Thyrotropin-releasing hormone (TRH), but not histidyl-proline diketopiperazine (cyclo[His-Pro]), induced transient hyperglycemia associated with hyperglucagonemia and marked hyperinsulinemia when placed intracerebroventricularly (i.c.v.) in anesthetized rats. This TRH-induced hyperglycemia was prevented by acute adrenalectomy. However, adrenalectomy did not prevent TRH-induced hyperinsulinemia or hyperglucagonemia. In streptozotocin-induced diabetic rats, i.c.v. administration of TRH caused progressive and pronounced hyperglycemia. i.c.v. TRH-induced hyperinsulinemia was abolished by vagotomy and by systemic administration of hexamethonium or atropine. These results suggest that TRH induces hyperglycemia mediated by stimulation of the sympathetico-adrenal system and hyperinsulinemia by stimulation of the vagus nerve, and that the rapid decline of plasma glucose levels following transient hyperglycemia is due to hyperinsulinemia.