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Predictive Values of ANGPTL8 on Risk of All Zou et al. Cardiovasc Diabetol (2020) 19:121 https://doi.org/10.1186/s12933-020-01103-7 Cardiovascular Diabetology ORIGINAL INVESTIGATION Open Access Predictive values of ANGPTL8 on risk of all-cause mortality in diabetic patients: results from the REACTION Study Huajie Zou1, Yongping Xu1, Xi Chen1, Ping Yin2, Danpei Li1, Wenjun Li3, Junhui Xie1, Shiying Shao1, Liegang Liu4,5 and Xuefeng Yu1* Abstract Background: Angiopoietin-like protein 8 (ANGPTL8), an important regulator of lipid metabolism, is increased in diabetes and is associated with insulin resistance. However, the role of ANGPTL8 in the outcomes of diabetic patients remains unclear. This study aimed to investigate circulating levels of ANGPTL8 in participants with and without diabe- tes and its potential associations with clinical outcomes in a 5 year cohort study. Methods: Propensity-matched cohorts of subjects with and without diabetes from the Risk Evaluation of Cancers in Chinese Diabetic Individuals: A longitudinal (REACTION) study were generated on the basis of age, sex and body mass index at baseline. The primary outcome was all-cause mortality. The secondary outcomes were a composite of new-onset major adverse cardiovascular events, hospitalization for heart failure, and renal dysfunction (eGFR < 60/ min/1.73 m2). Results: We identifed 769 matched pairs of diabetic patients and control subjects. Serum ANGPTL8 levels were elevated in patients with diabetes compared to control subjects (618.82 ± 318.08 vs 581.20 ± 299.54 pg/mL, p 0.03). Binary logistic regression analysis showed that elevated ANGPTL8 levels were associated with greater risk ratios= (RRs) of death (RR in quartile 4 vs. quartile 1, 3.54; 95% CI 1.32–9.50) and renal dysfunction (RR in quartile 4 vs. quartile 1, 12.43; 95% CI 1.48–104.81) only in diabetic patients. Multivariable-adjusted restricted cubic spline analy- ses revealed a signifcant, linear relationship between ANGPTL8 and all-cause mortality in diabetic patients (p for nonlinear trend 0.99, p for linear trend 0.01) but not in control subjects (p for nonlinear trend 0.26, p for linear trend 0.80). According= to ROC curve analysis,= the inclusion of ANGPTL8 in QFrailty score signifcantly= improved its predictive= performance for mortality in patients with diabetes. Conclusion: Serum ANGPTL8 levels were associated with an increased risk of all-cause mortality and could be used as a potential biomarker for the prediction of death in patients with diabetes. Keywords: ANGPTL8, Diabetes, Mortality, CVD Background Diabetes is the fastest increasing disease worldwide and is a substantial threat to human health [1]. Among *Correspondence: [email protected] adults in China, diabetes was associated with twofold 1 Division of Endocrinology, Department of Internal Medicine, Tongji increased mortality compared with adults without Hospital, Tongji Medical College, Huazhong University of Science diabetes [2]. Patients with diabetes are at high risk for and Technology, 1095 Jiefang Avenue, Wuhan 430030, China Full list of author information is available at the end of the article adverse outcomes from cardiovascular disease (CVD) © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zou et al. Cardiovasc Diabetol (2020) 19:121 Page 2 of 10 [3], heart failure (HF) [4] and renal disease [5]. Diabetes Materials and methods and its macrovascular and microvascular complications Study design and population account for more than 2 million deaths every year [6] Te present study participants were recruited from and constitute the seventh most common cause of dis- Hubei Province, China, from 2011 to 2012 as part of ability worldwide [7]. Te role of dyslipidaemia in the the Risk Evaluation of Cancer in Chinese Diabetic Indi- progression of the macrovascular and microvascular viduals: a longitudinal (REACTION) study, which was complications of diabetes has long been known [8, 9]. conducted among 259,657 adults aged 40 years old and Angiopoietin-like protein 8 (ANGPTL8), also known older in 25 communities across mainland China during as betatrophin, TD26, “refeeding induced in fat and 2011–2012 (baseline) and which invited participants to liver” (RIFL), lipasin, and PRO1185, is a protein primar- attend follow-up visits during 2014–2016 [34–37]. At ily produced in the liver and adipose tissue and it plays baseline, a comprehensive set of questionnaires, clini- an important role in triglyceride (TG) metabolism [10]. cal measurements, oral glucose tolerance tests (OGTTs), ANGPTL8, together with ANGPTL3 and ANGPTL4, and laboratory examinations were conducted in all could regulate TG metabolism by inhibiting the activ- of the participants following standardized protocols. ity of lipoprotein lipase (LPL) and subsequently elevat- Te diagnosis of diabetes was based on the American ing serum TG since LPL is an enzyme for TG hydrolysis Diabetes Association 2014 criteria [38]. Diabetes was and plasma TG clearance [11–13]. Tese studies indi- defned as fasting plasma glucose (FPG) concentration of cated that ANGPTL8 is involved in lipid metabolism 7.0 mmol/L or more, 2 h plasma glucose concentration and the pathogenesis of atherosclerosis. ANGPTL8 lev- (2 h PG) of 11.1 mmol/L or more, glycated haemoglobin els were increased in diabetes [14–16], dyslipidaemia A1c (HbA1c) of 6.5% or more, or a self-reported previ- [17, 18], CVD [19], renal function [20–22], obesity [23], ous diagnosis of diabetes by health-care professionals. hypertension [24], and nonalcoholic fatty liver [25]. Te duration of pre-existing diabetes was counted from Furthermore, studies have revealed that ANGPTL8 the date of diagnosis, and the duration of newly diag- levels also increased with age [26, 27], suggesting its nosed diabetes was counted as 0. Propensity scores were potential association with aging and with age-related used to match subjects in the diabetic and control group metabolic diseases. (in a 1:1 ratio) with callipers of 0.05 using prespecifed Frailty, a state characterized by reduced physiologi- clinical variables, including age, sex and body mass index cal reserve and loss of resistance to stressors caused (BMI). Participants were excluded from the analysis if by accumulated age-related defcits, is a major health they had missing data for measures of glucose tolerance concern associated with aging [3, 4]. Te importance status at baseline or follow-up visits. Te Committee on of frailty is highlighted by its consistent association Human Research at Tongji Hospital, Tongji Medical Col- with all-cause mortality and adverse outcomes, such lege, Huazhong University of Science and Technology, as institutionalization, physical limitations, disability, approved the study protocol, and all of the participants recurrent hospitalizations, falls and fractures [28, 29]. provided written informed consent. All of the methods Te frailty index (FI) is a well-established predictor of were performed in accordance with the relevant guide- all-cause mortality [30] and other adverse health out- lines and regulations. comes in older adults [31]. Te FI has been used in many health services to assess hospital-acquired com- Study outcomes plications, worsening health, and loss of independence Te primary outcome was death from all causes. Te sec- [4–9], as well as conditions such as cognitive impair- ondary outcomes were a composite of new-onset major ment [10], heart disease [11], osteoporosis [12], intel- adverse cardiovascular events (MACE), hospitalization lectual disability [13], and systemic sclerosis [14]. It for HF and renal dysfunction. MACE were defned as is also used in epidemiological and clinical studies to cardiovascular death, myocardial infarction, or ischaemic grade the degree of risk of several adverse outcomes, stroke [39]. Renal dysfunction was defned as a glomeru- including mortality [32]. Hippisley-Cox et al. developed lar fltration rate (eGFR) less than 60 mL per minute per the FI as the QFrailty score and included further key 1.73 m2 of body-surface area and new end-stage renal determinants of death [33]. In this work, we retrospec- disease. All of these outcomes were confrmed by death tively investigated circulating levels of ANGPTL8 in certifcates and hospital records. participants with and without diabetes and its potential associations with death and cardiovascular and renal Clinical and biochemical evaluation outcomes in a 5 year cohort study. Furthermore, we Data were collected from local community clin- evaluated the predictive value of QFrailty score in con- ics at baseline and follow-up visits. As previously junction with the ANGPTL8 in the prediction of death. described in the REACTION study [37], information on Zou et al. Cardiovasc Diabetol (2020) 19:121 Page 3 of 10 sociodemographic characteristics, lifestyle factors, medi- and Stata software (version 12.0) were used for all of the cal history and family history was collected by trained analyses. staf using a standard questionnaire. All of the partici- pants were asked to fast for at least 10 h to undergo the Results OGTT and blood sampling for the analysis of various Baseline characteristics biochemical parameters.
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