Metformin is a first-line medication for type 2 diabetes mellitus (T2DM) that acts to reduce blood levels of glucose, food intake and body weight. The mechanisms behind the therapeutic effects of metformin are not completely understood and various modes of action have been proposed. Now, two independent studies published simultaneously in Nature Metabolism point towards a role for an appetite-suppressing metabolite, N-lactoyl-phenylalanine (Lac-Phe).

“We used liquid chromatography-mass spectrometry to measure Lac-Phe levels from cells, mice, and two different human cohorts,” says Xiao. Metformin treatment increased Lac-Phe levels in vitro, in mice and in humans. Further studies in primary mouse macrophages, Caco-2 cells (a human gut epithelial cell line) and BV-2 cells (a mouse microglial cell line) demonstrated that metformin was acting to inhibit complex I and drive Lac-Phe biosynthesis.