Diabetes Drug Mechanism Found

The long-sought mechanism of action of metformin, the most frequently prescribed drug for type 2 diabetes, may finally be in hand. Metformin is a guanidine-based compound that reduces overproduction of glucose by the liver, a hallmark of type 2 diabetes. How it achieves this reduction has been uncertain. A decade ago, researchers reported that metformin worked by activating adenosine monophosphate-activated protein kinase, an enzyme in liver cells. However, a 2010 study discredited that mechanism by showing that metformin works even in liver cells that don’t express that enzyme. Morris J. Birnbaum of the University of Pennsylvania Perelman School of Medicine and coworkers, including the group behind the 2010 study, now report that metformin works by inducing liver cells to produce extra adenosine monophosphate (Nature, DOI: 10.1038/nature11808). Overactivation of the enzyme adenylate cyclase by the hormone glucagon signals liver cells to overproduce glucose in diabetes, but the extra adenosine monophosphate blocks this process and thus reduces glucose overproduction. The findings suggest that adenosine-monophosphate-like inhibition of adenylate cyclase is a previously unappreciated route for the design of diabetes drugs.