Plasma Omentin Levels Are Inversely Associated with Atherosclerosis In
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Nishimura et al. Cardiovasc Diabetol (2019) 18:167 https://doi.org/10.1186/s12933-019-0973-3 Cardiovascular Diabetology ORIGINAL INVESTIGATION Open Access Plasma omentin levels are inversely associated with atherosclerosis in type 2 diabetes patients with increased plasma adiponectin levels: a cross-sectional study Masami Nishimura1, Tomoaki Morioka1* , Mariko Hayashi1, Yoshinori Kakutani1, Yuko Yamazaki1, Masafumi Kurajoh1, Katsuhito Mori2, Shinya Fukumoto3, Atsushi Shioi4,5, Tetsuo Shoji4,5, Masaaki Inaba1,5 and Masanori Emoto1 Abstract Background: Omentin and adiponectin are among the anti-infammatory and anti-atherogenic adipokines that have potentially benefcial efects on cardiovascular disorders. Recent studies indicate a paradoxical relationship between adiponectin and cardiovascular mortality across many clinical settings including type 2 diabetes. In this study, we characterized the clinical features of type 2 diabetes patients with increased adiponectin levels and exam- ined the association between omentin and atherosclerosis in those patients. Methods: The subjects were 413 patients with type 2 diabetes. Fasting plasma omentin and total adiponectin levels were measured by enzyme-linked immunosorbent assay. The intima-media thickness (IMT) of the common carotid artery was measured by ultrasonography. The subjects were stratifed according to the median value of plasma adiponectin. Results: In high-adiponectin group, omentin levels were higher, while IMT tended to be greater than those in low- adiponectin group. The high-adiponectin group also exhibited older age, higher systolic blood pressure, lower kidney function, body mass index, and insulin resistance index compared to the low-adiponectin group. Multivariate analysis revealed that omentin levels were independently and negatively associated with IMT in high-adiponectin group, but not in low-adiponectin group, after adjusting for adiponectin levels and traditional cardiovascular risk factors. On the other hand, adiponectin levels were not signifcantly associated with IMT in either group. Conclusions: Plasma omentin levels are inversely associated with IMT in type 2 diabetes patients with increased adi- ponectin levels and multiple cardiovascular risk factors. This study suggests a protective role of omentin against athero- sclerosis in type 2 diabetes patients, which is potentially infuenced by adiponectin level and cardiovascular risk status. Keywords: Omentin, Adiponectin, Atherosclerosis, Intima-media thickness, Type 2 diabetes Background enhances insulin action in human adipocytes in vitro [2] Omentin, also referred as intelectin-1, was frst identi- and its circulating levels are decreased in individuals with fed as a galactofuranose-binding lectin [1], and is abun- obesity [3, 4] and/or patients with type 2 diabetes (T2D) dantly expressed in human omental adipose tissue [2]. It [3, 5, 6]. Omentin also has benefcial efects on cardiovas- cular system in mice through its actions on endothelial *Correspondence: [email protected] cells, smooth muscle cells, macrophages, and cardio- 1 Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, myocytes [7, 8]. In line with the experimental evidence, Abeno-ku, Osaka 545-8585, Japan decreased circulating omentin levels were observed in Full list of author information is available at the end of the article patients with coronary artery disease [9], peripheral © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Nishimura et al. Cardiovasc Diabetol (2019) 18:167 Page 2 of 10 artery disease [10], and established carotid atherosclero- recent study showed that omentin, but not adiponectin, sis [11] compared to those without. An inverse relation- was positively associated with vascular endothelial func- ship was also observed in recent clinical studies between tion in high CVD risk subgroups of T2D patients [16], circulating omentin levels and surrogate makers of car- suggesting a dominant role of omentin, rather than adi- diovascular risk, including arterial stifness [6], endothe- ponectin, against endothelial dysfunction in patients at lial dysfunction [12], carotid intima-media thickness high CVD risk status. In the present study, we hypothe- (IMT) [13, 14], and carotid plaque instability [15]. More sized that omentin plays an anti-atherogenic efect, while recently, we reported that plasma omentin levels were adiponectin levels are increased but lose its efect, against higher in T2D patients than healthy controls and were atherosclerosis in patients with high-risk status for positively associated with fow-mediated vasodilatation, a CVDs. To this end, we investigated the clinical features of marker of endothelial function, in high-risk subgroups of patients with T2D and increased plasma adiponectin lev- T2D patients with older age, reduced kidney function, or els, and the relationship between plasma omentin levels preexisting cardiovascular diseases (CVDs) [16]. Tose and carotid IMT in those patients. prior studies [6, 9–14], including ours [16], suggest a pro- tective role of human omentin on atherosclerotic CVDs. Methods Adiponectin is well-recognized as an anti-infamma- Study design and subjects tory adipocytokine which exerts benefcial actions on Tis was a single-center, cross-sectional study. We con- metabolic and cardiovascular disorders [8, 17, 18]. Pre- secutively enrolled 413 Japanese patients with T2D from vious reports consistently demonstrated that circulating our inpatients at the Diabetes Center of the Osaka City adiponectin levels were decreased in obesity, T2D, and University Hospital who required hospitalization for gly- coronary artery disease [8, 17, 18]. However, despite its cemic control, education, and/or evaluation of diabetic anti-infammatory and cardioprotective properties in cel- complications between January 2009 and July 2014. Te lular and animal models, a number of prospective human total sample size was estimated to be at least 360, so that studies have indicated a positive, rather than the expected as many as 12 explanatory factors could be included in negative, association between circulating adiponectin a multiple regression analysis model consisting of two levels and all-cause and cardiovascular mortality across subgroups. T2D was diagnosed based on the criteria of many clinical conditions including diabetes, CVDs, and American Diabetes Association [22] and Japan Diabetes chronic kidney disease [19, 20]. Regarding subclinical Society [23]. Patients with type 1 diabetes or other types atherosclerosis, conficting results were reported on the of diabetes were not included in this study. A smoker was association between hypoadiponectinemia and sever- defned as a current smoker or an ex-smoker. Preexisting ity of carotid IMT, especially in subjects with metabolic CVDs, including coronary artery disease, cerebrovascu- disorders or infammatory diseases [21]. Namely, most lar disease, or peripheral artery disease, were confrmed studies in relatively healthy subjects or subjects with wide by medical records. range of glucose tolerance signifcantly associated lower Tis study was performed in accordance with the adiponectin levels with greater IMT, while the majority Declaration of Helsinki (1975, as revised in 2013) and of studies in subjects with T2D alone failed to show a sig- the Ethical Guidelines for Medical and Health Research nifcant association between adiponectin and IMT [21]. Involving Human Subjects (Te Japanese Ministry of Tese clinical fndings collectively suggest that adiponec- Health, Labour and Welfare, 2014). Te study protocol tin fails to exert its protective efect against atheroscle- was approved by the ethics committee of the institution rotic CVDs in individuals with T2D. (Approval No. 3909). All study participants provided Both omentin and adiponectin are among the adi- written informed consent. pokines with anti-infammatory and cardioprotective efects in experimental models [8]. However, no prior Physical and laboratory measurements study has investigated a direct molecular link between Blood pressure was determined using an automatic omentin and adiponectin. Evidence from clinical studies sphygmomanometer (Terumo Co., Ltd., Tokyo, Japan) indicates that circulating omentin levels are increased, with a conventional cuf after the subjects had rested while adiponectin levels are decreased in proinfam- for at least 5 min. Blood was drawn after an overnight matory states such as type 1 diabetes, Crohn’s disease, fast and biochemical parameters were analyzed using and nonalcoholic fatty liver disease [7]. Te reciprocal a standard laboratory method at the Central Clinical regulation observed between omentin and adiponectin Laboratory of the Osaka City University Hospital [16]. may point towards a more important role of omentin Glycated hemoglobin A1c (HbA1c) was assessed as the as a regulator of infammatory process. In addition, our National Glycohemoglobin