Does Citrulline Sit at the Nexus of Metformin's Pleotropic Effects on Metabolism and Mediate Its Salutatory Effects in Individuals With Type 2 Diabetes?

Abstract

For more than two decades, physicians have prescribed metformin as the frontline pharmacological therapy to treat type 2 diabetes (T2D) despite knowing little about its underlying mechanisms of action (1). Metformin reduces hepatic glucose production (1) and has pleotropic effects on multiple tissues, including liver (1), muscle (2), and adipose (3) tissue, as well as on immune cells (4). Clinically, metformin also reduces the risk for cardiovascular diseases, cancers, and other diseases (5,6). Pharmacometabolomics provides an opportunity to measure changes in absolute and/or relative concentrations of hundreds to thousands of small molecules in biofluids and tissue extracts to determine the response and variations in response to therapy (7). Pharmacometabolomics could facilitate identification of metabolic pathways and mechanisms of action that contribute to metformin’s widespread salutatory effects (7). In this issue of Diabetes , Adam et al. (8) utilize this approach to “uncover” metformin’s effect on citrulline metabolism in individuals with and without T2D participating in the KORA (Cooperative Health Research in the Region of Augsburg) study. Adam et al. should be commended on conducting a thorough investigation of metformin’s impact on serum metabolites in individuals with T2D using nontargeted, semiquantitative liquid chromatography–tandem mass spectrometry coupled with rigorous statistical and bioinformatic analyses. The cross-sectional “human discovery” study revealed that out of a total of 353 identified serum metabolites, the concentrations of citrulline were significantly lower and X-21365 significantly higher in metformin-treated participants with T2D compared with nontreated participants. The longitudinal “human validation” study further demonstrated that the initiation of metformin treatment during the 7-year follow-up significantly reduced citrulline and increased X-21365 serum concentrations. Subsequently, the “translational” study showed that daily treatment with metformin in db/db diabetic mice decreased plasma, skeletal muscle, and epididymal …