Insulin and glucagon are the body’s principal gluco-regulatory hormones. They are secreted by the pancreatic β- and α-cells in response to hyperglycaemia and hypoglycaemia, respectively. The metabolic regulation of insulin secretion is well understood: glucose-induced closure of ATP-sensitive potassium channels (KATP-channels), which are spontaneously active at low glucose, results in membrane depolarization, initiation of Ca2+-dependent electrical activity and stimulation of insulin granule exocytosis. An increase in plasma glucose leads to inhibition of glucagon secretion. Surprisingly, glucagon-secreting α-cells are equipped with KATP-channels of exactly the same molecular composition as those found in the β-cells. The role of the KATP-channels in α-cells remains enigmatic. How can closure of KATP-channels result in stimulation of insulin secretion from β-cells but inhibition of glucagon secretion from the α-cells? Our recent studies on α-cells in freshly isolated intact islets have established that the KATP-channels are active in α-cells exposed to 1mM glucose (a condition associated with stimulation of glucagon secretion) and that they close when glucose is increased to 6mM. This results in ~10mV membrane depolarization and <2-fold increase in action potential frequency. Yet, glucagon secretion measured in parallel from the same batch of pancreatic islets was inhibited by ~50%. The KATP-channel blocker tolbutamide mimicked the effects of glucose on electrical activity and glucagon secretion. Importantly, the depolarizing effect of glucose or tolbutamide was associated with a 10-15mV reduction of action potential peak voltage. The sodium channel blocker TTX and the P/Q-type calcium channel inhibitor agatoxin mimicked the effects of glucose on glucagon secretion/electrical activity. These data suggest that KATP-channel closure exert dual effects on secretion/electrical excitability depending on the complements of voltage-gated ion channels. In cells in which action potential firing depends on ion channels that do not undergo much voltage-dependent inactivation (as exemplified by the β-cell), membrane depolarization will stimulate secretion. In cells in which action potential firing instead involves ion channels that exhibit voltage-dependent inactivation (like the α-cell), membrane depolarization, via reduced action potential height and less activation of P/Q-type calcium channels, results in inhibition rather than stimulation of secretion. These data may help to explain why glucagon secretion is increased in diabetic patients (exacerbating the hyperglycemia due to the lack of insulin). Potential therapeutic implications of these findings will be discussed.