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 mu g/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. (C) 2013 Elsevier Inc. All rights reserved.

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–κβ 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.

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.

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. Copyright (C) 2010 John Wiley & Sons, Ltd.