Comparison of Salivary IGF-1, IGFBP-3, and CTX with Periodontal Status among Patients Belonging to Various Skeletal Maturity Groups.

PURPOSE: To compare the levels of salivary IGF-1, IGFBP-3, and CTX with periodontal status among patients belonging to various skeletal maturity groups. MATERIALS AND METHODS: This cross-sectional study was conducted on 80 participants 6 to 25 years of age. Based on skeletal maturity, the participants were categorised into 3 different stages: prepubertal, pubertal, and post-pubertal stages. The periodontal status of the participants was assessed using the simplified oral hygiene index (OHI-S), bleeding on probing (BOP), probing pocket depth (PPD), clinical attachment loss (CAL), and community periodontal index (CPI). The saliva samples were examined for IGF-1, IGFBP-3, and CTX using the respective ELISA kits. One-way ANOVA was used to determine statistically significant differences of means across the study groups for continuous variables. RESULTS: The study demonstrated statistically significant differences for the parameters OHI-S, bleeding on probing, PPD, CPI, and CAL (p < 0.05) depending on skeletal maturity stage. ANOVA test showed a statistically significant difference by stage in IGF-1, IGFPB3, and CTX (p < 0.01). CONCLUSION: An association exists between periodontal status and levels of salivary IGF-1, IGFBP-3, and CTX in patients belonging to various skeletal maturity groups.

Maternal Plasma and Amniotic Fluid LBP, Pentraxin 3, Resistin, and IGFBP-3: Biomarkers of Microbial Invasion of Amniotic Cavity and/or Intra-amniotic Inflammation in Women with Preterm Premature Rupture of Membranes.

BACKGROUND: We sought to determine whether lipopolysaccharide binding protein (LBP), pentraxin 3, resistin, and insulin-like growth factor binding protein (IGFBP)-3 in plasma and amniotic fluid (AF) can predict microbial invasion of the amniotic cavity (MIAC), intra-amniotic inflammation (IAI), and microbial-associated IAI in women with preterm premature rupture of membranes (PPROM). METHODS: This was a retrospective cohort study involving 168 singleton pregnant women with PPROM. AF obtained via amniocentesis was cultured and assayed for interleukin (IL)-6 to define IAI and for IL-8 to compare with AF biomarkers. Plasma samples were collected at the time of amniocentesis, and C-reactive protein (CRP) levels in serum were compared with plasma biomarkers. The stored plasma and AF samples were assayed for LBP, pentraxin 3 (PTX3), resistin, and IGFBP-3 by ELISA. RESULTS: Multivariate logistic regression analysis revealed that: 1) elevated plasma and AF levels of LBP were independently associated with increased risks of MIAC, IAI, and microbial-associated IAI; 2) elevated AF, but not plasma, PTX3, and resistin levels were independently associated with increased risks of MIAC, IAI, and microbial-associated IAI; 3) decreased IGFBP-3 levels in the plasma were independently associated with only IAI, whereas those in the AF were associated with only microbial-associated IAI. Among the tested biomarkers, AF PTX3 and resistin had the highest predictive performance for MIAC, IAI, and microbial-associated IAI (area under the curves [AUC] = 0.85-0.95), which is similar to the performance of AF IL-8. The AUCs of the plasma LBP and IGFBP-3 were similar to that of serum CRP with respect to IAI. CONCLUSION: Maternal plasma LBP and IGFBP-3 are potential biomarkers for the non-invasive identification of IAI in women with PPROM, with a similar accuracy to the serum CRP level. AF LBP, PTX3, resistin, and IGFBP-3 may be involved in the intra-amniotic inflammatory responses in PPROM complicated by MIAC.

Insulin-like growth factor ternary complex components as biomarkers for the diagnosis of short stature.

OBJECTIVE: The diagnosis of growth hormone deficiency (GHD) in children is not always straightforward because insulin-like growth factor 1 (IGF-I) or GH stimulation tests may not be able to discriminate GHD from constitutional delay of growth and puberty (CDGP) or other causes of short stature. DESIGN: Boys and girls (n = 429, 0.7-16 years) who attended our department for short stature participated in this study. They were followed up for an average period of 9 years. At the end of follow-up after reaching the final height, a definitive diagnosis was assigned, and all the components of ternary complex (IGF-I, IGF-binding protein-3 (IGFBP-3), acid-labile subunit (ALS), and IGF-I/IGFBP-3 ratio) were evaluated as biomarkers for the respective diagnosis. RESULTS: All the components of the ternary complex were tightly correlated with each other and were positively related to age. IGF-I, IGFBP-3, ALS, and IGF-I/IGFBP-3 ratio differed significantly between GHD and normal groups. IGF-I and ALS levels were lower in GHD compared to children with familial short stature, while IGF-I and IGF-I/IGFBP-3 ratio was significantly lower in GHD compared to children with CDGP. IGF-I and IGF-I/IGFBP-3 receiver operating curve cutoff points were unable to discriminate between GHD and normal groups or between GHD and CDGP groups. CONCLUSION: Despite the tight correlation among all the components of the ternary complex, each one shows a statistically significant diagnosis-dependent alteration. There is a superiority of IGF-I, ALS, and IGF-I/IGFBP-3 ratio in the distinction between GHD and CDGP or between GHD and normal groups but without usable discriminating power, making auxology as the primary criterion for establishing the diagnosis.

Maternal Plasma Lipids During Pregnancy, Insulin-like Growth Factor-1, and Excess Fetal Growth.

CONTEXT: Maternal lipids during pregnancy and placental growth factors are associated with excess fetal growth. However, how these factors interact to increase the risk of delivering large-for-gestational-age (LGA) neonates remains unclear. In this study, we investigated the relationship between maternal plasma triglycerides (TGs) and free fatty acids (FFAs) during pregnancy, cord blood insulin-like growth factors (IGF), and LGA. OBJECTIVE: In a cell model, we studied the effect of different FAs on placental IGF-1 secretion. METHODS: This cohort study included pregnant women with term pregnancy and without diabetes or hypertensive disorders in pregnancy. Maternal fasting plasma TGs and FFAs were measured in the second trimester. Cord blood IGF-1, IGF-2, and IGF binding protein-1 and protein-3 were measured at the time of delivery. A human trophoblast cell line, 3A-sub-E, was used to evaluate the effect of different FFAs on placental IGF-1 secretion. RESULTS: We recruited 598 pregnant women-neonate pairs. Maternal plasma TG (180 mg/dL [152.5-185.5 mg/dL] vs 166 mg/dL [133-206 mg/dL], P = .04) and cord blood IGF-1 concentrations (72.7 ±â€…23.0 vs 54.1 ±â€…22.8 ng/mL, P < .001) were higher in the LGA group and were significantly associated with birth weight z score. Maternal plasma free palmitic acid (PA) and stearic acid (SA), but not oleic acid (OA) or linoleic acid (LA), were significantly associated with cord blood IGF-1 concentrations. In 3A-sub-E cells, treatment with PA, SA, and LA, but not OA, induced IGF-1 expression and secretion. CONCLUSION: Certain FFAs can induce placental IGF-1 secretion, which suggests a potential pathophysiology linking maternal plasma lipids and LGA.

Investigating the Relationship Between IGF-I, IGF-II, and IGFBP-3 Concentrations and Later-Life Cognition and Brain Volume.

BACKGROUND: The insulin/insulin-like signaling (IIS) pathways, including insulin-like growth factors (IGFs), vary with age. However, their association with late-life cognition and neuroimaging parameters is not well characterized. METHODS: Using data from the British 1946 birth cohort, we investigated associations of IGF-I, IGF-II and IGF binding protein 3 (IGFBP-3; measured at 53 and 60-64 years of age) with cognitive performance [word-learning test (WLT) and visual letter search (VLS) at 60-64 years and 69 years of age] and cognitive state [Addenbrooke's Cognitive Exam III (ACE-III) at 69-71 years of age], and in a proportion, quantified neuroimaging measures [whole brain volume (WBV), white matter hyperintensity volume (WMHV), hippocampal volume (HV)]. Regression models included adjustments for demographic, lifestyle, and health factors. RESULTS: Higher IGF-I and IGF-II at 53 years of age was associated with higher ACE-III scores [ß 0.07 95% confidence interval (CI) (0.02, 0.12); scoreACE-III 89.48 (88.86, 90.1), respectively). IGF-II at 53 years of age was additionally associated with higher WLT scores [scoreWLT 20 (19.35, 20.65)]. IGFBP-3 at 60 to 64 years of age was associated with favorable VLS score at 60 to 64 and 69 years of age [ß 0.07 (0.01, 0.12); ß 0.07 (0.02, 0.12), respectively], higher memory and cognitive state at 69 years of age [ß 0.07 (0.01, 0.12); ß 0.07 (0.01, 0.13), respectively], and reduced WMHV [ß -0.1 (-0.21, -0.00)]. IGF-I/IGFBP-3 at 60 to 64 years of was associated with lower VLS scores at 69 years of age [ß -0.08 (-0.15, -0.02)]. CONCLUSIONS: Increased measure in IIS parameters (IGF-I, IGF-II, and IGFBP-3) relate to better cognitive state in later life. There were apparent associations with specific cognitive domains (IGF-II relating to memory; IGFBP-3 relating to memory, processing speed, and WMHV; and IGF-I/IGFBP-3 molar ratio related to slower processing speed). IGFs and IGFBP-3 are associated with favorable cognitive function outcomes.

Biomarker Modulation Study of Celecoxib for Chemoprevention in Women at Increased Risk for Breast Cancer: A Phase II Pilot Study.

In preclinical studies, celecoxib has been associated with reduced risk of breast cancer. In this study, the aim was to assess the biomodulatory effect of celecoxib on blood and benign breast tissue biomarkers in women at increased risk for breast cancer. Women at increased risk for breast cancer [5-year Gail risk score of >1.67%, history of atypical hyperplasia, lobular carcinoma in situ, or previous estrogen receptor (ER)-negative breast cancer] were treated with celecoxib at 400 mg orally twice daily for 6 months. Participants underwent random periareolar fine needle aspiration and blood draw at baseline and at 6 months for analysis of biomarkers: serum levels of insulin-like growth factor 1 (IGF-1), IGF-binding protein 1 (IGFBP-1), and IGFBP-3; tissue expression of Ki-67 and ER; as well as cytology. Forty-nine patients were eligible for analysis. Median IGFBP-1 levels increased significantly from 6.05 ng/mL at baseline to 6.93 ng/mL at 6 months (P = 0.04), and median IGFBP-3 levels decreased significantly from 3,593 ng/mL to 3,420 ng/mL (P = 0.01). We also detected favorable changes in cytology of 52% of tested sites after 6 months of celecoxib therapy. No changes in tissue Ki-67 and ER expression levels were observed. No grade 3 or 4 toxicity was recorded. Celecoxib was well tolerated and induced favorable changes in serum biomarkers as well as cytology in this pilot phase II trial. A phase IIb placebo-controlled study with celecoxib could be considered for women at increased risk for breast cancer.

The effects of physical activity on physiological markers in breast cancer survivors: A meta-analysis.

BACKGROUND: To systematically evaluate the effects of physical activity on physiological markers in breast cancer survivors. METHODS: A systematic search of the PubMed, Wed of Science, Medline, CNKI and Wanfang Database was performed to identify eligible randomized controlled trials to explore physical activity on physiological markers in breast cancer survivors. STATA version 13.0 (Stata Corp LP, College Station, TX) was used for all statistical analyses. RESULTS: A total of 11 articles with 941 cases were eligible in this meta-analysis. The results of the meta-analysis showed that physical activity could decrease the levels of insulin (SMD = -1.90, 95%CI: -3.2 to -0.60; I = 92.3%, P < .001), insulin-like growth factor 1 (IGF-I) (WMD = -4.67, 95%CI: -23.14 to 13.79; I = 96.2%, P < .001), insulin-like growth factor binding protein-3 (IGFBP-3) (WMD = -20.09, 95%CI: -47.15 to 6.97; I = 93.3%, P < .001). However, compared with the control group, there was not the significant change of insulin-like growth factor 2 (IGF-II), insulin-like growth factor binding protein-1 (IGFBP-1), leptin, adiponectin, glucose, C-reactive protein (CRP), Interleukin-6 (IL-6), Interleukin-10 (IL-10), and tumor necrosis factor alpha (TNF-ɑ) levels after the intervention. CONCLUSIONS: Physical activity could improve the insulin function that might be associated with decreasing the levels of IGF-I, IGFBP-3 and insulin in breast cancer survivors.

Once-Weekly Somapacitan vs Daily GH in Children With GH Deficiency: Results From a Randomized Phase 2 Trial.

CONTEXT: Daily growth hormone (GH) injections can be burdensome for patients and carers. Somapacitan is a long-acting, reversible albumin-binding GH derivative in development for once-weekly administration in patients with growth hormone deficiency (GHD). OBJECTIVE: The objective of this study is to evaluate the efficacy, safety, and tolerability of once-weekly somapacitan vs once-daily GH. DESIGN: REAL 3 is a multicenter, randomized, controlled, double-blind (somapacitan doses), phase 2 study with a 26-week main and 26-week extension phase (NCT02616562). SETTING: This study took place at 29 sites in 11 countries. PATIENTS: Fifty-nine GH treatment-naive prepubertal children with GHD were randomly assigned; 58 completed the trial. INTERVENTIONS: Interventions comprised 3 somapacitan doses (0.04 [n = 16], 0.08 [n = 15], or 0.16 mg/kg/wk [n = 14]) and daily GH (0.034 mg/kg/d [n = 14]), administered subcutaneously. MAIN OUTCOME MEASURES: The primary end point was height velocity (HV) at week 26. Secondary efficacy end points included HV SD score (SDS) and insulin-like growth factor-I (IGF-I) SDS. RESULTS: At week 26, mean (SD) annualized HV for the somapacitan groups was 8.0 (2.0), 10.9 (1.9), and 12.9 (3.5) cm/year, respectively, vs 11.4 (3.3) cm/year for daily GH; estimated treatment difference (somapacitan 0.16 mg/kg/week-daily GH): 1.7 [95% CI -0.2 to 3.6] cm/year. HV was sustained at week 52, and significantly greater with somapacitan 0.16 mg/kg/week vs daily GH. Mean (SD) change from baseline in HV SDS at week 52 was 4.72 (2.79), 6.14 (3.36), and 8.60 (3.15) for the somapacitan groups, respectively, vs 7.41 (4.08) for daily GH. Model-derived mean (SD) IGF-I SDS for the somapacitan groups was -1.62 (0.86), -1.09 (0.78), and 0.31 (1.06), respectively, vs -0.40 (1.50) observed for daily GH. Safety and tolerability were consistent with the profile of daily GH. CONCLUSIONS: In children with GHD, once-weekly somapacitan 0.16 mg/kg/week provided the closest efficacy match with similar safety and tolerability to daily GH after 26 and 52 weeks of treatment. A short visual summary of our work is available (1).

Targeted Analysis of Three Hormonal Systems Identifies Molecules Associated with the Presence and Severity of NAFLD.

AIMS: To investigate circulating levels and liver gene expression of 3 hormonal pathways associated with obesity, insulin resistance, and inflammation to identify leads towards potential diagnostic markers and therapeutic targets in patients with nonalcoholic fatty liver disease (NAFLD). METHODS: We compared circulating levels of (1) proglucagon-derived hormones (glucagon-like peptide [GLP]-1, GLP-2, glicentin, oxyntomodulin, glucagon, major proglucagon fragment [MPGF]), (2) follistatins-activins (follistatin-like [FSTL]3, activin B), (3) IGF axis (insulin-like growth factor [IGF]-1, total and intact IGF binding protein [IGFBP]-3 and IGFBP-4, and pregnancy-associated plasma protein [PAPP]-A) in 2 studies: (1) 18 individuals with early stage NAFLD versus 14 controls (study 1; early NAFLD study) and in (2) 31 individuals with biopsy proven NAFLD (15 with simple steatosis [SS] and 16 with nonalcoholic steatohepatitis [NASH]), vs 50 controls (24 lean and 26 obese) (study 2). Liver gene expression was assessed in 22 subjects (12 controls, 5 NASH, 5 NASH-related cirrhosis). RESULTS: Patients in early stages of NAFLD demonstrate higher fasting MPGF and lower incremental increase of glicentin during oral glucose tolerance test than controls. In more advanced stages, FSTL3 levels are higher in NASH than simple steatosis and, within NAFLD patients, in those with more severe lobular and portal inflammation. The IGF-1/intact IGFBP-3 ratio is lower in patients with liver fibrosis. Genes encoding follistatin, activin A, activin B, and the IGF-1 receptor are higher in NASH. CONCLUSION: MPGF and glicentin may be involved in early stages of NAFLD, whereas FSTL3 and IGF-1/intact IGFBP3 in the progression to NASH and liver fibrosis respectively, suggesting potential as diagnostic markers or therapeutic targets.

Oral Administration of Microencapsulated B. Longum BAA-999 and Lycopene Modulates IGF-1/IGF-1R/IGFBP3 Protein Expressions in a Colorectal Murine Model.

The Insulin-like growth factor-I/Insulin-like growth factor-I receptor (IGF-1/IGF-1R) system is a major determinant in colorectal cancer (CRC) pathogenesis. Probiotics (Bifidobacterium longum, BF) and lycopene (LYC) have been individually researched for their beneficial effects in the prevention of CRC. However, the effect of a combined treatment of microencapsulated BF and LYC on IGF-1/IGF-1R/IGFBPs (Insulin-like growth factor-binding proteins) expression in an azoxymethane (AOM)-dextran sulfate sodium (DSS)-induced CRC model have not been demonstrated. BF was microencapsulated by the spray drying technique, with high viability, and daily gavaged with LYC for 16 weeks to CD-1 mice in an AOM-DSS model. The results indicated that BF- and BF + LYC-treated groups had significantly lower inflammation grade, tumor incidence (13-38%) and adenocarcinoma (13-14%) incidence compared to the AOM + DSS group (80%), whereas LYC treatment only protected against inflammation grade and incidence. Caecal, colonic and fecal pH and ß-glucuronidase (ß-GA) values were significantly normalized by BF and LYC. Similarly, BF and BF + LYC treatments significantly reduced both the positive rate and expression grade of IGF-1 and IGF-1R proteins and normalized Insulin-like growth factor-binding protein-3 (IGFBP3) expression. Based on intestinal parameters related to the specific colon carcinogenesis in an AOM-DSS-induced model, LYC and microencapsulated BF supplementation resulted in a significant chemopreventive potential through the modulation of IGF-1/IGF-1R system.

The insulin-like growth factor binding protein-3 and its death receptor in pancreatic ductal adenocarcinoma poor prognosis.

Insulin-like growth factor binding protein-3 (IGFBP-3) and its newly discovered death receptor (IGFBP-3R) have been reported to involve in a wide variety of cancers. However, their role in pancreatic ductal adenocarcinoma (PDAC) has not been elucidated yet. Here, 478 pancreatic cancers were screened for primary PDAC tumors. The samples were evaluated using quantitative reverse-transcriptase polymerase chain reaction, western blotting, and immunohistochemistry staining. The results indicated that relative IGFBP-3 mRNA expression and its protein level were reduced stage dependently in the PDAC tumors (p < .001 and p < .05, respectively). The subcellular distribution of IGFBP-3 was mainly nuclear only in Stage 0 + 1 (about 150% compared to adjacent normal tissues [p < .05]). The value for IGFBP-3R messenger RNA (mRNA) and protein were also reduced in tumors in compared to adjacent normal pancreatic tissues (p < .05). The Kaplan-Meier analysis also showed that mRNA expression of IGFBP-3 and IGFBP-3R was positively associated with survival, (p = .001). In addition, there is a strong association between low expression of IGFBP-3 and tumor size (p = .032), the lymphatic invasion (p = .001), the TNM (tumor, node, metastasis) staging (p = .001), tumor differentiation (p = .001), and PNI status (p = .021). Down-regulation of IGFBP-3R was also correlated with the tumor size (p = .01), the lymphatic invasion (p = .012) TNM staging (p = .001), tumor differentiation (p = .021) and PNI status (p = .038). In conclusion, IGFBP-3 and its receptor were down-regulated and their expression was associated with poor prognosis of PDAC.

Relation of IGF-1 and IGFBP-3 with prevalent and incident atrial fibrillation in a population-based study.

BACKGROUND: Insulin-like growth factor 1 (IGF-1) and its main binding protein insulin-like growth factor binding protein 3 (IGFBP-3) have been related to several cardiovascular diseases. The relation with atrial fibrillation (AF) is largely unknown. OBJECTIVE: The objective of this study was to investigate the association of IGF-1 and IGFBP-3 levels with prevalent and incident AF in a large population-based study. METHODS: Data from the Study of Health in Pomerania (SHIP) were collected. At presentation, a medical examination, standardized electrocardiographic assessment, and measurements of serum IGF-1 and IGFBP-3 levels were performed. Incident AF was assessed in individuals without AF at baseline (SHIP-1) who developed AF during follow-up (SHIP-2; after a mean of 5.2 years). RESULTS: Of 3160 participants, 66 (2.1%) exhibited AF at baseline. IGF-1 levels and IGF-1/IGFBP-3 ratios were significantly lower in individuals with AF than in those without AF (IGF-1: 104.2 ± 41.6 ng/mL vs 142.9 ± 53.5 ng/mL, P < .001 and IGF-1/IGFBP-3: 0.031 ± (0.009 ng/mL vs 0.036 ± 0.010 ng/mL, P = .006, respectively). Multivariable-adjusted logistic regression models showed that a low IGF-1/IGFBP-3 ratio was associated with prevalent AF (odds ratios 0.67; 95% confidence interval 0.48-0.94; P = .021). Of 1817 individuals without AF at baseline, 27 (1.5%) developed AF during follow-up. In these participants, IGF-1 levels, but not IGF-1/IGFBP-3 ratios, were significantly lower (IGF-1: 113.3 ± 38.6 ng/mL vs 147.2 ± 51.6 ng/mL, P = .013 and IGF-1/IGFBP-3: 0.033 ± 0.008 ng/mL vs 0.036 ± 0.010 ng/mL, P = .176). CONCLUSION: Low IGF-1/IGFBP-3 ratios are associated with a higher prevalence of AF. There seems to be a similar impact in incident AF.

Systematic review of the biological variation data for diabetes related analytes.

BACKGROUND: Objective interpretation of laboratory test results used to diagnose and monitor diabetes mellitus in part requires the application of biological variation data (BVD). The quality of published BVD has been questioned. The aim of this study was to quality assess publications reporting BVD for diabetes-related analytes using the Biological Variation Data Critical Appraisal Checklist (BIVAC); to assess whether published BVD are fit for purpose and whether the study design and population attributes influence BVD estimates and to undertake a meta-analysis of the BVD from BIVAC-assessed publications. METHODS: Publications reporting data for glucose, HbA1c, adiponectin, C-peptide, fructosamine, insulin like growth factor 1 (IGF-1), insulin like growth factor binding protein 3 (IGFBP-3), insulin, lactate and pyruvate were identified using a systematic literature search. These publications were assessed using the BIVAC, receiving grades A, B, C or D, where A is of highest quality. A meta-analysis of the BVD from the assessed studies utilised weightings based upon BIVAC grades and the width of the data confidence intervals to generate global BVD estimates. RESULTS: BIVAC assessment of 47 publications delivered 1 A, 3 B, 39C and 4 D gradings. Publications relating to adiponectin, C-peptide, IGF-1, IGFBP-3, lactate and pyruvate were all assessed as grade C. Meta-analysis enabled global BV estimates for all analytes except pyruvate, lactate and fructosamine. CONCLUSIONS: This study delivers updated and evidence-based BV estimates for diabetes-related analytes. There remains a need for delivery of new high-quality BV studies for several clinically important analytes.

The Association Between IGF-I and IGFBP-3 and Incident Diabetes in an Older Population of Men and Women in the Cardiovascular Health Study.

Context: Insulin-like growth factor-I (IGF-I) has structural and functional similarities to insulin and may play a role in glucose homeostasis, along with insulin-like growth factor binding protein-3 (IGFBP-3), which binds the majority of circulating IGF-I. Objective: To assess whether IGF-I and IGFBP-3 are associated with a higher risk of incident diabetes in older adults. Design: Participants in the Cardiovascular Health Study (n = 3133), a cohort of adults aged ≥65 years, were observed for 16 years (n = 3133) for the development of incident diabetes. Statistical models were fit separately for men and women because of interactions with sex (P interaction: IGF-I, 0.02; IGFBP-3, 0.009) and were adjusted for relevant covariates. Setting: General community. Participants: Older adults who were nondiabetic at baseline and who did not develop diabetes within the first year of follow-up. Interventions: Not applicable. Main Outcome Measure: Incident diabetes as measured by fasting plasma glucose (FPG) ≥126 mg/dL, non-FPG ≥200 mg/dL, use of pharmacological treatment of diabetes, or existence of two or more inpatient or three or more outpatient or (at least one inpatient and at least one outpatient) Centers for Medicare & Medicaid Services claims with the diagnostic International Classification of Diseases, Ninth Revision, Clinical Modification code of 250.xx. Results: In women, higher IGFBP-3 (hazard ratio tertile 3 vs tertile 1 = 2.30; 95% confidence interval, 1.55 to 3.40; P trend < 0.0001) was significantly associated with incident diabetes. Total IGF-I was not significantly associated with incident diabetes. In men, neither IGF-I nor IGFBP-3 was significantly associated with incident diabetes. Conclusions: We confirmed a previously reported association between circulating IGFBP-3 and diabetes risk in the older adult population, establishing that this association is present among women but could not be shown to be associated in men.

Agreement between circulating IGF-I, IGFBP-1 and IGFBP-3 levels measured by current assays versus unavailable assays previously used in epidemiological studies.

OBJECTIVE: Levels of insulin-like growth factor (IGF) proteins are associated with the risk of cancer and mortality. IGF assays produced by Diagnostic Systems Laboratories (DSL) were widely used in epidemiological studies, were not calibrated against recommended standards and are no longer commercially available. DESIGN: In a split sample study among 1471 adults participating in the Cardiovascular Health Study, we compared values obtained using DSL assays with alternative assays for serum IGF-I (Immunodiagnostic Systems, IDS), IGFBP-1 (American Laboratory Products Company, ALPCO) and IGFBP-3 (IDS). RESULTS: Results were compared using kernel density estimation plots, quartile analysis with weighted kappa statistics and linear regression models to assess the concordance of data from the different assays. Participants had a mean age of 77years. Results between alternative assays were strongly correlated (IGF-I, r=0.93 for DSL versus IDS; log-IGFBP-1, r=0.90 for DSL versus ALPCO; IGFBP-3, r=0.92 for DSL versus IDS). Cross tabulations showed that participants were usually in the same quartile categories regardless of the assay used (overall agreement, 74% for IGF-I, 64% for IGFBP-1, 71% for IGFBP-3). Weighted kappa also showed substantial agreement between assays (kw, 0.78 for IGF-I, 0.69 for IGFBP-1, 0.76 for IGFBP-3). Regressions of levels obtained with DSL assays (denoted X) to alternative assays were, IGF-I: 0.52X+15.2ng/ml, log-IGFBP-1: 1.01X-1.73ng/ml IGFBP-3: 0.87X+791.1ng/ml. Serum values of IGF-I, IGFBP-1 and IGFBP-3 measured using alternative assays are moderately correlated. CONCLUSIONS: Care is needed in the interpretation of data sets involving IGF analytes if assay methodologies are not uniform.

[Insulin-like growth factor-1 (IGF-1) - structure and the role in the human body]. / Insulinopodobny czynnik wzrostu-1 (IGF-1) - budowa i rola w organizmie czlowieka.

In the recent years, managed to broadly explore the structure and role of insulin-like growth factors type 1 and 2 (IGF1 I 2). They belong to the structure of polypeptide hormones homologous to proinsulin. They are characterized by a wide range of activities. IGF-1 is a key mediator of most tissue effects of growth hormone (GH). In addition to effects on growth processes of the body, is also an important factor for cell homeostasis, is subject to both endocrine and tissue-specific auto- and paracrine regulation. In this paper, the current, general knowledge on the structure, function and mechanism of biological effects of IGF-1 in the human body was presented. Attention was also drawn to the directions of use of IGf-1 in the treatment of other diseases than the diseases of the hypothalamic-pituitary and growth disorders in children.

Current practice in diagnosis and treatment of growth hormone deficiency in childhood: a survey from Turkey.

OBJECTIVE: Approaches to diagnosis and treatment of growth hormone deficiency (GHD) in children vary among countries and even among centers in the same country. This survey, aiming to facilitate the process of preparing the new consensus on GHD by the Turkish Pediatric Endocrinology and Diabetes Society, was designed to evaluate the current practices in diagnosis and treatment of GHD in different centers in Turkey. METHODS: A questionnaire covering relevant items for diagnosis and treatment of GHD was sent out to all pediatric endocrinology centers. RESULTS: Twenty-four centers returned the questionnaire. The most frequently used GH stimulation test was L-dopa, followed by clonidine. Eighteen centers used a GH cut-off value of 10 ng/mL for the diagnosis of GHD; this value was 7 ng/mL in 4 centers and 5 ng/mL in 2 centers. The most frequently used assay was immunochemiluminescence for determination of GH, insulin-like growth factor-1 and insulin-like growth factor binding protein-3 concentrations. Sex steroid priming in both sexes was used by 19 centers. The most frequently used starting dose of recombinant human GH (rhGH) in prepubertal children was 0.025-0.030 mg/kg/day and 0.030-0.035 mg/kg/day in pubertal children. Growth velocity was used in the evaluation for growth response to rhGH therapy in all centers. Anthropometric measurements of patients every 3-6 months, fasting blood glucose, bone age and thyroid panel evaluation were used by all centers at follow-up. Main indications for cessation of therapy were decreased height velocity and advanced bone age. Fourteen centers used combined treatment (rhGH and gonadotropin-releasing analogues) to increase final height. CONCLUSION: Although conformity was found among centers in Turkey in current practice, it is very important to update guideline statements and to modify, if needed, the approach to GHD over time in accordance with new evidence-based clinical studies.

Targeted mass spectrometry analysis of the proteins IGF1, IGF2, IBP2, IBP3 and A2GL by blood protein precipitation.

Biomarker analysis of blood samples by liquid chromatography (LC) mass spectrometry (MS) is extremely challenging due to the high protein concentration range, characterised by abundant proteins that suppress and mask other proteins of lower abundance. This situation is further aggravated when using fast high-throughput methods, which are necessary for analysis of hundreds and thousands of samples in clinical laboratories. The blood proteins IGF1, IGF2, IBP2, IBP3 and A2GL have been proposed as indirect biomarkers for detection of GH administration and as putative biomarkers for breast cancer diagnosis. We describe a sensitive and scalable method to quantify these 5 proteins of medium and low abundance by selected reaction monitoring (SRM) LC-MS/MS analysis in blood samples. Our method requires 7µL of plasma and reaches a throughput of up to ca. 80 analyses per day. It includes an initial protein precipitation protocol optimised for extraction of low mass proteins from blood samples for reduced signal suppression and increased sensitivity in LC-MS/MS. We benchmarked this method for the analysis of 40 individual blood samples including 20 patients diagnosed with breast cancer. BIOLOGICAL SIGNIFICANCE: The interest for MS-based biomarker analysis in body fluids is steadily increasing as proteomics methodology translates into clinical laboratories. We describe a method for detection of 5 distinct proteins of low mass and medium to low abundance, which are of interest in anti-doping and clinical analysis. The analytical setup is simple and robust and is suitable for high-throughput instrument configurations.

Insulin-Like growth factor 1 related pathways and high-fat diet promotion of transgenic adenocarcinoma mouse prostate (TRAMP) cancer progression.

INTRODUCTION: We aimed to investigate the role of IGF-1 related pathway in high-fat diet (HFD) promotion of TRAMP mouse PCa progression. METHODS: TRAMP mice were randomly divided into two groups: HFD group and normal diet group. TRAMP mice of both groups were sacrificed and sampled on the 20th, 24th and 28th week respectively. Serum levels of insulin, IGF-1 and IGF-2 were tested by ELISA. Prostate tissue of TRAMP mice was used for both HE staining and immunohistochemical staining of IGF-1 related pathway proteins, including IGF-1Rα, IGF -1Rß, IGFBPs and AKT. RESULTS: The mortality of TRAMP mice from HFD group was significantly higher than that of normal diet group (23.81% and 7.14%, p=.035). The tumor incidence of HFD TRAMP mice at 20(th) week was significantly higher than normal diet group (78.57% and 35.71%, p=.022). Serum IGF-1 level of HFD TRAMP mice was significantly higher than that of normal diet TRAMP mice. Serum IGF-1 level tended to increase with HFD TRAMP mice's age. HFD TRAMP mice had higher positive staining rate of IGF-1Rα, IGF-1Rß, IGFBP3 and Akt than normal diet TRAMP mice. CONCLUSIONS: IGF-1 related pathway played an important role in high-fat diet promotion of TRAMP mouse PCa development and progression.

The influence of nutrition on the insulin-like growth factor system and the concentrations of growth hormone, glucose, insulin, gonadotropins and progesterone in ovarian follicular fluid and plasma from adult female horses (Equus caballus).

BACKGROUND: Feed intake affects the GH-IGF system and may be a key factor in determining the ovarian follicular growth rate. In fat mares, the plasma IGF-1 concentration is high with low GH and a quick follicular growth rate, in contrast to values observed in thin mares. Nothing is known regarding the long-term effects of differential feed intake on the IGF system. The objective of this experiment was to quantify IGFs, IGFBPs, GH, glucose, insulin, gonadotropin and progesterone (P4) in blood and in preovulatory follicular fluid (FF) in relation to feeding levels in mares. METHODS: Three years prior to the experiment, Welsh Pony mares were assigned to a restricted diet group (R, n = 10) or a well-fed group (WF, n = 9). All mares were in good health and exhibited differences in body weight and subcutaneous fat thickness. Follicular development was scanned daily and plasma was also collected daily. Preovulatory FF was collected by ultrasound-guided follicular aspiration. Hormone levels were assayed in FF and plasma with a validated RIA. RESULTS: According to scans, the total number of follicles in group R was 53% lower than group WF. Insulin and IGF-1 concentrations were higher in WF than in R mares. GH and IGF-2 concentrations were lower in plasma from WF mares than from R mares, but the difference was not significant in FF. The IGFBP-2/IGFBP-3 ratio in FF was not affected by feeding but was dramatically increased in R mare plasma. No difference in gonadotropin concentration was found with the exception of FSH, which was higher in the plasma of R mares. On the day of puncture, P4 concentrations were not affected by feeding but were higher in preovulatory FF than in plasma. CONCLUSIONS: The bioavailability of IGF-1 or IGF-2, represented by the IGFBP2/IGFBP3 ratio, is modified by feed intake in plasma but not in FF. These differences partially explain the variability in follicular growth observed between well-fed mares and mares on restricted diets.