The present study confirmed the previously reported increase in circulating OPG and decrease in ADPN in patients with T2DM versus health controls. We extended these data by showing inverse associations of OPG and cardiac function as well as aortic distensibility, whereas ADPN was positively related to cardiac metabolism.
These correlations were seen both in pooled analyses and the analyses of T2DM men separately, but not in the analyses of the controls alone.
Higher levels of OPG have documented in T2DM patients with asymptomatic coronary artery disease [28, 29], but at the same time also in experimental and clinical heart failure, even in the absence of ischemic cardiomyopathy. Similarly, in our population inducible ischemia was excluded. OPG has been associated with progression of atherosclerosis in symptomatic cardiovascular disease. For example, in a population based cohort, serum OPG was significantly associated with myocardial infarction, ischemic stroke, and total mortality . Although, some indicate a beneficial role of OPG [8, 31], the higher levels of OPG have been interpreted as a counter regulatory protective response to atherosclerosis. For instance, selective deletion of OPG in mice results in significant medial calcification of the aorta and renal arteries . Futhermore, Ueland et al.  showed enhanced systemic expression of RANKL and increased expression of the receptor RANK in cardiomyocytes, vascular smooth muscle cells and endothelial cells of the failing myocardium. OPG can act as a decoy receptor, binding to RANKL, preventing the interaction of RANK and RANKL. Thereby, OPG can potentially protect against the negative effects of RANKL. Besides, in patients with subclinical atherosclerosis serum OPG levels decreased linearly with increased calcification expressed as an increased echogenicity of the atherosclerotic plaques . In addition to LV diastolic function, in our study, plasma levels OPG were significantly associated with age and HbA1c in T2DM patients, showing close correlation between OPG and several cardiovascular risk factors, as demonstrated previously [10, 33]. This is the first study showing an inverse association between OPG levels and arterial- and LV diastolic function in asymptomatic T2DM patients in the absence of inducible myocardial ischemia. The multivariate analysis indicated that plasma OPG may contribute to the effect of aging and hyperglycemia on arterial- and LV diastolic function in T2DM. These results indicate a positive relationship between OPG and cardiovascular disease, instead of a protective role of OPG in cardiovascular disease.
The association between ADPN and systemic glucose metabolism has been documented before by others [12, 13]. In the present study, we found a positive association of ADPN and myocardial glucose metabolism, but not with cardiac function. This finding seems to be at odds with previous data, which have described an association of circulating levels of ADPN with parameters of cardiac structure and function in healthy adults , elderly  and patients with coronary artery disease and/or heart failure [36, 37]. In addition, in healthy subjects, circulating ADPN levels were inversely related to LV wall thickness and mass  and, in patients with coronary artery disease and/or heart failure, they were positively related to NT-proBNP and LV systolic dysfunction [36, 37]. In chronic heart failure, the paradoxical (positive) association of ADPN and cardiac function was ascribed to its role in wasting in cardiac cachexia . Differences in study population, and in methodology used to assess cardiac function and ADPN analysis, respectively, all could have accounted for the differential findings. Indeed, we studied men with well-controlled uncomplicated T2DM and with stress-echocardiography confirmed absence of inducible ischemia, whereas others included healthy adults , elderly  and patients with coronary artery disease and/or heart failure [36, 37].
Although in line with previous investigations, we have determined total circulating ADPN levels in our study, but other data suggest that high-molecular weight ADPN may have stronger associations with insulin resistance and coronary heart disease in T2DM patients .
Limitations of this study include the cross-sectional design, which precludes conferring a causal relationship between OPG, ADPN and the cardiac variables studied. Furthermore, the correlations of OPG with cardiac function and ADPN with myocardial glucose uptake were not observed in the healthy controls alone. This may be due to the relatively small number of a homogeneous control population.
In addition, the inclusion of only males with uncomplicated T2DM limits generalizations. On the other hand, a strength of this investigation is the use of state-of-the-art cardiac phenotyping methods in a relatively large group of well-characterized T2DM patients.