Normal Values of Circulating IGF-I Bioactivity in the Healthy Population: Comparison with five widely used IGF-I immunoassays

Background: IGF-I immunoassays are primarily used to estimate IGF-I bioactivity. Recently, an IGFI specific Kinase Receptor Activation Assay (KIRA) has been developed as an alternative method. However, no normative values have been established for the IGF-I KIRA. Objective: To establish normative values for the IGF-I KIRA in healthy adults. Design: Cross-sectional study in healthy non-fasting blood donors. Study participants: 426 healthy individuals (310 M, 116 F; age range: 18 – 79 yrs) Main outcome Measures: IGF-I bioactivity determined by the KIRA. Results were compared with total IGF-I, measured by five different IGF-I immunoassays. Results: Mean (± SD) IGF-I bioactivity was 423 (± 131) pmol/L and decreased with age (β = -3.4 pmol/L/yr, p < 0.001). In subjects younger than 55 yrs mean IGF-I bioactivity was significantly higher in women than in men. Above this age this relationship was inverse, suggesting a drop in IGF-I bioactivity after menopause. This drop was not reflected in total IGF-I levels. IGF-I bioactivity was significantly related to total IGF-I (rs varied between 0.46 – 0.52; P-values < 0.001). Conclusions: We established age-specific normative values for the IGF-I KIRA. We observed a significant drop in IGF-I bioactivity in women between 50 and 60 years, which was not perceived by IGF-I immunoassays. The IGF-I KIRA, when compared to IGF-I immunoassays, theoretically has the advantage that it measures net effects of IGF-binding proteins on IGF-I receptor activation. However, it has to be proven whether information obtained by the IGF-I KIRA is clinically more relevant than measurements obtained by IGF-I immunoassays

Low Circulating IGF-I Bioactivity in Elderly Men is associated with Increased Mortality

Context: Low IGF-I signaling activity prolongs lifespan in certain animal models, but the precise role of IGF-I in human survival remains controversial. The IGF-I kinase receptor activation assay (IGF-I KIRA) is a novel method for measuring IGF-I bioactivity in human serum. We speculated that determination of circulating IGF-I bioactivity is more informative than levels of immunoreactive IGFI. Objective: To study IGF-I bioactivity in relation to human survival. Design: Prospective observational study. Setting: A clinical research center at a university hospital. Study participants: 376 healthy elderly men (aged 73 to 94 years). Main outcome Measures: IGF-I bioactivity was determined by the IGF-I KIRA. Total and free IGF-I were determined by IGF-I immunoassays. Mortality was registered during follow-up (mean 82 months). Results: During the follow-up period of 8.6 years 170 men (45%) died. Survival of subjects in the highest quartile of IGF-I bioactivity was significantly better than in the lowest quartile, both in the total study group (HR = 1.8, (95% CI: 1.2 − 2.8, p = 0.01) as well as in subgroups having a medical history of cardiovascular disease (HR = 2.4 (95% CI: 1.3 − 4.3, p = 0.003) or a high inflammatory risk profile (HR = 2.3 (95% CI: 1.2 − 4.5, p = 0.01). Significant relationships were not observed for total or free IGF-I. Conclusion: Our study suggests that a relatively high circulating IGF-I bioactivity in elderly men is associated with extended survival and with reduced cardiovascular risk

Effect of estrogen on tendon collagen synthesis, tendon structural characteristics, and biomechanical properties in postmenopausal women

Udgivelsesdato: 2009-AprThe knowledge about the effect of estradiol on tendon connective tissue is limited. Therefore, we studied the influence of estradiol on tendon synthesis, structure, and biomechanical properties in postmenopausal women. Nonusers (control, n = 10) or habitual users of oral estradiol replacement therapy (ERT, n = 10) were studied at rest and in response to one-legged resistance exercise. Synthesis of tendon collagen was determined by stable isotope incorporation [fractional synthesis rate (FSR)] and microdialysis technique (NH(2)-terminal propeptide of type I collagen synthesis). Tendon area and fibril characteristics were determined by MRI and transmission electron microscopy, whereas tendon biomechanical properties were measured during isometric maximal voluntary contraction by ultrasound recording. Tendon FSR was markedly higher in ERT users (P &lt; 0.001), whereas no group difference was seen in tendon NH(2)-terminal propeptide of type I collagen synthesis (P = 0.32). In ERT users, positive correlations between serum estradiol (s-estradiol) and tendon synthesis were observed, whereas change in tendon synthesis from rest to exercise was negatively correlated to s-estradiol. Tendon area, fibril density, fibril volume fraction, and fibril mean area did not differ between groups. However, the percentage of medium-sized fibrils was higher in ERT users (P &lt; 0.05), whereas the percentage of large fibrils tended to be greater in control (P = 0.10). A lower Young's modulus (GPa/%) was found in ERT users (P &lt; 0.05). In conclusion, estradiol administration was associated with higher tendon FSR and a higher relative number of smaller fibrils. Whereas this indicates stimulated collagen turnover in the resting state, collagen responses to exercise were negatively associated with s-estradiol. These results indicate a pivotal role for estradiol in maintaining homeostasis of female connective tissue

Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort

Data from epidemiological and animal model studies suggest that nutrition during pregnancy may affect the health status of subsequent generations. These transgenerational effects are now being explained by disruptions at the level of the epigenetic machinery. Besides in vitro environmental exposures, the possible impact on the reprogramming of methylation profiles at imprinted genes at a much earlier time point, such as during spermatogenesis or oogenesis, has not previously been considered. In this study, our aim was to determine associations between preconceptional obesity and DNA methylation profiles in the offspring, particularly at the differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene

Insulin resistance in type 1 diabetes: what is ‘double diabetes’ and what are the risks?

In this review, we explore the concept of ‘double diabetes’, a combination of type 1 diabetes with features of insulin resistance and type 2 diabetes. After considering whether double diabetes is a useful concept, we discuss potential mechanisms of increased insulin resistance in type 1 diabetes before examining the extent to which double diabetes might increase the risk of cardiovascular disease (CVD). We then go on to consider the proposal that weight gain from intensive insulin regimens may be associated with increased CV risk factors in some patients with type 1 diabetes, and explore the complex relationships between weight gain, insulin resistance, glycaemic control and CV outcome. Important comparisons and contrasts between type 1 diabetes and type 2 diabetes are highlighted in terms of hepatic fat, fat partitioning and lipid profile, and how these may differ between type 1 diabetic patients with and without double diabetes. In so doing, we hope this work will stimulate much-needed research in this area and an improvement in clinical practice

Subclinical inflammation during third trimester of pregnancy was not associated with markers of the metabolic syndrome in young adult offspring.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files.Growing evidence indicates that the metabolic syndrome (MS) is rooted in adverse exposures during fetal life. The aim of this study was to assess the possible associations between biomarkers of inflammation during third trimester of pregnancy and markers of MS in adult offspring.High-sensitive C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleuki-6 (IL-6) were measured in serum samples obtained in gestational week 30. Offspring were clinically examined at age 20 years. Analyses based on 439 mother-offspring dyads were adjusted for maternal smoking during pregnancy, height, prepregnancy body mass index (BMI), education, and offspring's sex. Offspring MS markers included waist circumference, BMI, blood pressure, HOMA insulin resistance, and plasma levels of fasting glucose, triglycerides, cholesterol fractions, insulin, and leptin.The median level was 2.8 (interquartile range = 3.3) µg/ml for CRP, for TNF-α: 5.7 (3.2) pg/ml, for IL-1β: 0.5 (0.4) pg/ml, and for IL-6: 1.1 (0.7) pg/ml. Concentrations were not significantly associated with MS markers in the offspring. The results remained essentially unchanged after correction for potential confounding.Markers for subclinical inflammation in third trimester in healthy women were not associated with components of MS in their adult offspring

The IGF system in patients with inflammatory bowel disease treated with prednisolone or infliximab:Potential role of the stanniocalcin-2 / PAPP-A / IGFBP-4 axis

Background: Patients with inflammatory bowel disease (IBD) present with reduced serum insulin-like growth factor I (IGF-I). Anti-inflammatory treatment with prednisolone or infliximab ameliorates symptoms and increases circulating IGF-I, but prednisolone induces catabolism, whereas infliximab may promote protein synthesis. Recently, stanniocalcin-2 (STC2) was discovered as a novel inhibitor of the enzyme pregnancy-associated plasma protein-A (PAPP-A), which modulates IGF-I activity. PAPP-A can cleave IGF binding protein-4 (IGFBP-4), upon which IGF-I is liberated. We hypothesized that prednisolone and infliximab exert different effects on levels of STC2, PAPP-A, and IGFBP-4, thereby explaining the distinct metabolic effects of prednisolone and infliximab. Methods: Thirty-eight patients with active IBD treated with either prednisolone (n = 17) or infliximab (n = 21) were examined before and after 7 days of treatment. Circulating levels of IGF-I, IGF-II, IGFBP-3, PAPP-A, and STC2 were measured by immunoassays. Intact IGFBP-4 and two IGFBP-4 fragments were determined by a novel immunoassay. Bioactive IGF was assessed by cell-based IGF receptor activation assay. Concentrations of IGFBP-4, PAPP-A, and STC2 on day 0 and 7 were compared to healthy control subjects. Results: Following seven days of prednisolone treatment, total and bioactive IGF-I were increased (p &lt; 0.001 and p &lt; 0.05, respectively). Upon infliximab treatment, total IGF-I levels were augmented (p &lt; 0.05), yet IGF bioactivity remained unaltered. Intact IGFBP-4 and the two IGFBP-4 fragments generated upon cleavage by PAPP-A were all decreased following treatment with either prednisolone or infliximab (all p &lt; 0.05). PAPP-A levels were only increased by infliximab (p = 0.005), whereas the inhibitor STC2 did not respond to any of the treatments. Conclusion: IGF-I and IGFBP-4 concentrations were markedly altered in patients with IBD and near-normalized with disease remission following treatment with prednisolone or infliximab. Thus, IGFBP-4 may modulate IGF bioavailability in IBD. The effect of immunosuppression did not appear to extend beyond the regulation of IGF and IGFBP-4, as neither PAPP-A nor STC2 were discernibly affected. Trial registration: ClinicalTrials.gov: NCT00955123. Date of registration: August 7, 2009 (retrospectively registered).</p

Growth hormone/insulin-like growth factor I axis in health and disease states:an update on the role of intra-portal insulin

Growth hormone (GH) is the key regulator of insulin-like growth factor I (IGF-I) generation in healthy states. However, portal insulin delivery is also an essential co-player in the regulation of the GH/IGF-I axis by affecting and regulating hepatic GH receptor synthesis, and subsequently altering hepatic GH sensitivity and IGF-I generation. Disease states of GH excess (e.g., acromegaly) and GH deficiency (e.g., congenital isolated GH deficiency) are characterized by increased and decreased GH, IGF-I and insulin levels, respectively, where the GH/IGF-I relationship is reflected by a “primary association”. When intra-portal insulin levels are increased (e.g., obesity, Cushing’s syndrome, or due to treatment with glucocorticoids and glucagon-like peptide 1 receptor agonists) or decreased (e.g., malnutrition, anorexia nervosa and type 1 diabetes mellitus), these changes secondarily alter hepatic GH sensitivity resulting in a “secondary association” with discordant GH and IGF-I levels (e.g., high GH/low IGF-I levels or low GH/high IGF-I levels, respectively). Additionally, intra-portal insulin regulates hepatic secretion of IGFBP-1, an inhibitor of IGF-I action. Through its effects on IGFBP-1 and subsequently free IGF-I, intra-portal insulin exerts its effects to influence endogenous GH secretion via the negative feedback loop. Therefore, it is important to understand the effects of changes in intra-portal insulin when interpreting the GH/IGF-I axis in disease states. This review summarizes our current understanding of how changes in intra-portal insulin delivery to the liver in health, disease states and drug therapy use and misuse that leads to alterations in GH/IGF-I secretion that may dictate management decisions in afflicted patients.</p

Analyses of IGFBP2 DNA methylation and mRNA expression in visceral and subcutaneous adipose tissues of obese subjects

Insulin-like growth factor binding-protein 2 (IGFBP-2) is secreted by differentiating white adipocytes. Clinical studies demonstrate that circulating IGFBP-2 levels associated inversely with body mass index (BMI) and insulin resistance. To explore possible epigenetic changes of the IGFBP2 gene in obesity, we analyzed DNA methylation and mRNA expression in adipocytes from different depots. Healthy lean controls (BMI = 24.5 ± 0.3 kg/m 2 , n = 19) and obese subjects (BMI &gt; 35 kg/m 2 , n = 24) were recruited. All subjects were Swedish Caucasian. Visceral abdominal adipose tissue (VAT) and subcutaneous adipose tissue (SAT) fragments were homogenized. Genomic DNA and total RNAs were extracted. Four CpG sites in the IGFBP2 gene promoter region were analyzed with bisulfite pyrosequencing. IGFBP2 gene expression at mRNA levels was determined with TaqMan real time RT-PCR. Serum samples were used for measurement of circulating IGFBP-2 and leptin levels. IGFBP2 DNA methylation levels in VAT were increased in obese subjects compared with controls (P &lt;.05). By contrast, IGFBP2 mRNA expression levels in VAT were lower in obesity subjects than in controls (P &lt;.05). In SAT, IGFBP2 DNA methylation and RNA expression levels were lower than in VAT, irrespective of obesity. Obese subjects demonstrated increased serum leptin levels (P &lt;.001) and reduced serum IGFBP-2 levels compared to controls (P &lt;.05). In conclusion, the current study demonstrates that IGFBP2 DNA methylation levels are increased in VAT from obese subjects. This suggests that IGFBP-2 is epigenetically regulated in abdominal obesity. </p