Glucagon and the Permissive Action of Fatty Acids in Hepatic Gluconeogenesis

1 The effect of suppression of endogenous lipolysis by glycodiazine (2‐benzene sulfonamido‐5‐β‐methoxyethoxy pyrimidine) on gluconeogenesis from lactate in isolated perfused livers from fasted rats has been investigated. Glycodiazine, when recirculated for 20 min before onset of the experimental period completely inhibited ketone body formation from endogenous sources. Simultaneously, gluconeogenesis was considerably decreased. 2 Even in the presence of glucagon (0.57 μM) ketogenesis remained completely inhibited by glycodiazine. Thus, glucagon did not overcome the inhibition of lipolysis by glycodiazine. Nevertheless, gluconeogenesis was stimulated by glucagon though much less than in the absence of glycodiazine. 3 Glycodiazine did not suppress ketogenesis from exogenously added fatty acid. Equally, the increased rate of gluconeogenesis in the presence of fatty acid was not altered by glycodiazine. This confirms that glycodiazine acts primarily on hepatic lipolysis and furthermore excludes direct interference of the drug with gluconeogenesis. 4 Glucagon added together with oleic acid did not stimulate ketogenesis when glycodiazine was present. There was however, an additional effect of glucagon on gluconeogenesis which exceeded that observed in the absence of fatty acid. 5 These data support the view that hepatic gluconeogenesis may be limited by the supply and oxidation of fatty acids. Furthermore unrestricted fatty acid oxidation seems to be required for permitting glucagon to display its full stimulatory effect on gluconeogenesis.