The effect of exercise on osteoprotegerin and TNF-related apoptosis-inducing ligand in obese patients.

BACKGROUND: Biomarkers of cardiovascular (CV) risk are tests that predict a patient's risk of future CV events. Recently, two proteins involved in vascular calcification; serum levels of osteoprotegerin (OPG) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) have emerged as potentially useful biomarkers. OPG levels are positively correlated with CV risk, whereas TRAIL levels show a negative correlation. Exercise training is known to reduce risk factors for CV disease by improving metabolism, vascular biology and blood flow. This study examined the effects of a 6-month exercise training programme on levels of OPG and TRAIL. Pulse wave velocity (PWV) and high-sensitivity C-reactive protein (hsCRP) were measured for comparative purposes. MATERIALS AND METHODS: Overweight and obese patients undertook a 6-month exercise programme. Patients participated in 4 h of primarily aerobic exercise per week of which 2 h were supervised. At the beginning and end of the programme, anthropometric measurements, PWV and serum levels of OPG, TRAIL and hsCRP were measured. RESULTS: A total of 21 patients (17 men) aged 55.2 ± 10 years completed the programme. Mean body mass index decreased from 34.1 ± 5.8 to 32.6 ± 5.4 kg/m(2) (P<0.05), while waist circumference decreased from 111.8 ± 12.4 to 109.6 ± 12.8 cm (P<0.05). PWV decreased from 9.2 to 8.5 m/s (P<0.02). OPG, TRAIL and hsCRP levels did not change significantly. CONCLUSIONS: Exercise training reduced PWV but not OPG, TRAIL or hsCRP in this population. These data suggest that while an intervention of this nature improves vascular tone, it does not exert significant effects on serum biomarkers related to atherosclerotic inflammation and calcification.

Weight regulation and bone mass: a comparison between professional jockeys, elite amateur boxers, and age, gender and BMI matched controls.

The aim of this study was to compare bone mass between two groups of jockeys (flat: n = 14; national hunt: n = 16); boxers (n = 14) and age, gender and BMI matched controls (n = 14). All subjects underwent dual energy X-ray absorptiometry (DXA) scanning for assessment of bone mass, with measurements made of the total body, vertebra L2-4 and femoral neck. Body composition and the relative contribution of fat and lean mass were extrapolated from the results. Data were analysed in accordance with differences in body composition, in particular, height, lean mass, fat mass and age. Both jockey groups were shown to display lower bone mass than either the boxers or control group at a number of sites including total body bone mineral density (BMD) (1.019 ± 0.06 and 1.17 ± 1.05 vs. 1.26 ± 0.01 and 1.26 ± 0.06 g cm(-2) for flat, national hunt, boxer and control, respectively), total body bone mineral content (BMC) less head, L2-4 BMD and femoral neck BMD and BMC (p < 0.05). Regression analysis revealed that lean mass and height were the primary predictors of total body BMC, although additional group-specific influences were present which reduced bone mass in the flat jockey group and enhanced it in the boxers (R (2) = 0.814). Reduced bone mass in jockeys may be a consequence of reduced energy availability in response to chronic weight restriction and could have particular implications for these athletes in light of the high risk nature of the sport. In contrast, the high intensity, high impact training associated with boxing may have conveyed an osteogenic stimulus on these athletes.

Osteoprotegerin and biomarkers of vascular inflammation in type 2 diabetes.

BACKGROUND: Osteoprotegerin (OPG), receptor activator for nuclear factor kappa beta ligand (RANKL) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) are newly discovered members of the tumour necrosis factor-alpha receptor superfamily. While their role in bone metabolism is well described, their function within the vasculature is poorly understood. OPG inhibits vascular calcification in vitro and high serum levels have been demonstrated in type 2 diabetes, but serum RANKL and TRAIL and their potential correlation with well-established biomarkers of subclinical vascular inflammation such as high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) have not been described. METHODS: Sixty-two patients with well-controlled type 2 diabetes and an age, gender and body mass index-matched group of 58 healthy individuals were recruited. Serum OPG, RANKL and TRAIL were measured using commercial enzyme-linked immunosorbent assays, as were hsCRP and IL-6. RESULTS: Serum OPG, IL-6 and hsCRP levels, but not RANKL or TRAIL, were higher in patients with type 2 diabetes mellitus than in healthy controls, after adjustment for age and gender. After exclusion of diabetes patients with a history of micro- or macrovascular disease, OPG remained significantly higher in those with diabetes, but IL-6 and hsCRP levels were no longer elevated. There was a positive correlation between OPG and IL-6 in the group as a whole, but no correlation was found between RANKL or TRAIL and either hsCRP or IL-6. CONCLUSION: OPG, but not RANKL or TRAIL, is significantly increased in type 2 diabetes. Higher OPG (but not IL-6 or hsCRP) in those without vascular disease suggests these biomarkers reflect separate pathophysiological processes in the vasculature.

The Effects of Atorvastatin on Arterial Stiffness in Male Patients with Type 2 Diabetes.

Statin therapy improves lipid profiles and reduces vascular inflammation, but its effects on central arterial stiffness in type 2 diabetes are unclear. The aim of this study was to determine whether statin therapy reduces central arterial stiffness, in a dose-dependent manner, in male patients with type 2 diabetes. Fifty-one patients ceased statin therapy for 6 weeks, followed by randomisation to either 10 or 80 mg of atorvastatin. At randomization, 3 and 12 months, central arterial stiffness was measured via carotid-femoral pulse wave velocity (PWV), along with serum markers of vascular inflammation including high-sensitivity c-reactive protein (hsCRP) and osteoprotegerin (OPG). PWV decreased from 10.37 ± 1.30 to 9.68 ± 1.19 m/sec (p < 0.01 from baseline) at 3 months and 9.10 ± 1.17 m/sec (p < 0.001 from baseline) at 12 months. hsCRP and OPG decreased significantly at 3 and 12 months. Reductions in PWV did not differ significantly between the groups. Baseline PWV and OPG values correlated strongly (r = 0.48, p < 0.01), as did their response to atorvastatin over 12 months (r = 0.36 delta-OPG and delta-PWV, p < 0.01). Atorvastatin therapy appeared to reduce central arterial stiffness in male type 2 diabetes, with no dose-dependent effect observed. The correlation observed between reductions in PWV and OPG suggests that atorvastatin reduces PWV via direct anti-inflammatory effects on the vasculature.

The effects of insulin and liraglutide on osteoprotegerin and vascular calcification in vitro and in patients with type 2 diabetes.

OBJECTIVE: Vascular calcification (VC) is inhibited by the glycoprotein osteoprotegerin (OPG). It is unclear whether treatments for type 2 diabetes are capable of promoting or inhibiting VC. The present study examined the effects of insulin and liraglutide on i) the production of OPG and ii) the emergence of VC, both in vitro in human aortic smooth muscle cells (HASMCs) and in vivo in type 2 diabetes. DESIGN/METHODS: HASMCs were exposed to insulin glargine or liraglutide, after which OPG production, alkaline phosphatase (ALP) activity and levels of Runx2, ALP and bone sialoprotein (BSP) mRNA were measured. A prospective, nonrandomised human subject study was also conducted, in which OPG levels and coronary artery calcification (CAC) were measured in a type 2 diabetes population before and 16 months after the commencement of either insulin or liraglutide treatment and in a control group that took oral hypoglycemics only. RESULTS: Exposure to insulin glargine, but not liraglutide, was associated with significantly decreased OPG production (11 913±1409 pg/10(4) cells vs 282±13 pg/10(4) cells, control vs 10 nmol/l insulin, P<0.0001), increased ALP activity (0.82±0.06 IU/10(4) cells vs 2.40±0.16 IU/10(4) cells, control vs 10 nmol/l insulin, P<0.0001) and increased osteogenic gene expression by HASMCs. In the clinical study (n=101), insulin treatment was associated with a significant reduction in OPG levels and, despite not achieving full statistical significance, a trend towards increased CAC in patients. CONCLUSION: Exogenous insulin down-regulated OPG in vitro and in vivo and promoted VC in vitro. Although neither insulin nor liraglutide significantly affected CAC in the present pilot study, these data support the establishment of randomised trials to investigate medications and VC in diabetes.

A comparison of osteoprotegerin with adiponectin and high-sensitivity C-reactive protein (hsCRP) as a marker for insulin resistance.

OBJECTIVE: Insulin resistance (IR) is associated with low adiponectin and elevated high sensitivity C-reactive protein (hsCRP). Osteoprotegerin (OPG) has been shown to be elevated in type 2 diabetes, but whether it reflects underlying IR is unclear. We aimed to compare the ability of serum OPG with adiponectin and hsCRP to act as a marker for IR in individuals with normal and abnormal glucose tolerance. MATERIALS/METHODS: 115 men underwent a 75 g oral glucose tolerance test. OPG, hsCRP and adiponectin were measured using ELISA. IR was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: Men with abnormal glucose tolerance (n=38) were older (58.3±11.2 vs 47.3±11.4 years, P<.001), had higher body mass index (BMI) (31.1±2.9 vs 27.9±3.2 kg/m(2), P<.001) and were more insulin resistant (median (I.Q.) HOMA-IR 5.88 (3.38) vs 1.13 (1.14), P<.001) than those with normal glucose tolerance (n=77). After adjustment for age and BMI, OPG (6.28 (2.32) vs 5.16 (1.86) pmol/L, P<.001) and hsCRP (2.07 (5.47) vs 0.78 (1.05) mg/L, P<.001) were higher and adiponectin (3.02±1.17 vs 4.78±2.38 µg/mL, P<.001) was lower in those with AGT. After adjustment for age and BMI, adiponectin (r=-0.317, P<.001) and hsCRP (r=0.318, P<.001), but not OPG (r=0.126, P=.196) correlated with HOMA-IR. On multiple linear regression analysis, adiponectin and hsCRP but not OPG were independent predictors of HOMA-IR. CONCLUSIONS: OPG is higher in individuals with abnormal glucose tolerance, but unlike adiponectin and hsCRP, does not correlate with HOMA-IR, suggesting its elevation within this cohort of individuals is due to factors other than insulin resistance.

Identifying coronary artery disease in men with type 2 diabetes: osteoprotegerin, pulse wave velocity, and other biomarkers of cardiovascular risk.

OBJECTIVES: In patients with type 2 diabetes, high serum levels of osteoprotegerin (OPG) have been associated with a greater risk of cardiovascular events. However, it remains unclear how well OPG performs when compared with traditional biomarkers of cardiovascular risk such as high-sensitivity C-reactive protein (hsCRP). Furthermore, OPG levels are also high in the presence of diabetes-related microvascular disease, and it is unclear whether OPG can distinguish microvascular disease from large-vessel atherosclerosis. The first aim of this study was to compare OPG levels against other biomarkers of cardiovascular risk in the identification of patients with documented multivessel coronary artery disease (CAD). The second aim was to compare OPG levels in patients with microvascular complications (microalbuminuria) against those with established CAD. METHODS: Three groups of male patients with type 2 diabetes were recruited: patients without microvascular complications or large-vessel atherosclerosis (n = 24), patients with microalbuminuria only (n = 23), and patients with microalbuminuria and documented multivessel CAD (n = 25). OPG, hsCRP, interleukin 6, urate, and pulse wave velocity were measured. RESULTS: Serum OPG levels were significantly higher in patients with a combination of microalbuminuria and CAD than in those with microalbuminuria alone. There were no significant differences in any of the other biomarkers between the groups. CONCLUSION: OPG was found to be superior to the other biomarkers studied in identifying patients with documented CAD. The presence of CAD was a greater determinant of serum OPG levels than microalbuminuria in our population. These findings support the use of OPG as a biomarker of cardiovascular risk.

Similar to adiponectin, serum levels of osteoprotegerin are associated with obesity in healthy subjects.

An increase in serum osteoprotegerin (OPG) is associated with type 2 diabetes mellitus, the severity of vascular calcification, and coronary artery disease. Obesity is a risk factor for diabetes and cardiovascular disease, but little is known about the relationship between OPG and obesity. The purpose of this study was to determine if changes in body mass index (BMI) and insulin sensitivity influence circulating OPG in healthy subjects. A total of 100 subjects (36 lean, 41 overweight, and 23 obese) with normal glucose tolerance, blood pressure, and electrocardiogram stress test result volunteered for this study. Insulin sensitivity was estimated using a 2-hour oral glucose tolerance test with oral glucose insulin sensitivity analysis. Osteoprotegerin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL),soluble receptor activator of nuclear factor-κß ligand (sRANKL), and adiponectin were analyzed using commercially available enzyme-linked immunosorbent assays. Osteoprotegerin (P < .01) and adiponectin (P < .001) were significantly decreased in the obese compared with lean subjects. There was no significant difference between BMI categories for TRAIL or sRANKL. Controlling for age and sex, there was a significant correlation between OPG and adiponectin (r = 0.391, P < .001), BMI (r = -0.331, P < .001), waist circumference (r = -0.268, P < .01), homeostasis model assessment of insulin resistance (r = -0.222, P < .05), and oral glucose insulin sensitivity (r = 0.221, P < .05). Both OPG and adiponectin were negatively correlated with body weight, BMI, waist circumference, and fasting plasma insulin while being positively correlated with insulin sensitivity (P < .05). Controlling for age, sex, and BMI, TRAIL was positively related to fat mass (r = 0.373, P < .001) and waist circumference (r = 0.257, P < .05). In contrast to patients with type 2 diabetes mellitus, circulating OPG is lower in obese, but otherwise healthy subjects and is positively correlated with indices of insulin sensitivity.

Osteoprotegerin is higher in peripheral arterial disease regardless of glycaemic status.

INTRODUCTION: Peripheral arterial disease (PAD) and type 2 diabetes mellitus (DM) are both associated with excessive vascular calcification and elevated levels of inflammatory markers IL-6 and hsCRP. The recently identified Osteoprotegerin(OPG)/RANKL/TRAIL pathway has been implicated in vascular calcification, but data on levels in PAD and effect of co-existent DM are lacking. MATERIALS AND METHODS: 4 groups of patients were recruited - 26 with PAD and DM, 35 with DM alone, 22 with PAD alone, and 21 healthy individuals. Serum OPG, RANKL, TRAIL, hsCRP and IL-6 were measured using commercial ELISA assays. Presence and severity of PAD was defined using ankle brachial index (ABI). RESULTS: Serum OPG (7.4±0.3 vs.5.8±0.2 pmol/l, p<0.0001), TRAIL (95.5±5.2 ng/ml vs. 76.2±4.4 ng/ml, p=0.006), hsCRP (2.6±0.3 vs. 1.8±0.3 mg/l, p=0.048), and IL-6 (4.1±0.4 vs. 2.9±0.4 pg/ml, p=0.06) were higher in patients with PAD. There was no difference in RANKL. Only OPG was significantly higher in PAD and DM (7.2±0.3 pmol/l) and PAD alone (7.7±0.4 pmol/l) compared to DM only (5.8±0.3 pmol/l) and healthy controls (5.6±0.4 pmol/l), p<0.01, but OPG was no higher in those with DM plus PAD versus those with PAD alone (p<0.3). Only OPG was associated with PAD severity, correlating negatively with ABI (r=-0.26, p=0.03), independent of age, gender, glycaemic status, hsCRP and IL-6. CONCLUSIONS: PAD is associated with higher serum OPG, regardless of the co-existence of DM. This finding, in addition to its correlation with severity of PAD, suggests that OPG may be a novel marker for the presence and severity of PAD, possibly by reflecting the degree of underlying vascular calcification.