Fang et al. (1) have insightfully considered and highlighted the future research directions of choline metabolites and diabetes in response to our article on associations between choline metabolites and incident diabetes in the Coronary Artery Risk Development in Young Adults (CARDIA) study (2). We greatly appreciate the commentary from Fang et al. and address several specific points here.
Our data suggest that an inverse association between betaine and incident diabetes may be limited to, or stronger among, men. We agree with Fang et al. that further study is needed in this area. As a first step, our findings must be replicated in a larger sample. Fang et al. recommend specific focus on sex hormones. In our analysis, we were able to account for hormonal birth control use but lacked data on circulating concentrations of sex hormones.
Fang et al. propose exploration of the potential for betaine to enhance the efficacy of diabetes medications. Such study, focused on individuals with treated diabetes, would require a sample with much larger prevalence of diabetes than that in CARDIA. That said, we note that a randomized trial of betaine supplementation among individuals with prediabetes yielded inconsistent results (3), which may reflect the distinction between circulating betaine concentrations and ingestion of betaine or betaine precursors. Recent data indicate that circulating betaine concentrations may be materially increased by choline intake (4) through conversion of choline to betaine. In a trial among participants with type 2 diabetes, plasma betaine increased in response to a physical activity and dietary intervention. Foods rich in betaine, such as whole grains and certain vegetables, may contribute other nutritional components that may reduce diabetes risk as well as raise plasma betaine (5). Further research is needed to assess the relevance of betaine ingestion as well as the potential for betaine to serve as a biomarker of beneficial metabolic health.
Fang et al. highlight the potential for residual confounding in studies of choline metabolites and incident diabetes, including genetic factors, early life experiences, and environmental exposures. Although we adjusted for many confounding variables, the potential for residual confounding exists, including from a lack of adjustment for an unmeasured variable or due to random measurement error in adjusted measures. At the same time, in our experience, much variability is explained through adjustment for sociodemographics, health behaviors, and clinical measures, which may limit the impact of residual confounding by variables unmeasured in CARDIA, such as early life experiences and environmental exposures.
We greatly appreciate the insightful considerations from Fang et al. and applaud their illumination of future research directions for choline metabolism and diabetes.
Article Information
Funding. This work was supported by R01-HL143885 from the National Institutes of Health.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.
Handling Editors. The journal editors responsible for overseeing the review of the manuscript were Steven E. Kahn and Csaba P. Kovesdy.
