The plasma glucose level is tightly controlled throughout life in the normal individual. This pre-cise control is best seen during periods of food consumption or food deprivation. The stability of the plasma glucose level is a reflection of the balance between the rates of whole body glucose production and glucose utilization. Each of these processes is tightly regulated by the levels of hormones and substrates in blood. Figure 1 depicts the situation known to exist after an overnight fast. Glucose is produced by both the liver and the kidneys. While the magnitude of the renal contribution to glucose appearance in overnight fasted humans is still in debate (estimates range from 5 to 23%)(1–3), in the overnight fasted dog it represents~ 10% of tracer-determined glucose production (4). Interestingly the kidneys take up~ 10% of the glucose produced, so that in a net sense they do not supply glucose to the other tissues of the body. It is the liver, therefore, that is responsible for providing glucose to both insulin-insensitive (nervous, formed elements of the blood, skin, red blood cells, smooth muscle, etc.) and insulin-sensitive (skeletal muscle and fat) tissues. In view of the central role of the liver in maintaining glucose homeostasis, we undertook studies to define the mechanisms by which hepatic glucose production is acutely regulated in vivo. We used the overnight fasted conscious dog as our model because it provides a good reflection of glucose metabolism in humans and because it has the advantage of allowing invasive experimental design, which facilitates the performance of mechanistic studies in vivo.