AMP-activated protein kinase (AMPK) is an integral part of the system in cells that allows them to sense and respond to metabolic stress and the consequent threat of lowered ATP levels. AMPK responds to various stresses, through sensing a raised cellular AMP/ATP ratio, resulting in increased kinase activity. This initiates multiple cellular outcomes predicated to oppose loss of high-energy phosphates by stimulating ATP producing processes and inhibiting non-essential ATP consuming processes. In single celled eukaryotes AMPK subunit homologs are required for their response to glucose starvation. Some mammalian cells are also capable of sensing alterations in the physiological levels of glucose. The best-known examples of such specialized cells are pancreatic beta cells and certain hypothalamic neurons, with their ability to sense changes in local glucose concentration coupled to the regulation of insulin secretion and to changes in feeding behaviour, respectively. The archetypal glucose-responsive cell is the pancreatic beta cell, where GLUT2, glucokinase (GK; also called hexokinase IV) and ATP-sensitive K+ (K_ATP) channels combine to act as regulators of glucose sensing. In addition, certain glucose-responsive central neurons may use the same molecular mechanisms to recognize and respond to changes in extracellular glucose. In both cases, alteration of physiological glucose levels results in changes in cellular excitability, driven mainly through variation in the activity of K_ATP channels. We have attempted to address the question whether AMPK contributes to this glucose sensing and transduction system (i.e through alteration of K_ATP channel opening) in these cells. To that end, we have utilized two main approaches: genetic deletion of the AMPKα2 subunit, and pharmacological activation of AMPK activity. The results of deletion of the AMPKα2 subunit from defined hypothalamic neurons and pancreatic beta cells will be presented, showing that their glucose-sensing mechanisms utilize AMPK activity to link glucose metabolism with changes in excitability. We are currently investigating the effects of AMPK activation on the electrical activity of an insulin secreting cell line (CRI-G1). Preliminary data indicate that manipulations designed to increase AMPK activity can alter glucose sensing in these cells, but in a rather unexpected manner.