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Effects of fasting on glucose, ketone bodies, free fatty acids (FFA), insulin and glucagon metabolism were studied in eight fed, five 1-d-fasted and five 3-d-fasted ewes. The 3-d fast decreased blood glucose from 55 to 49 mg/dl due to a 40% reduction in its splanchnic output. Plasma FFA increased from 280 to 872 and 912 microM in 1- and 3-d-fasted ewes concomitant with increased omental and peripheral release. Hepatic uptake of FFA increased three- and fourfold and was concentration-dependent. Consequently, hepatic release of acetoacetate and beta-hydroxybutyrate increased from -43 and 276 to 90 and 1304 mumol/min, respectively, in 3-d-fasted ewes. Alimentary ketogenesis ceased entirely due to lack of substrate and gut tissue was actually utilizing both ketone bodies by d 3 of fast. Lower hindquarter utilization of both ketone bodies increased with increasing circulating concentrations. Insulin seemed to be the major mechanism of regulation of glucose, FFA and ketone body metabolism since pancreatic production and arterial concentrations of insulin decreased with progressive fasting. No changes were observed in glucagon concentrations or net fluxes, and therefore the role of glucagon was passive and secondary to that of insulin.

To determine the mechanism of autoregulation of ketogenesis, beta-hydroxybutyrate was infused into 5 normal; 3 diabetic, insulin-treated; and 3 diabetic, untreated anesthetized sheep. Net flux of fatty acids, acetoacetate, beta-hydroxybutyrate, and insulin were measured across splanchnic tissues by multiplying venoarterial differences by blood flow. beta-hydroxybutyrate depressed fatty acid concentrations and hepatic uptake. This decrease in hepatic uptake was not due solely to decreased concentrations, because hepatic extraction decreased 40% in normal and insulin-treated sheep. Portal-drained visceral release of acetoacetate was increased by beta-hydroxybutyrate infusion in normal and insulin-treated sheep, but this was associated with even larger increases in hepatic uptake, resulting in decreased total splanchnic release. Portal-drained viscera switched from release to uptake of beta-hydroxybutyrate in both normal and insulin-treated animals, but hepatic release increased slightly in normal sheep. beta-hydroxybutyrate increased insulin concentration, pancreatic production, and hepatic uptake. Because effects of ketone infusion on net fluxes of fatty acids, acetoacetate, and beta-hydroxybutyrate were similar in normal and diabetic, insulin-treated sheep but were diminished or totally absent in diabetic, untreated animals, the mechanism of autoregulation of ketogenesis may be mediated at the insulin receptor or at the site of hepatic fatty acid uptake.

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