The in vivo effects of acute changes in the concentration of plasma free fatty acids on hepatic glucose output and peripheral glucose utilization were defined in thirteen studies in dogs. Dogs with chronic end-to-side portacaval shunts . were used thereby permitting not only measurement of hepatic rather than splanchnic glucose output but also the rate of peripheral glucose utilization. In eighteen additional studies the effect of acute elevations of plasma free fatty acids on serum insulin, plasma glucagon, blood ketones and alpha-amino nitrogen was determined. The quantitative and qualitative changes in plasma free fatty acids which occur during starvation were simulated by the intravenous administration of a cottonseed oil emulsion plus heparin. The acute elevation of plasma free fatty acids produced a 37 per cent decrease in hepatic glucose output and a 30 per cent inhibition of peripheral glucose utilization. This decrease in hepatic glucose output was the consequence both of a significant increase in the secretion of insulin and a decrease in glucagon secretion. These changes in hormonal milieu which attended the increase in plasma free fatty acids could not be ascribed to changes in blood ketones or amino acids since the concentrations of these substances remained unchanged. These data suggest that this feedback of free fatty acids on secretion of insulin and glucagon plays an important physiologic role during starvation in the safe transition from carbohydrate to fat metabolism without the danger of progressive ketoacidosis. it is likely that during starvation plasma free fatty acids contribute to the control and maintenance of a low but vital concentration of plasma insulin.

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