Association of Betaine, Choline, and TMAO with Type 2 Diabetes in Rural China: A Nested Case-Control Study from the Handan Eye Study (HES).

Background: Conflicting evidence exists regarding the association of gut microbiota-related metabolites - TMAO and its precursor choline and betaine with type 2 diabetes Mellitus (T2DM), particularly in rural Chinese populations. This study aimed to prospectively examine these relationships in a northern rural Chinese cohort.

Methods: A nested case-control study was conducted within the Handan Eye Study. At baseline (2006-2007), 5,512 participants aged ≥30 years were enrolled. After 6.5 years of follow-up, 209 incident T2DM cases and 394 age- and sex-matched controls were included. Plasma choline, betaine, and TMAO levels were measured using ultra-performance liquid chromatography. Logistic regression and linear models assessed associations with T2DM risk, insulin resistance (IR), and metabolic parameters.

Results: Baseline betaine level was lower in the T2DM group compared to controls (betaine: 7431.4 ng/mL versus 7821.5 ng/mL). After adjusting for BMI, waist-to-hip ratio, and diabetes history, no significant associations were found between choline, betaine, or TMAO and T2DM risk. However, higher betaine quartiles showed a trend toward reduced T2DM risk (Q4 vs Q1 OR: 0.59, 95% CI: 0.34-1.06). Betaine was inversely correlated with HOMA-IR (β = -0.16), HOMA-β (β = -0.13), and TyG index (β = -0.21) (p < 0.05). Plasma choline levels were positively associated with fruit intake frequency, while TMAO levels decreased with higher exercise intensity.

Conclusion: Betaine may play a protective role against dyslipidemia, adiposity, and T2DM risk in rural Chinese populations. Further studies are needed to explore TMAO's complex role in diabetes development.