Targeting an energy sensor to treat diabetes

Obesity occurs when whole-body energy intake exceeds energy expenditure for prolonged periods. This is a major public health issue because obesity increases the risk of disorders such as type 2 diabetes mellitus (T2DM). The liver and muscle store excess energy in the form of fat, leading to resistance to the hormone insulin. Released when blood glucose rises after meals, insulin normally promotes glucose uptake by muscle and represses glucose production by the liver, thus rapidly returning blood glucose to normal. However, this process is impaired in insulin-resistant individuals, who may eventually develop persistently elevated blood glucose (i.e., T2DM), which can cause debilitating or life-threatening complications. Because the energy sensor AMPK (adenosine monophosphate-activated protein kinase) promotes muscle glucose uptake by insulin-independent mechanisms, it was proposed in 1999 that AMPK-activating drugs might represent a novel approach to treating T2DM (1). Representing the culmination of more than 15 years of developing this concept, a study by Myers et al. (2) on page 507 of this issue and a study by Cokorinos et al. (3) show that compounds that bind to a unique site on AMPK can promote glucose uptake by muscle, and hence reverse elevated blood glucose in animal models of T2DM.