Autoregulation of alimentary and hepatic ketogenesis in sheep.

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.