Clinical ScienceHigh serum C1q-adiponectin/total adiponectin ratio correlates with coronary artery disease in Japanese type 2 diabetics
Introduction
Adiponectin is an adipocyte-derived plasma protein [1] present abundantly in injured arteries [2], [3] and atherosclerotic lesions [4]. It has anti-atherogenic and insulin-sensitizing properties [5]. Previous studies demonstrated a close relationship between low circulating levels of total-adiponectin (Total-APN, i.e., hypoadiponectinemia, < 4 μg/mL) and type 2 diabetes mellitus (T2DM) [6] and coronary artery disease (CAD) [7], [8], [9], [10]. Adiponectin circulates in blood mainly in three forms: trimer, hexamer, and high-molecular weight (HMW) form [11]. However, the main form of blood adiponectin remains to be elucidated. We recently reported that adiponectin forms a protein-complex with C1q in human blood, and introduced measurement of human serum C1q-binding adiponectin (C1q-APN), and serum C1q-APN/Total-APN ratio as a novel marker of the metabolic syndrome [12]. We also reported recently that serum C1q-APN/Total-APN ratio correlates with polyvascular lesions detected by vascular ultrasonography [13]. The activated complement system plays a role in atherosclerosis [14], [15], [16], [17]. These results suggest that adiponectin may have a protective role in activated complement system in the development of atherosclerosis. What proportion of tissue damage-defensive adiponectin forms protein complex with tissue damage-offensive C1q remains unclear. Analysis of this adiponectin complex, in addition to Total-APN, is likely to enhance our understanding of the pathogenesis of CAD.
The aim of the present study was to determine the role of serum C1q-APN in the pathogenesis of CAD in T2DM patients.
Section snippets
Participants
The study (ADMIT study; UMIN 000002271) subjects were 107 consecutive Japanese patients with T2DM, who visited the outpatient clinic of “Diabetes & Metabolic Station”, Osaka University Hospital, between September 2009 and September 2011. Patients treated with pioglitazone, which is known to increase serum levels of Total-APN and C1q-APN in T2DM [18], [19] and those with renal dysfunction [estimated glomerular filtration rate (eGFR) < 30 mL/min] [20] were excluded from the study. The Medical
Characteristics of T2DM patients
Table 1 summarizes the characteristics of the study subjects. C1q-APN correlated significantly and positively with Total-APN in all, males and females (Fig. 1A). There was no significant correlation between C1q-APN and C1q in all, males and females (Fig. 1B). C1q-APN correlated significantly and negatively with Total-APN in all and females, but not in males (Fig. 1C). C1q-APN/Total-APN correlated significantly and negatively with Total-APN in all, males and females (Fig. 1D). There were no
Discussion
The major finding of the present study was that high serum C1q-APN/Total-APN ratio, but not C1q-APN, correlates with CAD, in T2DM patients. High serum C1q-APN/Total-APN ratio was associated with 4-fold increase in CAD prevalence, independent of other CAD risk factors. Thus, high serum C1q-APN/Total-APN ratio (≥ 13.5) can be considered an important risk factor for CAD, in addition to low serum levels of Total-APN (< 4 μg/mL), hypoadiponectinemia, in T2DM.
A proposed relative cutoff value from the
Author contributions
AH and KK researched and analyzed the data. KK also participated in the concept and design of the study, interpretation of data and reviewed/edited the manuscript. HK analyzed the data. HN recruited the patients and collected the data. TF and IS contributed to the discussion and wrote the manuscript. All authors read and approved the final version of the manuscript.
Funding
This research was supported in part by a Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area) "Molecular Basis and Disorders of Control of Appetite and Fat Accumulation" (#22126008, to T.F. and K.K.), and Osaka University's academia–industry collaboration policy position between Osaka University and Otsuka Pharmaceutical Co., Ltd.
Conflict of interests
KK, TF and IS are promotional speakers for Otsuka Pharmaceutical Co., Ltd. TF is a member of the “Department of Metabolism and Atherosclerosis”, a sponsored course endowed by Kowa Co. Ltd.. The company has a scientific officer who oversees the program. All other authors declare no competing interests. Human serum C1q-binding adiponectin complex assay is under patent application in Japan.
Acknowledgments
We thank all staff of the “Diabetes & Metabolic Station” for the excellent medical care, and Messrs Shigeo Takahashi, Suguru Akamatsu, and Tetsuya Oda for the statistical advice and helpful discussion, and Messrs Hideaki Tanaka and Tohru Hadama and Mrs. Miyuki Nakamura for the excellent technical assistance.
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