Research Report Serum betatrophin levels are increased and associated with insulin resistance in patients with polycystic ovary syndrome Journal of International Medical Research 2017, Vol 45(1) 193–202 ! The Author(s) 2017 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0300060516680441 journals.sagepub.com/home/imr Qinglan Qu1,*, Dongmei Zhao1,*, Fengrong Zhang1,*, Hongchu Bao1 and Qiuhua Yang2 Abstract Objective: Betatrophin is a newly identified circulating protein that is significantly associated with type diabetes mellitus (T2DM), adiposity, and metabolic syndrome The aim of this study was to investigate whether betatrophin levels and polycystic ovary syndrome (PCOS) were associated Methods: Circulating betatrophin levels were measured in 162 patients with PCOS and 156 matched control females using specific enzyme-linked immunosorbent assay kits Correlations between betatrophin levels and PCOS incidence as well as multiple key endocrine PCOS parameters were analyzed using multiple statistical methods Results: Betatrophin levels were significantly increased in patients with PCOS (685.3 Ỉ 27.7 vs 772.6 Ỉ 42.5 pg/ml) When sub-grouping all investigated subjects according to the presence of insulin resistance, women with PCOS and insulin resistance exhibited markedly higher betatrophin concentrations Furthermore, betatrophin levels were significantly correlated with fasting insulin levels and homeostatic model assessment of insulin resistance only in females with PCOS (r ¼ 0.531 and r ¼ 0.628, respectively) Conclusion: We provide the first report that betatrophin is strongly associated with PCOS This study suggests that betatrophin may potentially serve as an independent predictor for the development of PCOS in at-risk women, especially those with insulin resistance *These authors contributed equally to this work Department of Reproductive Medicine, Yantai Yuhuangding Hospital, Affiliated Hospital of Qingdao University, Yantai, Shandong, China Department of Obstetrics, Yantai Yuhuangding Hospital, Affiliated Hospital of Qingdao University, Yantai, Shandong, China Corresponding author: Hongchu Bao, Department of Reproductive Medicine, Yantai Yuhuangding Hospital, Affiliated Hospital of Qingdao University, 20 Yuhuangding East Rd, Yantai Shandong 264000, China Email: hongchubao@outlook.com Creative Commons CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us sagepub.com/en-us/nam/open-access-at-sage) 194 Journal of International Medical Research 45(1) Keywords Betatrophin, polycystic ovary syndrome, insulin resistance, type diabetes mellitus Date received: 23 August 2016; accepted: 27 October 2016 Introduction Polycystic ovary syndrome (PCOS) is the primary cause of anovulatory infertility1 and affects up to 10% of women of reproductive age.2 The exact pathophysiology of PCOS is complex and remains largely unclear However, the aetiology of PCOS is underpinned by both insulin resistance and hyperandrogenism, with insulin resistance exacerbating hyperandrogenism.3 Insulin resistance occurs in approximately 80% of women with PCOS and occurs independently of obesity.4 Furthermore, women with PCOS are believed to be at an increased risk of developing type diabetes mellitus (T2DM).5 A recent meta-analysis of 13 studies reported a 4-fold increased risk of T2DM in women with PCOS.6 Thus, PCOS is a well-defined clinical model of insulin resistance and the pre-diabetic state Betatrophin, also known as angiopoietinlike protein (ANGPTL8), is a newly identified circulating protein predominantly produced in the liver and adipose tissue Betatrophin is induced as a result of insulin resistance,7 therefore attracting increasing attention Betatrophin was reported to promote pancreatic beta cell proliferation and improve metabolic control by increasing the beta cell division rate in insulin resistant mice.7 However, in humans, the associations of serum betatrophin levels with diabetes, obesity, and lipid profiles remain controversial.8,9 Some studies have suggested that circulating betatrophin levels are elevated in T2DM as well as type diabetes,10–17 correlating with lipid profiles,18 while others reported that betatrophin levels were reduced in subjects with diabetes.19 Accumulating evidence suggests that betatrophin is significantly associated with adiposity, type diabetes, and the metabolic syndrome.17,18,20 To date, there have been no reports on the relationship between betatrophin and PCOS In fact, most women with PCOS display impaired glucose tolerance and are at higher risk for developing T2DM.21 Moreover, betatrophin has a close relationship with insulin resistance and T2DM.8,14,17 These observations raise the question of whether abnormal betatrophin might associate with PCOS Therefore, the present study aimed to detect circulating betatrophin levels in subjects with PCOS and healthy control female patients We also evaluated the association between betatrophin levels and clinical, hormonal, and metabolic variables to achieve a better understanding of the relationship between betatrophin and PCOS Patients and methods Study participants This case-control study was approved by the Institutional Ethical Review Board of Yantai Yuhuangding Hospital (H20130381) Written informed consent was obtained from all patients before the initiation of the study We included 162 women with a diagnosis of PCOS and 156 non-hirsute ovulatory women (regular cycles and luteal phase progesterone levels higher than 3.8 ng/mL), ranging from 18 to 45 years of age, in the study at our clinic between February 2013 and November 2015 PCOS diagnosis was determined according to the Rotterdam PCOS Qu et al Consensus criteria.22 Each subject underwent a complete medical examination and an endocrine profile and haematological, hepatic, and renal function analysis Women with body mass index (BMI) ranging from 18.0 to 40.0 kg/m2 were selected for the study We made further subgroupings based on the presence of insulin resistance, defined as a homeostatic model assessment (HOMA) index of !2.4.23 None of the women from either group had received any drugs known to interfere with hormone levels, blood pressure, or metabolic variables for at least months before the study Women with diabetes, liver or kidney disease, thyroid dysfunction, or pregnancy were excluded Biochemical and hormonal assays Blood samples were obtained during the midfollicular phase of the menstrual cycle after at least 12 hours of fasting Blood samples from all subjects were separated immediately by centrifugation at 4000 Â g for 10 and stored at À80 C until analysis Automated chemiluminescence immunoassay systems were used for measuring luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone (ADVIA Centaur, Siemens Healthcare Diagnostics, Eschborn, Germany), dehydroepiandrosterone sulfate, and sex hormone–binding globulin (SHBG) (Immulite 2000 XPi, Siemens Healthcare Diagnostics) The free androgen index (FAI) was estimated by dividing total testosterone (nmol/L) by SHBG (nmol/L) Â 100 Low-density lipoprotein cholesterol was estimated indirectly with the Friedewald formula.24 Total cholesterol, high-density lipoprotein cholesterol, triglyceride, and glucose levels were determined by colorimetric-enzymatic methods (Siemens Advia System, Deerfield, IL, USA) Intra- and inter-assay coefficient of variation values for these parameters were