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  • Author: Kieran A McCaul x
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Bu B Yeap, S A Paul Chubb, Leon Flicker, Kieran A McCaul, Peter R Ebeling, John P Beilby and Paul E Norman

Objective

Bone-derived undercarboxylated osteocalcin regulates insulin secretion and sensitivity in mice, and reduced serum total osteocalcin (TOC) is associated with diabetes in humans. However, the relationship between TOC levels and other cardiovascular risk factors is uncertain. We sought to determine whether serum TOC is associated with metabolic syndrome and its components in older men.

Design

Cross-sectional analysis from a population-based cohort of men aged ≥70 years.

Methods

Early morning sera were assayed for TOC. Insulin resistance was estimated using a homeostatic model (HOMA2-IR). Metabolic syndrome was defined according to NCEP-ATPIII criteria.

Results

TOC was assayed in 4047 men. Men who were not fasting and reported having bone fractures, Paget's disease, or bisphosphonate, glucocorticoid, or warfarin use were excluded, leaving 2765 men with metabolic syndrome present in 797 (28.8%). TOC was inversely associated with waist circumference, glucose, and triglyceride levels and HOMA2-IR (all P<0.001), and was lower in men with metabolic syndrome (mean±s.e.m.: 20.1±0.4 vs 21.4±0.2 μg/l, P=0.002). In multivariate analysis, men with TOC of 13.25–16.55 and <13.25 μg/l had 1.5- to 2-fold increased risk of metabolic syndrome compared with men with levels ≥30 μg/l. TOC remained associated with metabolic syndrome after adjustment for individual components, but not after adjusting for both waist circumference and glucose.

Conclusions

Increased waist circumference, reduced TOC, elevated glucose, and triglyceride levels are inter-related in aging men. Osteocalcin may lie in the causal pathway between central adiposity and insulin resistance. Further research is required to evaluate whether interventions which raise osteocalcin levels might decrease cardiovascular risk.

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Bu B Yeap, S A Paul Chubb, Leon Flicker, Kieran A McCaul, Peter R Ebeling, John P Beilby and Paul E Norman

In the above article published in the European Journal of Endocrinology (2010) 163 265–272, the authors apologise for an error and clarify that total osteocalcin was measured in aliquots of plasma and not in serum as stated. The authors opine that as the assay is appropriate for either serum or plasma, it is not likely to have influenced the results.

Free access

Zoë Hyde, Paul E Norman, Leon Flicker, Graeme J Hankey, Kieran A McCaul, Osvaldo P Almeida, S A Paul Chubb and Bu B Yeap

Context

Hypogonadism in men is associated with insulin resistance, elevations in pro-inflammatory cytokines and fibrinogen, and an atherogenic lipid profile. However, it is uncertain whether the age-related decline in testosterone is associated with ischaemic heart disease (IHD) events.

Objective

To determine whether testosterone and its associated hormones, sex hormone-binding globulin (SHBG) and LH, predict IHD events in older men.

Design

Prospective cohort study.

Methods

Between 2001 and 2004, 3637 community-dwelling men aged 70–88 years underwent a clinical assessment of cardiovascular risk factors and biochemical assessment of testosterone, SHBG and LH. Free testosterone was calculated using mass action equations. Participants were followed until December 2008 using electronic record linkage to capture IHD events (hospital admission or death).

Results

Mean follow-up was 5.1 years. During this period, 618 men (17.0%; 95% confidence interval (CI) 15.8, 18.3%) experienced an event, of which 160 were fatal. Men with higher baseline total or free testosterone levels experienced fewer IHD events (hazard ratio (HR)=0.89; 95% CI 0.82, 0.97 and HR=0.86; 95% CI 0.79, 0.94 for each one s.d. increase in total and free testosterone respectively). These associations were maintained after adjustment for age and waist:hip ratio but did not persist after adjustment for prevalent IHD or other cardiovascular risk factors. SHBG was not associated with IHD events. In contrast, higher LH levels were associated with reduced event-free survival in both univariate (HR=1.15; 95% CI 1.08, 1.22) and adjusted analyses (HR=1.08; 95% CI 1.01, 1.15).

Conclusions

Dysregulation of the hypothalamic–pituitary–gonadal axis may be a risk factor for IHD. Further studies of men with either elevated LH or low testosterone are warranted.

Free access

Bu B Yeap, S A Paul Chubb, Ken K Y Ho, Johnson W S Setoh, Kieran A McCaul, Paul E Norman, Konrad Jamrozik and Leon Flicker

Objective

Circulating IGF1 declines with age, and reduced circulating IGF1 is associated with increased cardiovascular mortality in some but not all studies. The relationship between IGF-binding proteins 3 and 1 (IGFBP3 and IGFBP1) with risk of cardiovascular disease remains unclear. We sought to examine associations between IGF1, IGFBP3 and IGFBP1 with metabolic syndrome in older men.

Design

Cross-sectional analysis of 3980 community-dwelling men aged ≥70 years.

Methods

Morning plasma levels of IGF1, IGFBP3 and IGFBP1 were assayed. Metabolic syndrome was defined according to National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) criteria.

Results

For IGF1 and IGFBP3, there was a U-shaped relationship, with middle quintiles possessing the lowest odds ratios (OR) for metabolic syndrome (reference Q1, Q3 IGF1: OR 0.74, 95% confidence intervals 0.57–0.96, Q3 IGFBP3: OR 0.67, 0.51–0.87). Increasing IGFBP1 was associated with reduced risk of metabolic syndrome with a dose–response gradient (reference Q1, OR for Q2 to Q5 IGFBP1: 0.56, 0.33, 0.22 and 0.12 respectively, P<0.001). IGF1 was associated with two, IGFBP1 with four and IGFBP3 with all five components of the metabolic syndrome. The ratio of IGF1/IGFBP3 was not associated with metabolic syndrome.

Conclusions

In older men, both lower and higher IGF1 and IGFBP3 levels may be metabolically unfavourable. IGFBP1, as a marker of insulin sensitivity, is relevant in the assessment of metabolic syndrome, while the IGF1/IGFBP3 ratio is less informative. Longitudinal follow-up of this cohort would be needed to determine whether these distributions of IGF1, IGFBP3 and IGFBP1 predict incidence of cardiovascular events during male ageing.

Free access

Bu B Yeap, S A Paul Chubb, Kieran A McCaul, Ken K Y Ho, Graeme J Hankey, Paul E Norman and Leon Flicker

Objective

Circulating IGF1 declines with age while ill-health increases. Controversy remains whether differences in the levels of IGF1 and its binding proteins 1 and 3 (IGFBP1 and IGFBP3) determine health outcomes during ageing. We examined associations of IGF1, IGFBP1 and IGFBP3 with all-cause and cardiovascular mortality in older men.

Design

We conducted a prospective cohort study of community-dwelling men aged ≥70 years.

Methods

Plasma collected at baseline (2001–2004) was assayed for total IGF1, IGFBP1 and IGFBP3. Incidence and causes of death from time of recruitment to 31 December 2008 were ascertained using the Western Australian Data Linkage System. Cox regression analyses were performed, adjusting for conventional cardiovascular risk factors.

Results

Among 3983 men followed for 5.2 years (median), 694 deaths occurred, 243 from cardiovascular disease (CVD). There was no difference in survival according to quintiles of IGF1. Increased IGFBP1 predicted increased all-cause mortality (highest versus lowest quintile: adjusted hazard ratio (HR)=1.98, 95% confidence interval (CI)=1.52–2.57, P<0.001 for trend) and increased cardiovascular mortality (HR=3.42 (2.03–5.77), P<0.001 for trend). Decreased IGFBP3 predicted increased all-cause mortality (lowest versus highest quintile: HR=1.57, 95% CI=1.23–2.01, P=0.007 for trend). Associations of IGFBP1 and IGFBP3 with all-cause mortality were not attenuated by adjustment for IGF1 levels.

Conclusions

In older men, higher IGFBP1 and lower IGFBP3 levels predict overall and CVD-related mortality, while IGF1 levels are not associated with mortality. Further studies are needed to clarify the underlying mechanisms by which IGFBP1 and IGFBP3 levels are associated with mortality risk, and whether this occurs independently of IGF1.

Free access

Bu B Yeap, S A Paul Chubb, Kieran A McCaul, Leon Flicker, Ken K Y Ho, Jonathan Golledge, Graeme J Hankey and Paul E Norman

Objective

Abdominal aortic aneurysm (AAA) is most prevalent in older men. GH secretion declines with age resulting in reduced IGF1 levels. IGF1 and its binding proteins (IGFBPs) are expressed in vasculature, and lower IGF1 levels have been associated with cardiovascular risk factors and disease. However, the relationship of the IGF1 system with aortic dilation and AAA is unclear. We tested the hypothesis that circulating IGF1 and IGFBPs are associated with AAA and aortic diameter in older men.

Design

A cross-sectional analysis involving 3981 community-dwelling men aged 70–89 years was performed.

Methods

Abdominal aortic diameter was measured by ultrasound. Plasma total IGF1, IGFBP1 and IGFBP3 were measured by immunoassays.

Results

After adjustment for age, body mass index, waist:hip ratio, smoking, hypertension, dyslipidemia, diabetes, coronary heart disease and serum creatinine, a higher IGF1 level was associated with AAA (odds ratio (OR)/1 s.d. increase 1.18, 95% confidence interval (CI) 1.05–1.33, P=0.006), as was the ratio of IGF1/IGFBP3 (OR=1.22, 95% CI 1.10–1.35, P<0.001). Highest IGF1 concentrations compared with lowest quintile were significantly associated with AAA (quintile (Q) 5 vs Q1: OR=1.80, 95% CI 1.20–2.70, P=0.004) as were IGF1/IGFBP3 ratios (Q5 vs Q1: OR=2.52, 95% CI 1.59–4.02, P<0.001). IGF1 and IGFBP1 were independently associated with aortic diameter (β=0.200, 95% CI 0.043–0.357, P=0.012 and β=0.274, 95% CI 0.098–0.449, P=0.002 respectively).

Conclusions

In older men, higher IGF1 and an increased ratio of IGF1/IGFBP3 are associated with AAA, while IGFBP1 is independently associated with increased aortic diameter. Components of the IGF1 system may contribute to, or be a marker for, aortic dilation in ageing men.