Abstract
It has been emphsized that glucagon, as one of the counter-regulatory hormones, plays a major role in worsening diabetic ketoacidosis and an important role in producing ketone bodies in the liver. The present study was undertaken to determine whether the glucagon action on ketogenesis in the liver is mediated through the cyclic AMP system, using isolated perfused rat liver preparations.
Fed male Wistar rats weighing 200-250 g were used. Experimental detailed procedures were as reported previously. The initial circulating solution was the Krebs-Ringer bicarbonate buffer, containing 2.5% bovine albumin, 25% bovine erythrocytes, 10 mmol/l glucose and 5 mmol/l lactate. Oleate, octanoate, glucagon and dibutyryl cyclic AMP were added to the circulating solution after 30 min of pre-perfusion. Then metabolites such as acetoacetate and β-hydroxybutyrate in the perfusate were determined serially during 90 min of the liver perfusion.
Glucagon significantly promoted the production of ketone body from oleate, but not from octanoate. When glucagon was replaced by dibutyryl cyclic AMP, ketogenesis increased beyond the increase with either oleate or octanoate alone. Emeriamine, an inhibitor of carnitine acyltransferase I, significantly suppressed the ketone body production from oleate alone. Emeriamine completely removed the net increase of ketogenesis from oleate in the presence of either glucagon or dibutyryl cyclic AMP. However, it did not suppress the ketogenesis from octanoate alone. In addition, the additive effect of dibutyryl cyclic AMP on ketogenesis from octanoate remained.
This indicates that the main site of glucagon action on ketogenesis exists in the system mediated through the carnitine acyltransferase I which is located on the outer surface of the internal membrane of the mitochondria. Secondly, this action of glucagon is not always mediated through the cyclic AMP system. Finally, the dibutyryl cyclic AMP stimulation of ketogenesis of the liver in the presence of free fatty acid may be in the metabolic process beyond the carnitine acyltransferase I.
