Metformin at the Interface of Chemistry, Pharmacokinetics, and Clinical Translation: Mechanistic Insights into Efficacy and Adverse Effects

Metformin is a key drug for the treatment of type 2 diabetes. Its efficacy and side effects depend on its chemical properties and how it is transported through transporters in the body. Research has shown that these factors influence metformin's function, individual variability, and potential safety issues. Metformin exerts its effects by inhibiting mitochondrial complex I and activating AMP-activated protein kinase (AMPK) during periods of energy deprivation. Furthermore, it alters glucose processing in the intestine and liver through the PEN2-ATP6AP1 signaling pathway. These effects also influence gut hormones and the composition of the gut microbiota. This process explains metformin's effects on blood glucose, gastrointestinal intolerance, vitamin B12 deficiency, and lactic acidosis. Understanding the underlying mechanisms of these effects opens new avenues for clinical application. Adjusting dose based on transporter differences can improve efficacy. Modifying the gut microbiota can alleviate gastric intolerance. Developing new drugs in this class could provide more effective treatment options. These results suggest that understanding metformin's function could lead to more personalized and effective treatments for type 2 diabetes.