Studies in humans implicate the medial prefrontal cortex (MPFC) in complex cognitive and emotional states. We measured regional cerebral blood flow (CBF) four times each during euglycemia (5.2 +/- 0.2 mmol/liter) and hypoglycemia (3.0 +/- 0.3 mmol/liter) in nine normal human volunteers. Autonomic responses during hypoglycemia were manifested by increases in neurogenic symptoms, heart rate, and plasma levels of epinephrine, norepinephrine, and pancreatic polypeptide. Typical symptoms of hypoglycemia were mild, and none reflected evidence of cognitive or emotional stress. Quantitative CBF fell 6-8% in the cerebrum, brainstem, and cerebellum. Analysis of regional CBF differences identified neuronal activation during hypoglycemia in bilateral MPFC (areas 24 and 32) and bilateral thalamus. These results provide evidence that the MPFC participates in the autonomic responses to simple physiological stimuli in humans.