The Roles of Insulin, Glucagon, and Free Fatty Acids in the Regulation of Ketogenesis in Dogs

The roles of basal insulin, glucagon, and free fatty acids in the regulation of ketogenesis were studied in three-day-fasted anesthetized dogs. Four protocols were employed: (1) infusion of somatostatin, resulting in combined insulin and glucagon deficiency, (2) somatostatin and intraportal glucagon replacement (1 ng./kg./min.) to produce insulin deficiency, (3) somatostatin combined with intraportal insulin replacement (350 μU./kg./min.) to produce glucagon deficiency, and (4) saline controls. Simultaneous blood sampling from the femoral artery and portal and hepatic veins allowed determination of hepatic uptake or production of free fatty acids, glycerol, ketone bodies, and glucose. When combined deficiency of insulin and glucagon was produced, no significant effect on hepatic ketone production was noted (108 ± 6 per cent of mean basal), whereas the induction of selective Insulin deficiency (basal glucagon level maintained) resulted in a rise of net hepatic ketone production (185 ± 24 per cent of mean basal, P To assess the effect of increased substrate supply on ketogenesis, all experiments included a period of acute elevation of free fatty adds (FFA), produced by infusion of Intralipld and heparin. FFA elevation in saline controls caused only a moderate stimulation of ketone production (149 ± 16 per cent of mean basal, P The study demonstrated that basal insulin plays an important role in repressing ketogenesis and that basal amounts of glucagon, while ineffective in the presence of insulin, exert a stimulatory effect on ketogenesis when insulin is deficient. Glucagon9s stimulatory effect on ketogenesis was due to an effect in the liver rather than to an increase in lipolysis or in hepatic FFA uptake. Increasing FFA supply per se was associated with only limited stimulation of ketogenesis, whereas the combination of insulin deficiency, basal concentrations of glucagon, and increased FFA load produced a synergistic augmentation of hepatic ketone production.