Figure 1. Mechanism of metformin action on hepatic glucose production and muscle glucose consumption. Metfromin decreases hepatic gluconeogenesis by interfering with respiratory oxidation in mitochondria. It suppresses gluconeogenesis from several substrates, including lactate, pyruvate, glycerol, and amino acids. In addition, metformin increases intramitochondrial levels of calcium (Ca++), a modulator of mitochondrial respiration. In insulin-sensitive tissues (such as skeletal muscle), metformin facilitates gulcose transport by increasing tyrosince kinase activity in insulin receptors and enhancing glucose transportrer (GLUT) trafficking to the cell membraine. ADP = adenosine diphosphate; ATP = adenosine triphosphate; Ca++ = intracellular calcium levels; OAA = oxaloacetate; PEP = phosphoenolpyruvate; Pi = inorganic phosphate; TK = tyrosine kinase(9)