PMID- 31683780 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220514 IS - 2077-0383 (Print) IS - 2077-0383 (Electronic) IS - 2077-0383 (Linking) VI - 8 IP - 11 DP - 2019 Nov 1 TI - High Betaine, a Trimethylamine N-Oxide Related Metabolite, Is Prospectively Associated with Low Future Risk of Type 2 Diabetes Mellitus in the PREVEND Study. LID - 10.3390/jcm8111813 [doi] LID - 1813 AB - BACKGROUND: Gut microbiota-related metabolites, trimethylamine-N-oxide (TMAO), choline, and betaine, have been shown to be associated with cardiovascular disease (CVD) risk. Moreover, lower plasma betaine concentrations have been reported in subjects with type 2 diabetes mellitus (T2DM). However, few studies have explored the association of betaine with incident T2DM, especially in the general population. The goals of this study were to evaluate the performance of a newly developed betaine assay and to prospectively explore the potential clinical associations of betaine and future risk of T2DM in a large population-based cohort. METHODS: We developed a high-throughput, nuclear magnetic resonance (NMR) spectroscopy procedure for acquiring spectra that allow for the accurate quantification of plasma/serum betaine and TMAO. Assay performance for betaine quantification was assessed and Cox proportional hazards regression was employed to evaluate the association of betaine with incident T2DM in 4336 participants in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. RESULTS: Betaine assay results were linear (y = 1.02X - 3.75) over a wide range of concentrations (26.0-1135 microM). The limit of blank (LOB), limit of detection (LOD) and limit of quantitation (LOQ) were 6.4, 8.9, and 13.2 microM, respectively. Coefficients of variation for intra- and inter-assay precision ranged from 1.5-4.3% and 2.5-5.5%, respectively. Deming regression analysis of results produced by NMR and liquid chromatography coupled to tandem mass spectrometry(LC-MS/MS) revealed an R(2) value of 0.94 (Y = 1.08x - 1.89) and a small bias for higher values by NMR. The reference interval, in a cohort of apparently healthy adult participants (n = 501), was determined to be 23.8 to 74.7 microM (mean of 42.9 +/- 12.6 microM). In the PREVEND study (n = 4336, excluding subjects with T2DM at baseline), higher betaine was associated with older age and lower body mass index, total cholesterol, triglycerides, and hsCRP. During a median follow-up of 7.3 (interquartile range (IQR), 5.9-7.7) years, 224 new T2DM cases were ascertained. Cox proportional hazards regression models revealed that the highest tertile of betaine was associated with a lower incidence of T2DM. Hazard ratio (HR) for the crude model was 0.61 (95% CI: 0.44-0.85, p = 0.004). The association remained significant even after adjusting for multiple clinical covariates and T2DM risk factors, including fasting glucose. HR for the fully-adjusted model was 0.50 (95% CI: 0.32-0.80, p = 0.003). CONCLUSIONS: The newly developed NMR-based betaine assay exhibits performance characteristics that are consistent with usage in the clinical laboratory. Betaine levels may be useful for assessing the risk of future T2DM. FAU - Garcia, Erwin AU - Garcia E AUID- ORCID: 0000-0002-2956-2715 AD - Laboratory Corporation of America Holdings (LabCorp), Morrisville, NC 27560, USA. garce14@labcorp.com. FAU - Oste, Maryse C J AU - Oste MCJ AD - Department of Nephrology, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, The Netherlands. m.c.j.oste@umcg.nl. FAU - Bennett, Dennis W AU - Bennett DW AD - Laboratory Corporation of America Holdings (LabCorp), Morrisville, NC 27560, USA. dwbent@uwm.edu. FAU - Jeyarajah, Elias J AU - Jeyarajah EJ AD - Laboratory Corporation of America Holdings (LabCorp), Morrisville, NC 27560, USA. eliasjey@gmail.com. FAU - Shalaurova, Irina AU - Shalaurova I AD - Laboratory Corporation of America Holdings (LabCorp), Morrisville, NC 27560, USA. shalaui@labcorp.com. FAU - Gruppen, Eke G AU - Gruppen EG AUID- ORCID: 0000-0002-5259-9882 AD - Department of Nephrology, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, The Netherlands. e.g.gruppen@umcg.nl. AD - Department of Endocrinology, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, The Netherlands. e.g.gruppen@umcg.nl. FAU - Hazen, Stanley L AU - Hazen SL AD - Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, OH 44195, USA. HAZENS@ccf.org. AD - Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA. HAZENS@ccf.org. FAU - Otvos, James D AU - Otvos JD AD - Laboratory Corporation of America Holdings (LabCorp), Morrisville, NC 27560, USA. otvosj@labcorp.com. FAU - Bakker, Stephan J L AU - Bakker SJL AUID- ORCID: 0000-0003-3356-6791 AD - Department of Nephrology, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, The Netherlands. s.j.l.bakker@umcg.nl. FAU - Dullaart, Robin P F AU - Dullaart RPF AUID- ORCID: 0000-0003-4520-1239 AD - Department of Endocrinology, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, The Netherlands. r.p.f.dullaart@umcg.nl. FAU - Connelly, Margery A AU - Connelly MA AD - Laboratory Corporation of America Holdings (LabCorp), Morrisville, NC 27560, USA. connem5@labcorp.com. LA - eng GR - P01 HL147823/HL/NHLBI NIH HHS/United States GR - R01HL103866/National Institutes of Health (NIH) and Office of Dietary Supplements/ PT - Journal Article DEP - 20191101 PL - Switzerland TA - J Clin Med JT - Journal of clinical medicine JID - 101606588 PMC - PMC6912391 OTO - NOTNLM OT - betaine OT - nuclear magnetic resonance spectroscopy OT - trimethylamine N-oxide related metabolites OT - type 2 diabetes mellitus COIS- E.G., D.W.B., E.J., I.S., J.D.O. and M.A.C. are currently, or were at the time of this study, employees of LabCorp. M.C.J.O., E.G.G., X.S.L., S.J.L.B. and R.P.F.D. have no conflicts of interest to reveal. S.L.H. reports being listed as a co-inventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics, having been paid as a consultant for Proctor & Gamble, and having received research funds from LipoScience, Pfizer, Inc., and Proctor & Gamble. EDAT- 2019/11/07 06:00 MHDA- 2019/11/07 06:01 PMCR- 2019/11/01 CRDT- 2019/11/06 06:00 PHST- 2019/08/20 00:00 [received] PHST- 2019/10/25 00:00 [revised] PHST- 2019/10/29 00:00 [accepted] PHST- 2019/11/06 06:00 [entrez] PHST- 2019/11/07 06:00 [pubmed] PHST- 2019/11/07 06:01 [medline] PHST- 2019/11/01 00:00 [pmc-release] AID - jcm8111813 [pii] AID - jcm-08-01813 [pii] AID - 10.3390/jcm8111813 [doi] PST - epublish SO - J Clin Med. 2019 Nov 1;8(11):1813. doi: 10.3390/jcm8111813.