Identification and clinical associations of three forms of circulating T-cadherin in human serum.

CONTEXT T-cadherin (T-cad) is a glycosylphosphatidylinositol (GPI)-anchored cadherin that mediates adiponectin to induce exosome biogenesis and secretion, protect cardiovascular tissues, promote muscle regeneration, and stimulate therapeutic heart protection by transplanted mesenchymal stem cells. CDH13, the gene locus of T-cad, affects plasma adiponectin levels most strongly, in addition to affecting cardiovascular disease risk and glucose homeostasis. Recently, it has been suggested that T-cad exists in human serum, although the details are still unclear. OBJECTIVE To validate the existence of T-cad forms in human serum and investigate the association with clinical parameters of type 2 diabetes patients. DESIGN AND SUBJECTS Using newly developed monoclonal antibodies against T-cad, pooled human serum was analyzed, and novel T-cad ELISAs were developed. The serum T-cad concentrations of 183 Japanese type 2 diabetes patients were measured in a cross-sectional observational study. MAIN OUTCOME MEASURES Existence of soluble T-cad in human serum. RESULTS There were three forms of soluble T-cad, a 130-kDa form with a prodomain, a 100-kDa mature form, and a 30-kDa prodomain in human serum. Using newly developed ELISAs to measure them simultaneously, we found that the 130-kDa form of T-cad positively correlated with plasma adiponectin (r=0.28, p<0.001), although a physiological interaction with adiponectin was not observed in serum. Of note, the unique 30-kDa prodomain was associated with several clinical parameters in diabetes patients. CONCLUSIONS We identified three novel forms of soluble T-cad. Their importance as disease markers and/or biomarkers of adiponectin function and the possible bioactivity of the respective molecules require further investigation.