Metformin, a widely used drug for glucose metabolism and diabetes management, has complex mechanisms of action that are not fully understood. Physiologically, it reduces hepatic glucose production, but its effects extend beyond this mechanism, with increasing evidence suggesting a key role for the gut. At the molecular level, metformin acts through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms. It inhibits mitochondrial respiration, possibly by targeting mitochondrial glycerophosphate dehydrogenase, and involves a lysosomal pathway. Metformin's benefits include improving insulin sensitivity, reducing hepatic lipid stores, and altering the gut microbiome. The drug also has AMPK-independent effects, such as inhibiting fructose-1,6-bisphosphatase by AMP. Genetic studies have identified novel targets for metformin action, including genes involved in liver and gut function. Further research is needed to fully understand the mechanisms of metformin in humans, particularly in long-term treatment.Metformin, a widely used drug for glucose metabolism and diabetes management, has complex mechanisms of action that are not fully understood. Physiologically, it reduces hepatic glucose production, but its effects extend beyond this mechanism, with increasing evidence suggesting a key role for the gut. At the molecular level, metformin acts through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms. It inhibits mitochondrial respiration, possibly by targeting mitochondrial glycerophosphate dehydrogenase, and involves a lysosomal pathway. Metformin's benefits include improving insulin sensitivity, reducing hepatic lipid stores, and altering the gut microbiome. The drug also has AMPK-independent effects, such as inhibiting fructose-1,6-bisphosphatase by AMP. Genetic studies have identified novel targets for metformin action, including genes involved in liver and gut function. Further research is needed to fully understand the mechanisms of metformin in humans, particularly in long-term treatment.