Serum total bile acids associate with risk of incident type 2 diabetes and longitudinal changes in glucose-related metabolic traits

Background Bile acids have been found to be related to changes in gut microbiota and multiple metabolic disorders, including type 2 diabetes (T2D). We aimed to prospectively investigate associations of serum total bile acids (TBAs) with risk of incident T2D and longitudinal changes in glycemic traits. Methods A community-based study was conducted at baseline in 2010, including 4968 nondiabetic participants aged >= 40 years followed up for an average of 4.3 years. Incident T2D was defined by using the 1999 WHO criteria based on 75-g oral glucose tolerance tests. Multivariate Cox proportional hazards regression was used to examine the association of serum TBAs with incident T2D. Fasting plasma glucose (FPG), 2-hour postload plasma glucose (2-h PPG), and fasting serum insulin (FSI) were measured at baseline and follow-up. Results During 21 653.7 person-years of follow-up, 605 cases of incident diabetes were identified (incidence rate 2.8%). Comparing to quartile 1 of serum TBAs, quartile 2, 3, and 4 were significantly associated with a 14.2%, 15.0%, and 31.4% higher risk of incident T2D (P = .029). Each one unit of log-TBAs was associated with an increase of 0.034 mmol/L in FPG, 0.111 mmol/L in 2-h PPG, 0.023 in log-FSI, and 0.012 in log-HOMA-IR (homeostasis model assessment of insulin resistance) (all P <= .024). The association was attenuated after further adjustment for HOMA-IR. Mediation analysis showed that insulin resistance indicated by HOMA-IR might mediate 28.5% of indirect effect on the association of TBAs with T2D (P = .0004). Conclusions Baseline serum TBAs were significantly associated with incident T2D and longitudinal changes in glycemic traits. Insulin resistance might partially mediate the association of TBAs and T2D. Highlights Serum total bile acids (TBAs) are significantly associated with a high risk of incident type 2 diabetes (T2D). Serum TBAs are positively associated with longitudinal changes in glucose-related metabolic traits. Insulin resistance indicated by homeostasis model assessment of insulin resistance (HOMA-IR) might partially mediate this association of TBAs with T2D. Our findings spark novel therapeutic approaches for metabolic diseases depending on bile acids.