Effect of folate supplementation on insulin sensitivity and type 2 diabetes: a meta-analysis of randomized controlled trials.

Systematic review and meta-analysis of 29 randomized controlled trials including 22,250 adults older than 18 years. Participants came from diverse health backgrounds, including healthy adults and people with type 2 diabetes, cardiovascular disease, metabolic syndrome traits, HIV, polycystic ovary syndrome, and other conditions, with many studies conducted in European populations.

Across the included randomized trials, folate was given orally as folic acid or 5-methyltetrahydrofolate, typically once daily, for durations ranging from weeks to years. Doses ranged from 0.4 to 15 mg/day, with most trials using 0.8 to 5 mg/day; some regimens also included vitamin B12 and/or vitamin B6.

Folate supplementation improved insulin sensitivity markers but did not meaningfully change fasting glucose, HbA1c, or type 2 diabetes incidence overall. Pooled effects favored folate for fasting insulin (WMD -13.47 pmol/L; 95% CI -21.41, -5.53; P < 0.001) and HOMA-IR (WMD -0.57; 95% CI -0.76, -0.37; P < 0.001), while fasting glucose was unchanged (WMD -0.02 mmol/L; 95% CI -0.06, 0.02; P = 0.43) and HbA1c was unchanged (WMD -0.06%; 95% CI -0.24, 0.12; P = 0.34). For type 2 diabetes development, the pooled RR was 0.91 (95% CI 0.80, 1.04; P = 0.16), so evidence was insufficient to conclude a preventive effect. Greater homocysteine reduction was associated with larger improvements in fasting glucose and HbA1c, suggesting a possible mediating pathway.

The evidence base was heterogeneous in participant health status, folate form, dose, duration, and co-supplementation, which limits direct comparability across trials. Insulin effects showed moderate heterogeneity (I2 = 55%), and only two studies contributed to the type 2 diabetes incidence analysis, making that endpoint imprecise. Several outcomes were not consistently reported across arms, and many studies were short-term rather than designed for long-term diabetes prevention.