Ketogenic action of glucagon in insulin-dependent diabetic subjects.

Abstract

In order to determine whether glucagon has a ketogenic effect through the activation of hepatic ketogenesis or not, 1mg of glucagon was injected intravenously in bolus in normal and in mild or severe (insulin-dependent) diabetics, and plasma levels of 3-hydroxybutyrate (3-OHBA) and free fatty acid (FFA) were measured.The ketogenic effect of insulin-free glucagon was also tested in the diabetic rats. The effect of (+)-decanoylcarnitine, an inhibitor of hepatic fatty acid oxidation at a step catalyzed by carnitine palmitoyltransferase, upon the ketogenic action of glucagon was also studied in the diabetic rats.In normal and in mild diabetics, glucagon had no effect on plasma 3-OHBA concentration, but a significant elevation (0.55m mole/l at 30min) was observed following glucagon in insulin-dependent diabetics. The hyperketonemic effect of glucagon was most marked (1.6m mole/l at 30 min) in those who exhibited mild ketonemia before the glucagon injection. No comparable rise of plasma FFA was observed in these subjects. In normal subjects, plasma FFA significantly decreased following glucagon, presumably due to the anti-lipolytic effect of released endogenous insulin.In normal rats, insulin-free glucagon (0.5mg iv) produced a small but significant rise of plasma levels of FFA and 3-OHBA within 20 min. In diabetic rats, the greater rise of plasma 3-OHBA (1.4m mole/l at 20 min) following glucagon was observed without any rise of FFA. And this rise was abolished by the concomitant injection of (+)-decanoylcarnitine.These results indicate that glucagon has ketogenic action through the activation of hepatic ketogenesis under conditions where insulinopenia and the absence of endogenous release of insulin coexist.