Metformin - Mechanism of Action

Mechanism of Action

Metformin improves hyperglycemia primarily by suppressing glucose production by the liver (hepatic gluconeogenesis). The "average" person with type 2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one third. Metformin activates AMP-activated protein kinase (AMPK), an enzyme that plays an important role in insulin signaling, whole body energy balance, and the metabolism of glucose and fats; activation of AMPK is required for metformin's inhibitory effect on the production of glucose by liver cells. Research published in 2008 further elucidated metformin's mechanism of action, showing activation of AMPK is required for an increase in the expression of SHP, which in turn inhibits the expression of the hepatic gluconeogenic genes PEPCK and Glc-6-Pase. Metformin is frequently used in research along with AICAR as an AMPK agonist. The mechanism by which biguanides increase the activity of AMPK remains uncertain; however, research suggests that metformin increases the amount of cytosolic AMP (as opposed to a change in total AMP or total AMP/ATP).

In addition to suppressing hepatic glucose production, metformin increases insulin sensitivity, enhances peripheral glucose uptake (by phosphorylating GLUT-4 enhancer factor), increases fatty acid oxidation, and decreases absorption of glucose from the gastrointestinal tract. Increased peripheral utilization of glucose may be due to improved insulin binding to insulin receptors. AMPK probably also plays a role, as metformin administration increases AMPK activity in skeletal muscle. AMPK is known to cause GLUT4 deployment to the plasma membrane, resulting in insulin-independent glucose uptake. Some metabolic actions of metformin do appear to occur by AMPK-independent mechanisms; a 2008 study found "the metabolic actions of metformin in the heart muscle can occur independent of changes in AMPK activity and may be mediated by p38 MAPK- and PKC-dependent mechanisms."