Metformin increases BCAA and glutamine plasma levels in aged nondiabetic subjects with CVD
±, nondiabetic insulin-resistant heart failure, coronary heart disease, diabetes
INSULIN RESISTANCE, MINOR, CORONARY HEART DISEASE, DIABETES
The GoDARTS cohort does not itself have data on plasma amino acids and in addition its observational nature means it is vulnerable to confounding, prompting us to further confirm selectivity of effects of metformin on BCAA in a RCT of metformin in a group of nondiabetic insulin-resistant heart failure patients. This allowed us to study effects of metformin on amino acids in aged humans, without selection bias or diabetes as potentially confounding factors. Investigation of intestinal cells suggested that metformin does not affect amino-acid uptake across the gut and there is in any case substantial absorption of dipeptides and polypeptides across the gut wall, irrespective of any possible effects on amino acid transporters. In such circumstances, suppression of aminoacid uptake might be expected to lead to a build-up of circulating amino acids and this is exactly what we found. Consistent with the evidence that SNAT2 is inhibited by metformin, this increase was mainly restricted to each BCAA and glutamine, which was the most robustly increased of all. We attribute a minor effect on arginine to the modest effects on CAT1 and CAT2 expression, supporting the idea that metformin might also act weakly on this arginine sensing mechanism in humans. Alanine, a gluconeogenic substrate, was also increased consistent with previous findings [No other amino acids measured were significantly increased, strongly suggesting that effects of metformin on glutamine and BCAA transport that were the salient changes in cells are also critical for the effect of metformin on amino acids in this nondiabetic cohort. A previous study of metformin in coronary heart disease found that metformin tended to raise BCAA levels in plasma for up to 1 year but those changes were non-significant [Our proof of concept trial was not powered to investigate clinical outcome but we have shown earlier in these patients that metformin treatment significantly decreased fasting insulin resistance index (FIRI, from 5.8 ± 3.8 to 4.0 ± 2.5, P < 0.001) [In addition to the amino acid increases already discussed, a modest decrease in tyrosine was observed which is unexplained by our model. In an earlier study, longer durations of treatment produced a larger effect of metformin in decreasing tyrosine [We acknowledge some limitations in our study. Limitations inherent in observational nonrandomized observational cohort data mean it was impossible to account for all possible confounding influences that may have biased our observed differences between groups. In addition, the functional effect of the rs9838915 risk allele of KLF15, which is intronic, has not been established experimentally [