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Circulating insulin is thought to provide a major feedback signal for the hypothalamic regulation of energy homeostasis and food intake, although this signaling appears to be slowed by a time-consuming blood-to-brain transport. Here we show, by recording direct current potentials, a rapid onset of the effects of circulating insulin on human brain activity. Recordings were obtained from 27 men who were intravenously injected with insulin (0.1 mU/kg body wt as bolus) and placebo. In a euglycemic condition, hypoglycemia was prevented, while in the hypoglycemic condition, plasma glucose reached a postinjection nadir of 43 mg/dl. Insulin injection induced a marked negative direct current (DC) potential shift starting within 7 min in all subjects. With euglycemic conditions, the DC potential at 10-60 min postinsulin injection averaged -621.3 microV (compared with preinjection baseline). Hypoglycemia reduced this potential to an average of -331.2 microV. While insulin per se did not affect oscillatory electroencephalographic activity, hypoglycemia peaking 25 min after insulin injection was accompanied by an immediate increase in theta activity. The rapid emergence of the DC potential shift, reflecting gross ionic changes in brain tissues, indicates that systemic insulin can serve as an immediate feedback signal in the control of hypothalamic and higher brain functions.