Search

Context: In a recent study a pattern of 27 metabolites, including serum glycine, associated with bone mineral density (BMD).Objective: To investigate associations for serum and urinary glycine levels with BMD, bone microstructure, and fracture risk in men.Methods: In the population-based Osteoporotic Fractures in Men (MrOS) Sweden study (men, 69-81 years) serum glycine and BMD were measured at baseline (n = 965) and 5-year follow-up (n = 546). Cortical and trabecular bone parameters of the distal tibia were measured at follow-up using high-resolution peripheral quantitative computed tomography. Urinary (n = 2682) glycine was analyzed at baseline. X-ray-validated fractures (n = 594) were ascertained during a median follow-up of 9.6 years. Associations were evaluated using linear regression (bone parameters) or Cox regression (fractures).Results: Circulating glycine levels were inversely associated with femoral neck (FN)-BMD. A meta-analysis (n = 7543) combining MrOS Sweden data with data from 3 other cohorts confirmed a robust inverse association between serum glycine levels and FN-BMD (P = 7.7 × 10-9). Serum glycine was inversely associated with the bone strength parameter failure load in the distal tibia (P = 0.002), mainly as a consequence of an inverse association with cortical cross-sectional area and a direct association with cortical porosity. Both serum and urinary glycine levels predicted major osteoporotic fractures (serum: hazard ratio [HR] per SD increase = 1.22, 95% CI, 1.05-1.43; urine: HR = 1.13, 95% CI, 1.02-1.24). These fracture associations were only marginally reduced in models adjusted by FRAX with BMD.Conclusions: Serum and urinary glycine are indirectly associated with FN-BMD and cortical bone strength, and directly associated with fracture risk in men. [ABSTRACT FROM AUTHOR]

Objective: Several studies revealed relations between low or high insulin-like growth factor I (IGF-I) levels and risk of cardiovascular diseases or mortality, whereas the mechanisms behind these associations are still unknown. Design: The study aimed to explore the relations between IGF-I and changes in surrogate markers of cardiovascular disease including carotid intima-media thickness (IMT), left ventricular mass index (LVMI) and N-terminal pro-brain natriuretic peptide (NT-proBNP). Methods: Longitudinal data of the population-based cohort Study of Health in Pomerania (SHIP) were used. IMT was measured by ultrasonography and LVMI was determined based on echocardiography. IGF-I and IGF-binding protein-3 (IGFBP-3) levels were measured by chemiluminescent immunoassays and the IGF-I/IGFBP-3 ratio was calculated. Mixed linear regression models adjusted for known cardiovascular confounders were performed. Results: Statistical analyses demonstrated relations between low baseline IGF-I levels (beta for ΔIMT per s.d. increase -0.044 (s.e. 0.012)) or IGF-I/IGFBP-3 ratio (beta -0.045 (0.012)) and a long-term IMT increase. No associations between IGF-I, IGFBP-3 or IGF-I/IGFBP-3 ratio and changes in LVMI were detected. With respect to NT-proBNP sex-specific associations with IGF-I were found. In women, higher baseline IGF-I levels (beta for ΔNT-proBNP per s.d. increase 5.92 (2.2)) or IGF-I/IGFBP-3 ratio (beta 4.48 (2.2)) were related to an increase in NT-proBNP levels. Among men, U-shaped relations of baseline levels of IGF-I, IGFBP-3 and the IGF-I/IGFBP-3 ratio with an increase in NT-proBNP were found. Conclusions: The study detected significant relations between IGF-I and long-term changes in IMT and NT-proBNP but not LVMI. These findings argue for different effects of the IGF-I axis with respect to various cardiovascular entities. [ABSTRACT FROM AUTHOR]

ABSTRACT Milk fat globule-epidermal growth factor 8 (MFG-E8) is an anti-inflammatory glycoprotein that mediates the clearance of apoptotic cells and is implicated in the pathogenesis of autoimmune and inflammatory diseases. Because MFG-E8 also controls bone metabolism, we investigated its role in rheumatoid arthritis (RA), focusing on inflammation and joint destruction. The regulation of MFG-E8 by inflammation was assessed in vitro using osteoblasts, in arthritic mice and in patients with RA. K/BxN serum transfer arthritis (STA) was applied to MFG-E8 knock-out mice to assess its role in the pathogenesis of arthritis. Stimulation of osteoblasts with lipopolysaccharide (LPS) and tumor necrosis factor (TNF)-α downregulated the expression of MFG-E8 by 30% to 35%. MFG-E8-deficient osteoblasts responded to LPS with a stronger production of pro-inflammatory cytokines. In vivo, MFG-E8 mRNA levels were 52% lower in the paws of collagen-induced arthritic (CIA) mice and 24% to 42% lower in the serum of arthritic mice using two different arthritis models (CIA and STA). Similarly, patients with RA ( n = 93) had lower serum concentrations of MFG-E8 (-17%) compared with healthy controls ( n = 140). In a subgroup of patients who had a moderate to high disease activity ( n = 21), serum concentrations of MFG-E8 rose after complete or partial remission had been achieved (+67%). Finally, MFG-E8-deficient mice subjected to STA exhibited a stronger disease burden, an increased number of neutrophils in the joints, and a more extensive local and systemic bone loss. This was accompanied by an increased activation of osteoclasts and a suppression of osteoblast function in MFG-E8-deficient mice. Thus, MFG-E8 is a protective factor in the pathogenesis of RA and subsequent bone loss. Whether MFG-E8 qualifies as a novel biomarker or therapeutic target for the treatment of RA is worth addressing in further studies. © 2015 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Objective: There is no single clinical marker to reliably assess the clinical response to growth hormone replacement therapy (GHRT) in adults with growth hormone deficiency (GHD). The objective of this study was to propose a clinical response score to GHRT in adult GHD and to establish clinical factors that predict clinical response. Design: This was a prospective observational cohort study from the international KIMS database (Pfizer International Metabolic Database). Methods: We included 3612 adult patients with GHD for proposing the response score and 844 patients for assessing predictors of response. We propose a clinical response score based on changes in total cholesterol, waist circumference and QoL-AGHDA quality of life measurements after 2 years of GHRT. A score point was added for each quintile of change in each variable, resulting in a sum score ranging from 3 to 15. For clinical response at 2 years, we analysed predictors at baseline and after 6 months using logistic regression analyses. Results: In a baseline prediction model, IGF1, QoL-AGHDA, total cholesterol and waist circumference predicted response, with worse baseline parameters being associated with a favourable response (AUC 0.736). In a combined baseline and 6-month prediction model, baseline QoL-AGHDA, total cholesterol and waist circumference, and 6-month change in waist circumference were significant predictors of response (AUC 0.815). Conclusions: A simple clinical response score might be helpful in evaluating the success of GHRT. The baseline prediction model may aid in the decision to initiate GHRT and the combined prediction model may be helpful in the decision to continue GHRT. [ABSTRACT FROM AUTHOR]

Design: Abnormalities in glucose homeostasis have been described in patients with primary aldosteronism (PA) but most studies show inconsistent results. Therefore, we aimed to compare the prevalence of type 2 diabetes mellitus and metabolic syndrome (MetS) in newly diagnosed PA patients to a matched control cohort of the background population. Methods: In total, 305 PA patients of the prospective German Conn's Registry were compared to the population-based Study of Health In Pomerania (SHIP1; n=2454). A 1:1 match regarding sex, age, and BMI resulted in 269 matched pairs regarding type 2 diabetes and 183 matched pairs regarding MetS. Of the total, 153 PA patients underwent oral glucose tolerance testing (OGTT) at diagnosis and 38 PA patients were reevaluated at follow-up. Results: Type 2 diabetes and MetS were significantly more frequent in PA patients than in the control population (17.2% vs 10.4%, P=0.03; 56.8% vs 44.8%, P=0.02 respectively). Also, HbA1c levels were higher in PA patients than in controls (P<0.01). Of the total, 35.3% of non-diabetic PA patients showed an abnormal OGTT (¼ newly diagnosed type 2 diabetes and 3/4 impaired glucose tolerance). PA patients with an abnormal OGTTat baseline presented with significantly improved 2 h OGTT glucose (P=0.01) at follow-up. We detected a negative correlation between 2 h OGTT glucose levels and serum potassium (P<0.01). Conclusions: Type 2 diabetes and MetS are more prevalent in patients with PA than in controls matched for sex, age, BMI, and blood pressure. This may explain in part the increased cardiovascular disease morbidity and mortality in PA patients. [ABSTRACT FROM AUTHOR]

Background: Previous intervention studies in patients with GH disorders suggested an impact of IGF1 and IGF-binding protein 3 (IGFBP3) on lipid metabolism, whereas population-based studies revealed conflicting results. Therefore, we aimed to assess the cross-sectional and longitudinal associations between IGF1 or IGFBP3 serum levels and lipids (total, LDL, or HDL cholesterol and triglycerides) in a large-scale study. Methods: Data of 2935 subjects (1356 women) from the population-based Study of Health in Pomerania (SHIP) were used. ANOVA, quantile regression, and logistic regression models adjusted for age, waist circumference, physical activity, and alcohol consumption were performed. Results: In cross-sectional analyses, we detected that IGF1 and IGFBP3 levels were positively related to total and LDL cholesterol and inversely related to HDL cholesterol in both sexes. Furthermore, IGFBP3 levels showed a positive relationship to triglycerides. In total, IGFBP3 levels were more strongly associated to lipids than IGF1. In longitudinal analysis, we found no influence of baseline IGF1 or IGFBP3 serum concentration on incidentally elevated or reduced lipid levels. However, the positive relationship between IGFBP3 and incidentally elevated triglycerides barely missed statistical significance in women. Conclusion: The present study showed strong cross-sectional associations between IGF1 or IGFBP3 and lipids, whereas no longitudinal relationships were revealed. Therefore, our findings suggest IGF1 and IGFBP3 as a risk marker rather than a risk factor for alterations in lipid metabolism. Further studies are needed to elucidate the mechanisms underlying the association between the GH/IGF axis and lipid metabolism. [ABSTRACT FROM AUTHOR]

Aims Increased serum prolactin (PRL) concentrations have been associated with adverse cardiovascular risk profiles, but the relation between PRL and mortality risk is unknown. Methods and results We evaluated 3929 individuals (1946 men and 1983 women) aged 20–81 (mean 50.3 years) from the population-based Study of Health in Pomerania (SHIP). Associations of continuous [per standard deviation (SD) increase] and categorized (sex-specific tertiles) serum PRL concentrations with all-cause and cause-specific mortality were analysed separately for men and women by age- and multivariable-adjusted Cox regression models. During a median follow-up period of 10.1 years (38 231 person-years), 419 deaths (10.7%), 132 cardiovascular deaths (3.4%), and 152 cancer deaths (3.9%) were observed. After multivariable adjustment, we observed a positive association of PRL with all-cause mortality in men and women [hazard ratio (HR) per SD increase: 1.17, 95% confidence interval (CI): 1.07–1.29 and HR: 1.22, 95% CI: 1.03–1.46, respectively]. Similarly, individuals with PRL concentrations in the highest tertile (when compared with lowest PRL tertile) experienced the highest mortality risk (men: HR, 1.75; 95% CI, 1.32–2.32; women: HR, 1.66; 95% CI, 1.08–2.56), with a significant trend across PRL tertiles (P­ for trend <0.05). Cause-specific mortality analyses yielded similar associations for cardiovascular death in both sexes, but for cancer death only in men. Conclusion This is the first study to report an independent positive association of PRL concentrations with all-cause and cardiovascular mortality. Further studies are required to confirm our findings and to elucidate the potential role of PRL as a useful biomarker of cardiovascular risk and mortality assessment. [ABSTRACT FROM PUBLISHER]

Objective: Low total testosterone (TT) serum concentrations in men have been associated with various cardiometabolic risk factors. But given error-prone immunoassays used for TT assessment, upcoming mass spectrometry methods question the validity of these risk associations. Thus, we performed the first comparative study quantifying potential differences in the association of TT with cardiometabolic risk factors between the two methods. Methods:We used data from 1512 men aged 20-81 years, recruited for the cross-sectional populationbased Study of Health in Pomerania (SHIP), Germany. TT concentrations were repeatedly measured by chemiluminescent immunoassay (CLIA, Immulite 2500) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). We tested for significant differences between coefficients from CLIA- and LC-MS/MS-based multiple linear regression models associating TT with major cardiometabolic risk factors including adiposity, lipid metabolism, blood pressure, diabetic status, and inflammation. Results: TT measurements by CLIA and LC-MS/MS yielded a Pearson correlation coefficient of 0.84. Only three of the ten tested associations for TT with cardiometabolic risk factor showed significant differences between the two measurement methods: in comparison to LC-MS/MS, CLIA-based TT assessment significantly underestimated risk associations of TT with waist circumference (β: -- 0.54 vs -- 0.63), BMI (β: -- 0.19 vs -- 0.22), and serum glucose levels (β: -- 0.006 vs -- 0.008). Conclusion: In this comparative study, the CLIA platform showed a reasonable measurement error and yielded comparable risk associations, providing little support to measure TT concentrations in men from the general population exclusively by LC-MS/MS. [ABSTRACT FROM AUTHOR]

Background For the elderly, the association between waist circumference (WC) and mortality considering body mass index (BMI) remains unclear, and thereby also the evidence base for using these anthropometric measures in clinical practice. This meta-analysis examined the association between WC categories and (cause-specific) mortality within BMI categories. Furthermore, the association of continuous WC with lowest and increased mortality risks was examined.Methods Age- and smoking-adjusted relative risks (RRs) of mortality associated with WC–BMI categories and continuous WC (including WC and WC2) were calculated by the investigators and pooled by means of random-effects models.Results During a 5-year-follow-up of 32 678 men and 25 931 women, we ascertained 3318 and 1480 deaths, respectively. A large WC (men: &geq;102 cm, women: &geq;88 cm) was associated with increased all-cause mortality RRs for those in the ‘healthy’ weight {1.7 [95% confidence interval (CI): 1.2–2.2], 1.7 (95% CI: 1.3–2.3)}, overweight [1.1(95% CI: 1.0–1.3), 1.4 (95%: 1.1–1.7)] and obese [1.1 (95% CI: 1.0–1.3), 1.6 (95% CI: 1.3–1.9)] BMI category compared with the ‘healthy’ weight (20–24.9 kg/m2) and a small WC (<94 cm, men; <80 cm, women) category. Underweight was associated with highest all-cause mortality RRs in men [2.2 (95% CI: 1.8–2.8)] and women [2.3 (95% CI: 1.8–3.1]. We found a J-shaped association for continuous WC with all-cause, cardiovascular (CVD) and cancer, and a U-shaped association with respiratory disease mortality (P < 0.05). An all-cause (CVD) mortality RR of 2.0 was associated with a WC of 132 cm (123 cm) in men and 116 cm (105 cm) in women.Conclusions Our results showed increased mortality risks for elderly people with an increased WC—even across BMI categories— and for those who were classified as ‘underweight’ using BMI. The results provide a solid basis for re-evaluation of WC cut-points in ageing populations. [ABSTRACT FROM AUTHOR]

Aims: Although the association of low serum testosterone levels with mortality has gained strength in recent research, there are few population-based studies on this issue. This study examined whether low serum testosterone levels are a risk factor for all-cause or cause-specific mortality in a population-based sample of men aged 20–79. [ABSTRACT FROM PUBLISHER]

Objectives: There is current controversy on the association between subclinical hyperthyroidism and hypertension. Data from cohort studies have not been available yet. The present study was designed to longitudinally investigate possible associations of subclinical hyperthyroidism with blood pressure, pulse pressure and the risk of hypertension. Methods: We used data from the population-based, prospective cohort Study of Health in Pomerania and included 2910 subjects (1469 women) aged 20-79 years with completed 5-year examination follow-up. Subjects with increased serum TSH levels or overt hyperthyroidism were excluded. Serum TSH levels below 0.25 mIU/l with free triiodothyronine and free thyroxine levels within the reference range were defined as subclinical hyperthyroidism. Blood pressure was measured according to standard methods. Results: Multivariable analyses adjusted for age, sex, overweight, obesity, smoking status and time between the examinations did not reveal any statistically significant association between subclinical hyperthyroidism and any of the blood pressure-related variables in the whole study population. Although the 5-year hypertension incidence was higher in subjects with subclinical hyperthyroidism compared with those without (31.4 vs 19.2%; risk ratio 1.64; 95% confidence interval (CI) 1.17-2.28, P=0.006), both groups did not differ with respect to the risk of hypertension, after analyses were adjusted for confounders (relative risk 1.23, 95% CI 0.91-1.68, P=0.182). Analyses yielded similar results in subjects without thyroid disease and in those who took no antihypertensive medication. Conclusion: Subclinical hyperthyroidism is not associated with changes in blood pressure, pulse pressure or incident hypertension. [ABSTRACT FROM AUTHOR]