Hepatic Lipid Metabolism in Experimental Diabetes

Abstract 1. Livers from normal and alloxan diabetic rats were perfused in vitro with a medium in which the concentration of free fatty acid was maintained at relatively constant levels by the infusion of a complex of oleic acid and bovine serum albumin. Concentrations of free fatty acid up to 3.5 mm in the cell-free perfusate were attained. 2. Throughout the range of concentration of free fatty acid which might be expected in the blood under normal and pathological conditions in vivo, the uptake of free fatty acid by the liver in vitro was proportional to the concentration in the medium; rates of uptake of free fatty acid approached saturation only at concentrations of free fatty acid in excess of those encountered in vivo. 3. The accumulation of triglyceride in livers from normal and most probably also in livers from alloxan diabetic rats was proportional to the concentration of free fatty acid in the medium. In contrast to triglyceride, the concentrations of total phospholipid, cholesterol, cholesteryl esters, and free fatty acid in the livers from normal and alloxan diabetic animals was independent of the concentration of free fatty acid in the perfusate. 4. Ketogenesis by livers from normal rats was dependent on the concentration of oleate in the medium; the maximal rates of production of ketone bodies were observed at 1.7 mm oleate. The rate of ketogenesis by livers from normal rats never equaled that by livers from alloxan diabetic animals, regardless of the concentration of free fatty acid in the medium. Although ketogenesis by livers from diabetic rats was responsive to the presence of oleate in the medium, similar and rapid rates of production of ketone bodies were observed over the entire range of concentration of free fatty acid. When livers from normal animals were exposed to high concentrations of oleate and the free fatty acid was withdrawn subsequently, the rates of ketogenesis diminished rapidly even though the concentration of triglyceride was elevated in the liver; glucagon, infused for 3 hours after oleate had been discontinued, could sustain the high rate of ketogenesis only for the short period during which free fatty acid remained in the medium. These observations force us to consider that, unlike free fatty acid, triglyceride fatty acid which accumulates in the livers of normal, fed rats is oxidized slowly, and that glucagon may not exert a major ketogenic action by stimulation of a hepatic triglyceride lipase.