Short-chain fatty acids (SCFAs) serve as key signaling molecules linking gut microbiota and host health. Microbially produced SCFAs in the colon are generally acknowledged for their beneficial effects on cardiometabolic health, including enhancing insulin secretion, reducing plasma cholesterol and glucose levels, and controlling energy intake through the modulation of enteroendocrine hormones. Indeed, microbially produced SCFAs have been shown to reach the systemic circulation at micromolar concentrations, which is more directly linked to metabolic health parameters rather than its levels in the colon. However, limited research has been conducted to assess the concentrations of serum SCFAs, and evidence exploring associations of different blood SCFAs with the risk of T2DM is scarce.

Recently, Dr. Jieli Lu at Shanghai Jiao Tong University School of Medicine affiliated with Ruijin Hospital published a paper in Life Metabolism entitled “Circulating short-chain and branched short-chain fatty acids and the risk of incident type 2 diabetes: findings from the 4C Study”. The China Cardiometabolic Disease and Cancer Cohort (4C) study is a nationwide population-based prospective cohort study, which included 193,846 adults aged ≥ 40 years from local resident registration systems of 20 communities in China. Based on the 4C study, a total of 3414 subjects with incident diabetes and matched normoglycemic controls were included. The results showed that total SCFAs, total branched short-chain fatty acids (BCFAs), and isovaleric acid were significantly associated with incident T2DM (P < 0.05). Interestingly, gender-specific analysis showed that per standard deviation (SD) increment of SCFAs were positively associated with incident T2DM among women, with the OR (95% CI) of 1.16 (1.05−1.29) for total SCFAs and 1.18 (1.07−1.31) for propionate, respectively (P < 0.05, FDR < 0.05). No significant associations were observed in men. A significant interaction was detected between men and women for propionate (P_int < 0.001, FDR < 0.01). After further adjustment of insulin measures, the associations of serum propionate with diabetes remained significant (P < 0.05, FDR < 0.05). Meanwhile, the associations of total BCFAs and isovaleric acid with diabetes were found to be partially mediated by triglycerides, insulin resistance, and β-cell function in mediation analysis. These findings, for the first time in a large prospective cohort, provide evidence suggesting an association between circulating SCFAs and BCFAs with T2DM risk, and support the potential role of circulating propionate with gender disparities in the early pathogenesis of diabetes.

In conclusion, this study provides valuable insights into the association between circulating SCFAs and BCFAs with the risk of T2DM from a large nationwide prospective cohort. The gender-specific association with propionate emphasizes the importance of considering sex-specific factors in understanding diabetes susceptibility.