Central glucagon-induced hyperglycemia is mediated by combined activation of the adrenal medulla and sympathetic nerve endings.

Intracerebroventricular (ICV) microinjection of glucagon (0.0025-2.5 micrograms) produced significant dose-dependent hyperglycemia in mice. This hyperglycemic effect was prevented by pretreatment with the sympathetic ganglionic blocker chlorisondamine chloride or bilateral adrenalectomy plus chemical sympathectomy with 6-hydroxydopamine. Similar pretreatments had no effect on the plasma glucose responses to systemic glucagon administration. Pretreatment with somatostatin, which blocks pancreatic glucagon secretion had no effect on the hyperglycemic response to central glucagon administration. The results suggest that the increase in plasma glucose following central glucagon administration is mediated by combined action of adrenal and sympathetic amines to stimulate hepatic glucose production, or additionally to inhibit insulin release from the pancreas. The possible involvement of glucagon in the central nervous system in systemic glucoregulation is discussed.