBP-2 partially blunted the effect of 25 mm glucose on IRS-1 phosphorylation in ROP MC. Renal biopsies from patients with diabetic nephropathy also showed markedly decreased IGFBP-2 expression when compared with patients without nephropathy. In summary, glucose induces IRS-1 phosphorylation in MC isolated from ROP mice susceptible to glomerulosclerosis. IGFBP-2 expression was low in ROP MC and glomeruli from patients with diabetic nephropathy, suggesting that this may represent a new marker of susceptibility to diabetic nephropathy. Finally, addition of exogenous IGFBP-2 in ROP MC partially blunted the effect of high glucose on IRS-1 phosphorylation and might have a protective role.

Absence of hypoglycemia in response to varying doses of recombinant human insulin-like growth factor-I (rhIGF-I) in children and adolescents with low serum concentrations of IGF-I

To determine whether recombinant human insulin-like growth factor-I (rhIGF-I) administration to children with low IGF-I and relatively low insulin-like growth factor binding protein-3 (IGFBP3) serum concentrations would result in hypoglycemia. Eighteen children age 11-19 y with serum levels of IGF-I< -2 SDS and IGFBP3< 0 SDS were randomly assigned to receive rhIGF-I at 80 microg/kg body weight daily (n = 6), 40 microg/kg twice daily (n = 6), or 80 microg/kg twice daily (n = 6). After a 10-d dose escalation and 15 d of treatment at the specified dosage, a 25-h pharmacokinetic/pharmacodynamic profile was obtained, which included 22 blood glucose measurements. Regular meals and snacks were provided. No signs or symptoms of hypoglycemia were noted throughout the study. There were no differences in mean blood glucose concentrations among the three dosage groups. The lowest glucose value recorded, 3.44 mmol/l, was 15 min after a morning injection of 80 microg/kg IGF-I, and promptly rose. Although subjects were selected on the basis of low concentrations of IGF-I to represent proposed candidates for rhIGF-I therapy, the mean and range of SDS for height were not different from those of previously studied normal Ecuadorian controls. In normal individuals with low serum concentrations of IGF-I and relatively low concentrations of IGFBP3, the administration of therapeutic doses of rhIGF-I, while maintaining reasonable food intake, does not result in hypoglycemia.

Insulin-like growth factor-1 and insulin-like growth factor binding protein-3 for prostate cancer detection in patients undergoing prostate biopsy.

Laboratory and epidemiological studies suggest that high circulating insulin-like growth factor (IGF)-1 and low IGF binding protein-3 are associated with increased prostate cancer risk. However, the usefulness of serum IGF-1 or IGF binding protein-3 for predicting pathology results in men undergoing prostate biopsy is unclear. We examined the relationships of serum IGF-1, IGF binding protein-3 and the results of prostate biopsy. A total of 652 consecutive patients with elevated serum prostate specific antigen (PSA) or abnormal digital rectal examination who were referred for transrectal ultrasound sextant prostate needle biopsy underwent blood sampling before biopsy. PSA, free PSA, IGF-1 and IGF binding protein-3 were measured. There were 244 men (37.4%) with cancer and 408 controls with benign conditions. Mean IGF-1 plus or minus SD in the cancer and control groups was 176.1 +/- 58.3 and 178.7 +/- 54.7 ng./ml., respectively (p = 0.57). Mean IGF binding protein-3 in the cancer and control groups was 2,724 +/- 647 and 2,673 +/- 589 ng./ml., respectively (p = 0.3). Adjustment for age and PSA showed significantly lower IGF-1 in cancer cases, while IGF binding protein-3 was not significant. ROC values were significantly higher for free-to-total PSA and PSA than for crude and age adjusted IGF-1 and IGF binding protein-3. Our data indicate that serum IGF-1 or IGF binding protein-3 does not predict the results of prostate biopsy in men with elevated PSA or abnormal digital rectal examination. This finding implies that while there is evidence that the IGF-1 level is a risk factor for prostate cancer, neither IGF-1 nor IGF binding protein-3 can be used as a tumor marker for this disease.

Insulin-Like Growth Factor-1 and Insulin-Like Growth Factor Binding Protein-3 for Prostate Cancer Detection in Patients Undergoing Prostate Biopsy

Laboratory and epidemiological studies suggest that high circulating insulin-like growth factor (IGF)-1 and low IGF binding protein-3 are associated with increased prostate cancer risk. However, the usefulness of serum IGF-1 or IGF binding protein-3 for predicting pathology results in men undergoing prostate biopsy is unclear. We examined the relationships of serum IGF-1, IGF binding protein-3 and the results of prostate biopsy. A total of 652 consecutive patients with elevated serum prostate specific antigen (PSA) or abnormal digital rectal examination who were referred for transrectal ultrasound sextant prostate needle biopsy underwent blood sampling before biopsy. PSA, free PSA, IGF-1 and IGF binding protein-3 were measured. There were 244 men (37.4%) with cancer and 408 controls with benign conditions. Mean IGF-1 plus or minus SD in the cancer and control groups was 176.1 +/- 58.3 and 178.7 +/- 54.7 ng./ml., respectively (p = 0.57). Mean IGF binding protein-3 in the cancer and control groups was 2,724 +/- 647 and 2,673 +/- 589 ng./ml., respectively (p = 0.3). Adjustment for age and PSA showed significantly lower IGF-1 in cancer cases, while IGF binding protein-3 was not significant. ROC values were significantly higher for free-to-total PSA and PSA than for crude and age adjusted IGF-1 and IGF binding protein-3. Our data indicate that serum IGF-1 or IGF binding protein-3 does not predict the results of prostate biopsy in men with elevated PSA or abnormal digital rectal examination. This finding implies that while there is evidence that the IGF-1 level is a risk factor for prostate cancer, neither IGF-1 nor IGF binding protein-3 can be used as a tumor marker for this disease.

Plasma from patients undergoing major open surgery stimulates in vitro tumor growth: Lower insulin-like growth factor binding protein 3 levels may, in part, account for this change

Background. Plasma from laparotomized mice has been shown to stimulate in vitro tumor growth when compared to results with preoperative plasma. This study assessed the effect of plasma from patients who underwent major open (OS) or laparoscopic surgery (LS) on in vitro tumor cell growth. Methods. Eighty-four patients undergoing major abdominal surgery were studied (45 OS, 39 LS). Peripheral blood was collected preoperatively (PreOP) and on days 1 (POD1) and 3 (POD3) after operation. HT29 human colon cancer cells were plated with samples of the plasma. Proliferation was assessed by cell counts and the bromodeoxyuridine incorporation assay. Insulin-like growth factor binding protein 3 was detected in plasma by Western blot analysis. Results. Increased mitogenic activity was noted in POD1 OS plasma when compared to PreOP OS plasma results (P <.005). This increase correlated with the length of incision (r = 0.58, P <.01). No differences were noted when the PreOP LS and POD1 LS results were compared or for any of the POD3 versus PreOP comparisons. Conclusions. Major OS is associated with alterations in plasma composition that promote HT29 tumor cell proliferation in vitro. As shown, this effect was due, at least in part, to surgery-related depletion of insulin-like growth factor binding protein 3 in peripheral blood. (Surgery 2002;132:186-92.)