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In almost every case, the reason is due to high doses and the use of compounded formulations that are absorbed inconsistently
A retrospective study looking at concomitant use of proton pump inhibitors (PPIs) alongside metformin in 614 people with type 2 diabetes in the US found a significant reduction in B12 levels of 34% in patients taking both medications, compared to controls taking either drug alone (Long et al, 2012)
However, low expression levels of the three enzymes, specifically in beta cells of mice, have not been studied in detail