Metformin is a widely used drug that improves glucose metabolism and reduces diabetes-related complications. Its mechanisms are complex and not fully understood. Physiologically, it reduces hepatic glucose production, but other mechanisms, including gut involvement, are also important. At the molecular level, metformin acts through both AMPK-dependent and AMPK-independent pathways, such as inhibiting mitochondrial respiration and glycerophosphate dehydrogenase, and affecting lysosomes. Recent studies show that metformin's effects are more complex than previously thought, involving multiple mechanisms. Metformin is absorbed in the small intestine and excreted in the feces. It is concentrated in the liver, kidneys, and intestines. In the liver, metformin reduces gluconeogenesis and improves insulin sensitivity. It inhibits mitochondrial Complex I, leading to increased AMPK activation, which enhances insulin sensitivity and reduces cAMP levels. Metformin also inhibits fructose-1,6-bisphosphatase, further reducing gluconeogenesis. In the intestines, metformin increases glucose utilization, increases GLP-1 secretion, and alters the gut microbiome. These effects may contribute to its glucose-lowering effects. Metformin also affects the gut-brain-liver axis, influencing hepatic glucose production through pathways involving AMPK and GLP-1 receptors. Metformin can cause gastrointestinal side effects, possibly due to its high concentration in intestinal cells or its effect on serotonin. Genetic factors, such as OCT1 and SERT, may influence metformin intolerance. Metformin has anti-inflammatory effects, reducing pro-inflammatory cytokines and improving insulin sensitivity. It may also influence longevity through mTOR signaling and reduce the neutrophil to lymphocyte ratio in type 2 diabetes. Genetic studies suggest that metformin's effects on glucose metabolism may involve genes such as ATM and SLC2A2. These findings highlight the complex mechanisms of metformin and the need for further research to fully understand its actions in humans.Metformin is a widely used drug that improves glucose metabolism and reduces diabetes-related complications. Its mechanisms are complex and not fully understood. Physiologically, it reduces hepatic glucose production, but other mechanisms, including gut involvement, are also important. At the molecular level, metformin acts through both AMPK-dependent and AMPK-independent pathways, such as inhibiting mitochondrial respiration and glycerophosphate dehydrogenase, and affecting lysosomes. Recent studies show that metformin's effects are more complex than previously thought, involving multiple mechanisms. Metformin is absorbed in the small intestine and excreted in the feces. It is concentrated in the liver, kidneys, and intestines. In the liver, metformin reduces gluconeogenesis and improves insulin sensitivity. It inhibits mitochondrial Complex I, leading to increased AMPK activation, which enhances insulin sensitivity and reduces cAMP levels. Metformin also inhibits fructose-1,6-bisphosphatase, further reducing gluconeogenesis. In the intestines, metformin increases glucose utilization, increases GLP-1 secretion, and alters the gut microbiome. These effects may contribute to its glucose-lowering effects. Metformin also affects the gut-brain-liver axis, influencing hepatic glucose production through pathways involving AMPK and GLP-1 receptors. Metformin can cause gastrointestinal side effects, possibly due to its high concentration in intestinal cells or its effect on serotonin. Genetic factors, such as OCT1 and SERT, may influence metformin intolerance. Metformin has anti-inflammatory effects, reducing pro-inflammatory cytokines and improving insulin sensitivity. It may also influence longevity through mTOR signaling and reduce the neutrophil to lymphocyte ratio in type 2 diabetes. Genetic studies suggest that metformin's effects on glucose metabolism may involve genes such as ATM and SLC2A2. These findings highlight the complex mechanisms of metformin and the need for further research to fully understand its actions in humans.