U.S. Department of Health and Human Services

New Mechanism Proposed for Glucose-lowering Effect of Metformin, a Drug for Type 2 Diabetes

A new report may explain how the diabetes drug metformin exerts its effects, providing a potential target for development of new therapeutics. The liver plays an important role in blood glucose (sugar) levels by sending glucose into the bloodstream when levels start to drop between meals. Liver glucose output during fasting is triggered by glucagon, a hormone secreted by the pancreas that works in opposition to another hormone, insulin, which the pancreas secretes when blood glucose levels are high (after meals). In people with type 2 diabetes, not only does the body become resistant to the glucose‑lowering effect of insulin, but it also produces glucagon inappropriately. As a result, glucose 
enters the bloodstream from the liver when it is not needed, contributing to high blood glucose levels. The most commonly prescribed oral drug for treatment of type 2 diabetes, metformin, helps control blood glucose levels by reducing the amount of glucose coming from the liver. How it is able to do this has been unclear. Metformin treatment causes an increase in the levels of a molecule called AMP. AMP activates an enzyme called AMPK, and the activated AMPK was thought to reduce liver glucose production, accounting for metformin’s effects. Now, working in mouse liver cells and mouse models, researchers have uncovered evidence strongly suggesting that metformin interferes with glucagon‑induced glucose output by disrupting the initial steps of glucagon signaling in liver cells. In particular, their data suggest that the 
metformin‑induced rise in AMP inhibits glucagon’s activation of an enzyme called adenylate cyclase, the first step in the molecular signal for glucose production inside liver cells. If this theory is borne out, it paves the way to developing potential new drug treatments for type 2 diabetes that speciically target this enzyme. These indings also reinforce the importance of glucagon and inding ways to minimize its abnormal activity in type 2 diabetes. 

Miller RA, Chu Q, Xie J, Foretz M, Viollet B, and Birnbaum 
MJ. Biguanides suppress hepatic glucagon signalling by 
decreasing production of cyclic AMP. Nature 494: 256‑260,