Insights into the action of the pharmaceutical metformin: Targeted inhibition of the gut microbial enzyme agmatinase

Abstract

Metformin is the first-line treatment for type 2 diabetes, yet its mechanism of action is not fully understood. Recent studies suggest metformin's interactions with gut microbiota are responsible for exerting therapeutic effects. In this study, we report that metformin targets the gut microbial enzyme agmatinase, as a competitive inhibitor, which may impair gut agmatine catabolism. The metformin inhibition constant (Ki) of E.coli agmatinase is 1mM and relevant in the gut where the drug concentration is 1-10mM. Metformin analogs phenformin, buformin, and galegine are even more potent inhibitors of E.coli agmatinase (Ki= 0.6, 0.1, and 0.007mM, respectively) suggesting a shared mechanism. Agmatine is a known effector of human host metabolism and has been reported to augment metformin's therapeutic effects for type 2 diabetes. This gut-derived inhibition mechanism gives new insights on metformin's action in the gut and may lead to significant discoveries in improving metformin therapy.