Effect Modification of Trimethylamine N-Oxide and Lipoprotein Insulin Resistance with Post-Transplantation Diabetes After Liver Transplant

Post-transplant diabetes mellitus (PTDM) is a common complication after liver transplantation. Trimethylamine N-oxide (TMAO), a microbiota-derived metabolite, has been linked to insulin resistance, but epidemiological findings on type 2 diabetes remain inconsistent. The Lipoprotein Insulin Resistance (LP-IR) score is a nuclear magnetic resonance (NMR)-derived marker of insulin resistance, yet its role in PTDM and interaction with TMAO are unknown. Three hundred sixty-seven (367) liver transplant recipients (LTRs) from the TransplantLines cohort were studied. Baseline TMAO and LP-IR score were quantified by NMR spectroscopy. Incident PTDM was defined by international criteria. Associations were tested using logistic regression and Cox proportional regression analysis. Effect modification was tested with interaction terms. Thirty-one out of 246 LTRs at risk developed PTDM after a median follow-up of 7.1 years. Higher TMAO (OR 2.14, <i>p</i> = 0.015) and LP-IR score (OR 1.66, <i>p</i> = 0.015) were associated with increased PTDM risk after adjustment for eGFR and immunosuppressant use. A positive interaction was present (<i>p</i> = 0.029) with risk amplification when both biomarkers were elevated. TMAO's association with PTDM was strongest at high LP-IR (90th percentile; OR 3.20, <i>p</i> = 0.005), and LP-IR's association was strongest at high TMAO (90th percentile; OR 2.56, <i>p</i> = 0.002). Time-to-event analysis confirmed these findings. The independent and positive interaction of TMAO and LP-IR with PTDM in LTRs would suggest a pro-diabetic action of TMAO that depends on insulin resistance.