Pancreatic beta cells secrete insulin in response to an increase in the level of blood glucose above 5 mM, which is characteristic of the fasting state. Glucose metabolism is essential for glucose sensing, and both the high-Km glucose transporter GLUT2 and the high-Km glucose phosphorylating enzyme glucokinase have been implicated in coupling insulin secretion to extracellular glucose levels. Experiments in isolated islets, immortalized beta-cell lines and transgenic animals, together with findings in humans with maturity-onset diabetes of the young, indicate that the primary beta-cell glucose sensor is glucokinase. Although the level of GLUT2 is frequently reduced in animal models of type II diabetes, GLUT2 does not limit glucose metabolism in beta cells and does not appear to regulate glucose induction of insulin secretion.