Frystyk, J.

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

2008-07-01T00:00:00Z

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.

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

2008-07-01T00:00:00Z

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.

Administration of human insulin-like growth factor-binding protein-1 increases circulating levels of growth hormone in mice. (Article)

2004-09-01T00:00:00Z

GH is the major regulator of circulating IGF-I, which, in return, controls pituitary GH secretion by negative feedback. IGF-binding protein-1 (IGFBP-1) is believed to modify this feedback through its effects on free IGF-I. In the present study we investigated the potential influence of IGFBP-1 on GH secretion in the absence or presence of a GH receptor antagonist (GHRA) that specifically blocks peripheral GH action. We administered human (h) IGFBP-1 and GHRA to mice alone or in combination for 2 or 7 d. GHRA was administered in a dose previously shown to block GH action without an effect on circulating GH or IGF-I levels. hIGFBP-1 administration increased stimulated circulating GH levels and serum total IGF-I and IGFBP-3 levels. Coadministration of GHRA abolished the hIGFBP-1-induced increase in serum IGF-I and IGFBP-3 levels, whereas stimulated GH levels remained increased. Free IGF-I levels in serum were unchanged in all treatment groups. In conclusion, GH serum levels increased in response to hIGFBP-1 administration, even in the setting of normal IGF-I levels. This finding suggests a direct involvement of IGFBP-1 in GH secretion.