Is hepatic glycogen content a regulator of glucagon secretion?

The role of plasma glucose as a major regulator of glucagon secretion is well established. However, this feedback regulation appears to break down in several states in which a closer relationship is apparently evident between plasma glucagon and hepatic glycogen content. Therefore, we assessed plasma glucagon as well as glucose response (delta glucose) to intravenous (IV) bolus administration of 1 mg glucagon after an overnight fast (a reliable and accurate estimate of the magnitude of hepatic glycogen content) in a population of normal subjects and subjects with hepatic cirrhosis and hyperthyroidism, both of which are disorders characterized by hepatic glycogen depletion. Plasma glucose concentrations were not significantly different in either group. However, plasma glucagon and insulin concentrations were significantly increased and delta glucose significantly decreased in both cirrhotic patients and hyperthyroid patients as compared with normal subjects. Furthermore, a significant relationship (r = -.55, P less than .0001) was noted between delta glucose and plasma glucagon, but not plasma insulin. Therefore, we believe that pancreatic alpha-cell function may be dependent on hepatic glycogen content. Moreover, the primary action of glucagon may be to induce gluconeogenesis in the absence of hepatic glycogen stores due to declining insulin concentrations or insulin resistance.