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©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
Heterogeneously elevated branched-chain/aromatic amino acids among new-onset type-2 diabetes mellitus patients are potentially skewed diabetes predictors
Min Wang, Yang Ou, Xiang-Lian Yuan, Xiu-Fang Zhu, Ben Niu, Zhuang Kang, Bing Zhang, Anwar Ahmed, Guo-Qiang Xing, Heng Su
Min Wang, Xiu-Fang Zhu, School of Chemical Science and Technology, Yunnan University, Kunming 650091, Yunnan Province, China
Yang Ou, Xiang-Lian Yuan, Ben Niu, Zhuang Kang, Heng Su, Department of Endocrinology, The First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China
Bing Zhang, Clinical Laboratory, Nanchong Central Hospital & The Second Clinical Medical College of North Sichuan Medical University, Nanchong 637000, Sichuan Province, China
Anwar Ahmed, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, United States
Guo-Qiang Xing, The Affiliated Hospital and Second Clinical Medical College, North Sichuan Medical University, Nanchong 637000, Sichuan Province, China
Guo-Qiang Xing, Department of Research and Development, Lotus Biotech.com LLC, Gaithersburg, MD 20878, United States
Co-first authors: Min Wang and Yang Ou.
Co-corresponding authors: Guo-Qiang Xing and Heng Su.
Author contributions: Wang M, Xing GQ and Su H conceptualized and designed the research; Ou Y, Niu B and Kang Z screened patients and acquired clinical data; Wang M, Yuan XL, Zhang B and Zhu XF collected blood specimen and performed laboratory analysis; Wang M, Ahmed A, Yuan XL and Xing GQ performed Data analysis; Wang M, Su H and Xing GQ wrote the paper. All the authors have read and approved the final manuscript. Wang M proposed, designed and conducted serum amino acids analysis, performed data analysis and prepared the first draft of the manuscript. Ou Y was responsible for patient screening, enrollment, collection of clinical data and blood specimens. Both authors have made crucial and indispensable contributions towards the completion of the project and thus qualified as the co-first authors of the paper. Both Su H and Xing GQ have played important and indispensable roles in the experimental design, data interpretation and manuscript preparation as the co-corresponding authors. Su H applied for and obtained the funds for this research project. Su H conceptualized, designed, and supervised the whole process of the project. He searched the literature, revised and submitted the early version of the manuscript with the focus on the association between visceral adipose tissue (VAT) and BCAA/AAA. Xing GQ was instrumental and responsible for data re-analysis and re-interpretation, figure plotting, comprehensive literature search, preparation and submission of the current version of the manuscript with a new focus on BCAAs/AAAs as the predictors of diabetes and on potential underlying mechanisms. This collaboration between Su H and Xing GQ is crucial for the publication of this manuscript and other manuscripts still in preparation.
Supported by the Open Project Grant for Clinical Medical Center of Yunnan Province, No. 2019LCZXKF-NM03; Medical Leader Training Grant, No. L-201624; and Yunnan Province Ten Thousand Talents: “Medical Expert” grant, No. YNWR-MY-2019-020.
Institutional review board statement: The study was reviewed and approved by the Medical Ethics Review Committee of the First People's Hospital of Yunnan Province [Approval No. 2016(001)].
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: All authors declare no potential conflicts of interest.
Data sharing statement: Data are available from the corresponding authors upon reasonable request.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work noncommercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See:
https://creativecommons.org/Licenses/bync/4.0/ Corresponding author: Heng Su, MD, PhD, Professor, Department of Endocrinology, the First People’s Hospital of Yunnan Province, No. 157 Jinbi Road, Kunming 650032, Yunnan Province, China. su_hen@hotmail.com
Received: September 13, 2023
Peer-review started: September 13, 2023
First decision: October 24, 2023
Revised: November 3, 2023
Accepted: December 13, 2023
Article in press: December 13, 2023
Published online: January 15, 2024
Processing time: 120 Days and 17.9 Hours
ARTICLE HIGHLIGHTS
Research background
Type-2 diabetes mellitus (T2DM) is a major cause of comorbidity and mortality in society and was responsible for more than 4.2 million annual deaths in 2019 alone. The current world population of T2DM (approximately 450 million) is expected to double to 1 billion soon after 2050. This T2DM pandemic, however, can be curbed or prevented if the population at risk of T2DM can be identified and prophylactic actions be taken long before the onset of T2DM.
Research motivation
Research over the past decades has indicated that elevated branched-chain amino acids (BCAAs: Isoleucine, leucine, valine) and aromatic amino acids (AAAs: Tyrosine, tryptophan, phenylalanine) show high sensitivity and specificity (both > 97%) in predicting diabetes in animals and can successfully predict T2DM nearly 20 years before T2DM onset in select human populations. However, these findings have not been widely translated into clinical utilization due to unidentified factors.
Research objectives
We hypothesized that body weight and sex are potential confounding factors that could affect BCAAs/AAAs as general T2DM predictors. As the first step, the aim of our study was to determine the effects of body weight and sex on BCAAs/AAAs in new-onset T2DM individuals.
Research methods
Fasting blood samples were collected from 97 new-onset T2DM patients (53 male/44 female, 43.3 ± 11.2 years of age, differing in body mass index (BMI): Normal weight (NW), n = 33, BMI = 22.23 ± 1.60; overweight, n = 42, BMI = 25.9 ± 1.07; and obesity, n = 22, BMI = 31.23 ± 2.31). All T2DM cases were diagnosed within 12 mo at the First People's Hospital of Yunnan Province, Kunming, China. Serum amino acids were analyzed using ultra-performance liquid chromatography/triple stage quadrupole mass spectrometry.
Research results
Fasting serum AAAs, BCAAs, glutamate, and alanine levels were significantly greater and high-density lipoprotein levels were significantly lower in obese T2DM patients than in NW-T2DM patients, especially among male patients. Arginine, histidine, leucine, methionine, and lysine were greater in male patients than in female patients. Moreover, histidine, alanine, glutamate, lysine, valine, methionine, leucine, isoleucine, tyrosine, phenylalanine, and tryptophan were significantly correlated with abdominal adiposity, body weight and BMI, respectively.
Research conclusions
Heterogeneously elevated amino acids, especially BCAAs/AAAs, are found in new-onset T2DM patients in differing BMI categories, which may indicate a potentially skewed prediction of T2DM development by BCAA/AAAs, i.e., more accurate and reliable prediction in obese and male individuals than in NW individuals and females. This skewness may limit the universal application of this T2DM predictor.
Research perspectives
This study has limitations. The lack of BMI-matched healthy control individuals makes it impossible to determine whether a potential low grade hyperaminoacidemia/BCAA/AAA elevation exists in normal-weight T2DM patients. The moderate sample size and lack of lifestyle and genetic data of this cross-sectional study could not discern the causality and/or mechanisms of the heterogeneity. Further studies should include both metabolically healthy and metabolically unhealthy individuals in differing BMI categories to overcome the abovementioned limitations.
