AUTHOR=Lijing Wang , Sujie Ke , Linxi Wang , Lishan Huang , Liqin Qi , Zhidong Zhan , Kejun Wu , Mengjun Zhang , Xiaoying Liu , Xiaohong Liu , Libin Liu 

TITLE=Altered Caffeine Metabolism Is Associated With Recurrent Hypoglycemia in Type 2 Diabetes Mellitus: A UPLC–MS-Based Untargeted Metabolomics Study

JOURNAL=Frontiers in Endocrinology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.843556

DOI=10.3389/fendo.2022.843556

ISSN=1664-2392

ABSTRACT=<sec><title>Background</title><p>Recurrent hypoglycemia (RH) is well known to impair awareness of hypoglycemia and increase the risk of severe hypoglycemia; the underlying mechanism requires further understanding. We aimed to investigate the metabolic characteristic profile for RH in type 2 diabetes mellitus (T2DM) patients and explore the potential metabolic mechanism and prevention strategies.</p></sec><sec><title>Methods</title><p>We screened 553 community-based T2DM patients. T2DM with RH (DH group, <italic>n</italic>=40) and T2DM without hypoglycemia (DC group, <italic>n</italic>=40) were assigned in the case-control study, matched by propensity score matching. Non-targeted, global metabolite profiling was conducted using ultra-high performance liquid chromatography-mass spectrometry. Principal component analysis and supervised projections to latent structures-discriminant analysis were constructed to evaluate the potential biomarkers. Metabolites with a fold change of &gt;2.0 or &lt;0.5, a t-test <italic>q</italic>-value &lt;0.05, and variable importance in projection value of &gt;1 were identified as significantly differential metabolites. MetaboAnalyst was performed to analyze the related metabolic pathways.</p></sec><sec><title>Results</title><p>We identified 12 significantly distinct metabolites as potential biomarkers of RH, which were enriched in five pathways; the caffeine metabolic pathway was the most dominant related one. Caffeine and its main downstream metabolites (theophylline and paraxanthine, all <italic>q &lt;</italic>0.05) were significantly lower during RH. The combination of these metabolites can serve as a reliable predictor biomarker for RH (area under the curve = 0.88). Regarding lipid metabolism, triglyceride was upregulated (<italic>P</italic>=0.003) and the O-Acylcarnitine was downregulated (<italic>q</italic> &lt; 0.001). Besides, RH was accompanied by lower phenylalanine (<italic>q</italic>=0.003) and higher cortisone (<italic>q</italic>=0.005) levels.</p></sec><sec><title>Conclusions</title><p>RH in T2DM is accompanied by caffeine, lipolysis, phenylalanine, and cortisone metabolism abnormalities. Caffeine might be a reliable candidate biomarker and potential prevention strategy for RH, but further validation studies are needed.</p></sec><sec><title>Clinical Trial Registry</title><p>Chi CTR 1900026361, 2019-10-3.</p></sec>