Circulating glucose levels serve as the principal regulator of the rate of insulin secretion from the pancreatic β-cell, which, in turn, is the body’s principal mechanism preventing excessive elevation in circulating glucose. The control center for this critical negative feedback loop is generally thought to reside solely within the province of the β-cell. However, in the February issue of Diabetes , Osundiji et al. (1) provide evidence that there may be another player involved, namely, the hypothalamus. They observed that raising glucose levels locally or pharmacologically blocking glucose entry into cells close to the third ventricle of the rat altered the acute insulin secretory response to intravenous glucose, presumably by the extensive neural connections that exist between the hypothalamus and islet. As pointed out by the authors, it is now well recognized that a subgroup of hypothalamic neurons, and neurons elsewhere in the brain, have the capacity to sense glucose and influence the secretion of anti-insulin hormones and hepatic glucose production (2–6). Yet, the idea that the glucose-sensing capacity of these neurons may also influence the function of the β-cell has not been appreciated, and if shown to be true under more physiological conditions, could have important therapeutic implications. It is commonly believed that the KATP-dependent model of glucose-stimulated secretion coupling is the primary means used by the β-cell to activate insulin secretion (7–10). In this model, glucose enters the β-cell, …