Effect of Infused Ketone Bodies on Glucose Utilization in the Dog*

Abstract

shown that acetoacetate and p-hydroxybutyrate inhibit the uptake and oxidation of glucose in the isolated, perfused rat heart. This effect is ob-served both in the presence (1) and in the absence (2) of insulin. Long-chain fatty acids also im-pair glucose utilization as shown by Shipp, Opie, and Challoner (3), Bowman (4), and Minton and Raben (5). A similar inhibition of glucose uptake by ketone bodies and fatty acids has been observed by using the isolated rat diaphragm. The mechanism of this effect has been studied by Newsholme and associates (6, 7). They have shown that fatty acids reduce the sensitivity of glucose transport in muscle to the accelerating effect of insulin (7) and impair the intracellular phosphorylation of glucose by inhibition of the phosphofructokinase reaction (6). On the basis of these in vitro studies, Randle, Garland, Hales, and Newsholme (7) have re-cently advanced a general proposal that a rise in plasma fatty acids and ketone bodies may impair glucose utilization in the whole animal under certain conditions. On a clinical level, such an effect might relate to the diminished glucose uti-lization associated with diabetic ketoacidosis, and the glucose intolerance observed in Cushing's syndrome, acromegaly, and starvation. In these conditions, improvement in glucose tolerance co-incides with a reduction in blood lipids and ke-tones (8). In apparent contradiction to the proposal of