Tryptophan Predicts the Risk for Future Type 2 Diabetes

RESEARCH ARTICLE Tryptophan Predicts the Risk for Future Type 2 Diabetes Tianlu Chen1, Xiaojiao Zheng1, Xiaojing Ma2, Yuqian Bao2, Yan Ni3, Cheng Hu2, Cynthia Rajani3, Fengjie Huang1, Aihua Zhao1, Weiping Jia1,2*, Wei Jia1,3* 1 Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China, 2 Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai Diabetes Institute, Shanghai, China, 3 University of Hawaii Cancer Center, Honolulu, United States of America * (WJ); (WPJ) a11111 OPEN ACCESS Citation: Chen T, Zheng X, Ma X, Bao Y, Ni Y, Hu C, et al. (2016) Tryptophan Predicts the Risk for Future Type 2 Diabetes. PLoS ONE 11(9): e0162192. doi:10.1371/journal.pone.0162192 Editor: Gilles J. Guillemin, Macquarie University, AUSTRALIA Received: May 3, 2016 Accepted: August 18, 2016 Published: September 6, 2016 Copyright: © 2016 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Recently, 5 amino acids were identified and verified as important metabolites highly associated with type 2 diabetes (T2D) development. This report aims to assess the association of tryptophan with the development of T2D and to evaluate its performance with existing amino acid markers. A total of 213 participants selected from a ten-year longitudinal Shanghai Diabetes Study (SHDS) were examined in two ways: 1) 51 subjects who developed diabetes and 162 individuals who remained metabolically healthy in 10 years; 2) the same 51 future diabetes and 23 strictly matched ones selected from the 162 healthy individuals. Baseline fasting serum tryptophan concentrations were quantitatively measured using ultra-performance liquid chromatography triple quadruple mass spectrometry. First, serum tryptophan level was found significantly higher in future T2D and was positively and independently associated with diabetes onset risk. Patients with higher tryptophan level tended to present higher degree of insulin resistance and secretion, triglyceride and blood pressure. Second, the prediction potential of tryptophan is non-inferior to the 5 existing amino acids. The predictive performance of the combined score improved after taking tryptophan into account. Our findings unveiled the potential of tryptophan as a new marker associated with diabetes risk in Chinese populations. The addition of tryptophan provided complementary value to the existing amino acid predictors. Data Availability Statement: Data are provided for download, without restriction, as Supporting Information files. Funding: This work was supported by International Science & Technology Cooperation Program of China (2014DFA31870, http://www.most.gov.cn/kjjh/xmsb/) and Major State Basic Research Development Program (2011CB504001,http://www.most.gov.cn/ eng/programmes1/200610/t20061009_36223.htm). Competing Interests: The authors have declared that no competing interests exist. Introduction Type 2 diabetes (T2D) is estimated to affect over 550 million people worldwide by 2030 [1]. T2D will further increase the risk of developing hypertension, cardiovascular disease, coronary heart disease, stroke, and several types of cancers. When T2D and/or any of the consequent metabolic diseases are diagnosed, the pathophysiological status would be extremely difficult to reverse. Therefore, the identification of future type 2 diabetes is crucial for disease prevention and early intervention. PLOS ONE | DOI:10.1371/journal.pone.0162192 September 6, 2016 1 / 12 Tryptophan and T2D Risk It is commonly accepted that T2D is characterized by altered metabolic status[2, 3]. Some metabolites specific to T2D risk[4–6], diagnosis[7], and treatment assessment[8, 9] are reported in various populations. Recently, a number of studies have highlighted that the serum levels of branched-chain and aromatic amino acids, including leucine, isoleucine, valine, phenylalanine, and tyrosine, are closely correlated to insulin resistance, obesity, and future diabetes[4, 5, 10]. We also verified the T2D predictive value of these five amino acids (AAs) in Chinese populations [11]. Tryptophan, an aromatic amino acid metabolite, has expansive physiological functions in the regulation of growth and feed intake, mood and behavior, and immune responses[12, 13]. It is one of the essential amino acids for the human. However, the human body cannot synthesize it and thus it must be obtained from the diet (plants and bacteria). Our metabolic profiling study found that circulating tryptophan level rose in obese participants compared with healthy lean [14] and fell after dietary intervention[15]. Thus, the main goal of this report is to assess whether tryptophan is associated with the development of T2D. A total of 213 participants from a ten-year prospective study were involved in this work. Their baseline fasting serum tryptophan levels were quantitatively measured by a targeted ultra-performance liquid chromatography triple quadruple mass spectrometry (UPLC-TQ/MS) platform. The high risk individuals discrimination potential of tryptophan were examined in all (n = 213) and verified in strictly matched (n = 74) subjects. Its predictive performance was further compared to the other established amino acid markers. Materials and Methods Written informed consent was obtained from all participants before the start of the study. The Ethics Committee of our institution approved the study, in accordance with the World Medical Association’s Declaration of Helsinki. Study Population A group of 213 healthy individuals (20–75 year-old) with normal glucose tolerance was selected from a prospective cohort study called Shanghai Diabetes Study (SHDS)[16]. The SHDS started in 1997–2001, where fasting and 2 h postprandial serum and plasma of all the participants from two urban communities in Shanghai were collected and stored. After a median follow-up time of 10.0 years (SD = 3.1), 51 individuals (43% male) developed diabetes and 162 (27% male) remained free of type 2 diabetes. Twenty-three of the 162 healthy subjects were selected further with strictly matched age, BMI, cholesterol, triglyceride, glucose and insulin levels to future T2D. The diagnosis criteria of T2D was based on the 1999 WHO criteria: fasting plasma glucose  7.0mmol/l and/or 2 h plasma glucose  11.1mmol/l[17]. Sample Collection Serum samples were collected and stored following the standard operation protocol of Sixth People’s Hospital of Shanghai, China. Briefly, fasting venous blood samples were centrifuged immediately after collection from the subjects in the morning, and the resulting serum were delivered by dry ice storage boxes to the laboratory study and stored in aliquots (...truncated)