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  • Author: Annewieke W van den Beld x
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Annewieke W van den Beld, Olga D Carlson, Maire E Doyle, Dimitris Rizopoulos, Luigi Ferrucci, Aart Jan van der Lely and Josephine M Egan

Objective

Insulin-like growth factor-binding protein-2 (IGFBP-2) concentrations are low in subjects with metabolic syndrome and type 2 diabetes. Intriguingly, recent studies have demonstrated an association between high IGFBP-2 concentrations and increased mortality not only in populations with certain types of cancer, but also in relatively healthy populations. We evaluated the role of IGFBP-2 in relation to BMI and mortality.

Design and Participants

BMI, insulin sensitivity, insulin-like growth factor 1 (IGF-I) and IGFBP-2 were assessed repeatedly in 539 participants of the Baltimore Longitudinal Study of Aging around the ages of 55, 65 and 75 years.

Results

IGFBP-2 concentrations positively correlated with insulin sensitivity and inversely with BMI, both at baseline and follow-up. Independent of IGF-I, sex, BMI and insulin sensitivity, circulating IGFBP-2 levels positively correlated with age (P < 0.001). Changes over time in BMI were associated with an inverse correlation in IGFBP-2 concentrations. Furthermore, we found indications of a relationship between low baseline IGFBP-2 levels and mortality. Remarkably, after adjustment for insulin sensitivity, the opposite association was found, as a unit increase of log(IGFBP2) was associated with an increase in the log hazard by 1.43 (95% CI: 0.3–2.6). This accounted for both baseline (P = 0.02) as well as serial (P < 0.001) measurements of IGFBP2. Finally, in this longitudinal study, we found that IGF-I concentrations increased with age (0.82 ± 0.2 (µg/L)/year, P < 0.001).

Conclusion

This is the first study investigating the relationship between IGFBP-2 levels and age in a longitudinal setting. Serum IGFBP-2 levels increase with age after the age of 50 years and evolve in parallel with insulin sensitivity. IGFBP-2 may therefore be a potential marker for insulin sensitivity. We further show that IGFBP-2 levels can predict mortality in this aging population. However, its predictive value for mortality can only be interpreted in relation to insulin sensitivity. After adjustment for insulin sensitivity, high IGFBP-2 levels are predictive of increased mortality.

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Annewieke W van den Beld, Werner F Blum, Michael P Brugts, Joop A M J L Janssen, Diederick E Grobbee and Steven W J Lamberts

Objective

Serum IGF-binding protein 2 (IGFBP2) concentrations are reduced in obese humans and increase after a prolonged period of fasting. We investigated the association between IGFBP2 levels and mortality together with other factors that are related to IGFBP2, including the metabolic syndrome and physical function.

Design

A prospective observational study at a clinical research center of 403 independently living elderly men (aged 73–94 years).

Methods

Mortality was registered during 8.6 years of follow-up. Physical performance score (PPS), grip strength (GS), and bone mineral density (BMD) were measured. The measurements taken a baseline were: IGF1; IGFBP1, -2, and -3; IGF1 bioactivity; triiodothyronine (T3); and reverse T3. Further, BMI, insulin sensitivity, cholesterol, inflammatory markers, and albumin levels were also measured.

Results

During the follow-up, 180 men died. Higher PPS, GS, and BMD were independently related to a reduced mortality (hazard ratio (HR)=0.87/point, 95% confidence interval (95% CI)=0.82–0.91, P<0.001; HR=0.96/kp, 95% CI 0.94–0.98, P<0.001; and HR=0.21/(g/cm2), 95% CI 0.07–0.61, P<0.01). Higher serum IGFBP2 levels were strongly related to mortality (HR=2.26/(mg/l), 95% CI 1.57–3.27, P<0.001). This was independent of comorbidity, physical function, IGF1 bioactivity, and other somatotropic parameters, including BMI and the metabolic syndrome. In addition, IGFBP2 levels were higher in subjects with nonthyroidal illness, and higher IGFBP2 levels were significantly associated with lower albumin concentrations.

Conclusion

Despite the strong relationship between high IGFBP2 and low physical function, both were strongly and independently related to increased 8-year mortality in elderly men. IGFBP2 may be a useful biomarker integrating the nutritional status, as well as the biological effects of GH, IGF1, and insulin.