The pancreatic β-cell paradigm for glucose sensing has been proposed to apply to brain glucose sensors controlling counterregulation to hypoglycemia and feeding behavior. Over recent years, we tested this model in mice by first showing that inactivation of the GLUT2 gene suppressed glucose sensing and correctly regulated insulin secretion by pancreatic β-cells. Then, we restored the function of the β-cell in GLUT2-null mice by transgenic expression of a glucose transporter under the control of the rat insulin promoter. Using these rescued mice, we showed that GLUT2-dependent sensors are present in several anatomical sites, including the hepatoportal vein and the central nervous system. When these extrapancreatic glucose sensors are inactivated, the mice display loss of first-phase insulin secretion and hyperglucagonemia in the fed state, and they eat more than control mice—defects characteristic of developing obesity/diabetes. By gene complementation experiments, we further showed that glucose sensors controlling glucagon secretion require GLUT2 expression in glial cells. However, transgenic expression of GLUT2 in astrocytes or neurons failed to restore the normal control of feeding, indicating that different classes of glucose sensors control the response to hypoglycemia and food intake.