To investigate the associations between circulating folate forms and the prevalence of diabetic comorbidities among U.S. adults. This cross-sectional study used data from the National Health and Nutrition Examination Survey (NHANES), 2011–2018, including a nationally representative sample of 2,151 adults with diagnosed diabetes. Blood concentrations of folate-related metabolites were obtained from standardized laboratory assessments. Weighted logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between individual folate forms and the presence of major diabetic comorbidities. Restricted cubic spline analyses were applied to examine potential nonlinear relationships. Higher serum MeFox (pyrazino-s-triazine derivative of 4-α-hydroxy-5-methyl-tetrahydrofolate) concentrations were positively associated with the prevalence of heart failure, coronary heart disease (CHD), and chronic kidney disease (CKD). Elevated red blood cell folate (RBC folate) levels were associated with increased odds of heart failure, angina, and CKD, whereas unmetabolized folic acid (UMFA) was positively associated with angina, and non-methyl folate was positively associated with angina and CKD. Sensitivity analyses yielded consistent results across multiple model specifications. Restricted cubic spline analyses revealed nonlinear dose–response relationships, including U-shaped associations of MeFox and RBC folate with heart failure. Threshold or plateau effects were also observed for certain outcomes at higher folate concentrations. Stratified and interaction analyses revealed significant effect modification by sex and age, with positive associations of RBC folate and UMFA with CKD, heart failure, and stroke observed primarily in women and older adults (≥60 years), while inverse associations of 5-MTHF and total folate with stroke were observed among men. Higher concentrations of specific folate metabolites, particularly MeFox and RBC folate, were associated with greater odds of multiple diabetic cardiometabolic comorbidities among U.S. adults with diabetes. Detailed folate profiling may help improve understanding of metabolic health and vascular complications in diabetic populations. Study overview. Study population: Data were obtained from the National Health and Nutrition Examination Survey (NHANES) 2011-2012 to 2017-2018 cycles. A total of 2,151 individuals with diabetes were included in the present study (1,119 men and 1,032 women). Circulating folate forms: Five serum folate forms and red blood cell (RBC) folate were included as exposure variables. Diabetic comorbidities: Diabetic comorbidities with significant associations were presented, defined based on self-reported information and established criteria. Associations: Multivariable logistic regression models were used to examine the associations between circulating folate forms and diabetic comorbidities. Stratified and interaction analyses were conducted to evaluate potential effect modification by age and sex. Dose-response relationships: Restricted cubic spline (RCS) analyses were performed to assess potential nonlinear dose-response relationships between circulating folate forms and diabetic comorbidities. Created with BioRender.com, with icons adapted from its library. • Higher circulating folate metabolites, particularly MeFox and RBC folate, were associated with higher prevalence of several diabetic comorbidities. • Distinct folate forms showed nonlinear associations, with U-shaped or threshold patterns observed for multiple cardiometabolic outcomes. • MeFox, an oxidative degradation product of 5-MTHF, may serve as a potential biomarker reflecting oxidative stress and altered folate metabolism in diabetes. • Elevated RBC folate, a marker of long-term folate status, was associated with cardiovascular and renal comorbidities. • These findings suggest that both low and high folate levels may be linked to adverse health profiles, highlighting the need for further longitudinal studies to clarify these relationships.
Xu et al. (Fri,) studied this question.