Plasma trimethylamine-N-oxide and related metabolites are associated to type 2 diabetes risk in the PREDIMED trial (P 146-T)

Abstract

Background: The role of trimethylamine-N-oxide (TMAO) in type 2 diabetes (T2D) is currently partially understood and controversial. We aimed to investigate associations between TMAO and related metabolites with type 2 diabetes (T2D) risk in subjects at high risk of cardiovascular disease.

Material and methods: This is a case-cohort design study within the PREDIMED study, with 251 incident T2D cases and a random sample of 694 participants (641 non-cases and 53 overlapping cases) without T2D at baseline (median follow-up: 3·8 years). We used liquid chromatography-tandem mass spectrometry to measure plasma TMAO, L-carnitine, betaine, lyso-phosphatidylcholine (LPC) and lyso-phosphatidylethanolamine (LPE) species, phosphocholine, alpha-glycerophosphocholine, choline, at baseline and 1-year. We examined associations using weighted Cox proportional hazard models; accounting for the weighted case-cohort design by the Barlow method.

Results: After adjusting for recognized T2D risk factors and multiple testing, individuals in the highest quartile of baseline TMAO and alpha-glycerophosphocholine had lower risk of T2D; hazard ratio (HR) 0·52 (95% CI 0·29, 0·89), and 0·46 (95% CI 0·24, 0·89), respectively. The HR (95% CI) comparing the extreme quartiles of betaine was 0·41 (0·23, 0·74). Similar trends were observed for C16:0 LPC, C18:1 LPC, C18:0 LPC, C20:4 LPC, C22:6 LPC, C18:1 LPC plasmalogen and C16:0 LPE. After correcting for multiple comparisons, participants in the highest quartile of 1-year changes in C18:1 LPC plasmalogen levels had lower T2D risk as compared to the reference quartile.

Conclusions: Whether the associations between plasma TMAO and certain metabolites levels with T2D risk reflect its pathophysiology or represent an epiphenomenon need to be elucidated.