The Dual Mechanism of Glucagon-Induced Hyperglycemia

Recently glucagon has been found in several extrapancreatic tissues, mainly in the brain and gut. This wide distribution of glucagon raises the possibility that glucagon may exert its action in several ways at different places. As for glucose production in the liver, glucagon secreted from the pancreas acts directly on the liver either through cyclic AMP-mediated glycogenolysis or gluconeogenesis. Intravenous (iv) administration of glucagon produced transient hyperglycemia; glucagon-induced hyperglycemia occurs at first and is immediately suppressed by glucagon-induced hyperinsulinemia. In the brain, glucagon is localized mainly in the hypothalamus, thalamus and brain stem-the center of the autonomic nervous system-where glucagon is modulated by the changes in glucose homeostasis, starvation or glucose-insulin administration. The intracerebroventricular (icv) administration of glucagon in the rat induces more prolonged hyperglycemia than that induced by iv injected glucagon. This hyperglycemia is not associated with hyperglucagonemia or hyperinsulinemia, suggesting that icv administered glucagon does not leak into the peripheral circulation. Furthermore, icv glucagon-induced hyperglycemia is inhibited completely by pretreatment with atropine, phentolamine or hexamethonium, partially by bilateral adrenalectomy, but not by propranolol. Thus, glucagon-induced hyperglycemia seems to operate by a dual mechanism: a direct effect on the liver, and an indirect effect through cholinergic and alpha-adrenergic neural pathways to the liver