Controversial effects of metformin on human physiology and pathophysiology

Metformin is the first-line oral antihyperglycemic agent for type 2 diabetes mellitus (T2DM), with over 150 million individuals worldwide receiving treatment annually. Although synthesized in 1922, its clinical adoption began in the 1950s, and decades of widespread use have firmly established its efficacy in glycemic control and metabolic improvement. Nevertheless, growing evidence indicates that metformin exerts pleiotropic effects beyond glucose homeostasis-modulating neurocognitive function, gastrointestinal physiology, reproductive endocrinology, and cellular aging pathways. Many of these effects remain incompletely characterized, mechanistically ambiguous, or clinically inconsistent across populations. This review systematically synthesizes recent (2014-2024) preclinical and clinical evidence from PubMed and Google Scholar to critically evaluate the contested physiological and pathophysiological actions of metformin. We distinguish robustly replicated findings from preliminary or contradictory observations, clarify dose- and context-dependent mechanisms (e.g., mitochondrial vs. lysosomal AMPK activation), and highlight knowledge gaps impeding safe, personalized application. Emphasis is placed on reconciling mechanistic insights with real-world therapeutic outcomes-particularly regarding long-term safety, interindividual variability in pharmacokinetics (e.g., OCT/MATE transporter polymorphisms), and the need for prospective studies integrating multi-omics profiling and extended follow-up.