Metformin increases liver accumulation of vitamin B12-An experimental study in rats

Aims/hypothesis: Patients treated with metformin exhibit low levels of plasma vitamin B₁₂ (B₁₂), and are considered at risk for developing B₁₂ deficiency. In this study, we investigated the effect of metformin treatment on B₁₂ uptake and distribution in rats. Methods: Sprague Dawley rats (n = 18) were divided into two groups and given daily subcutaneous injections with metformin or saline (control) for three weeks. Following this, the animals received an oral dose of radio-labeled B ₁₂ (⁵⁷[Co]-B₁₂), and urine and feces were collected for 24 h. Plasma, bowel content, liver, and kidneys were collected and analyzed for B₁₂, unsaturated B₁₂-binding capacity, and ⁵⁷[Co]-B₁₂. Results: Three weeks of metformin treatment reduced plasma B₁₂ by 22% or 289 [47-383] pmol/L (median and [range]) (p = 0.001), while no effect was observed on unsaturated B₁₂-binding capacity. Compared with controls, the amount of B₁₂ in the liver was 36% (p = 0.007) higher in metformin-treated rats, while the B₁₂ content in the kidney was 34% (p = 0.013) lower. No difference in the total amount of absorbed ⁵⁷[Co]-B₁₂ present in the tissues and organs studied was found, suggesting that metformin has no decreasing effect on the B₁₂ absorption. Conclusions/interpretation: These results show that metformin treatment increases liver accumulation of B₁₂, thereby resulting in decreases in circulating B₁₂ and kidney accumulation of the vitamin. Our data questions whether the low plasma B₁₂ observed in patients treated with metformin reflects impaired B₁₂ status, and rather suggests altered tissue distribution and metabolism of the vitamin.