Hypoglycemic action of ketones. I. Effects of ketones on hepatic glucose output and peripheral glucose utilization

The effects of hyperketonemia induced by infusions of β-hydroxybutyrate and acetoacetate on carbohydrate and fat metabolism were examined by measurment of changes in hepatic glucose output, peripheral glucose utilization, and arterial concentrations of glucose and nonesterified fatty acids in 20 experiments in dogs. Ketone bodies were shown to have an immediate effect on glucose metabolism. Their administration produced a progressive hypoglycemia which was entirely the consequence of a 50 per cent reduction in hepatic glucose output. This hypoglycemia occurred despite a significant inhibition of peripheral glucose utilisation. Concomitant with the fall in hepatic glucose output and arterial glucose concentration, nonesterified fatty acid levels declined significantly. The qualitative similarity between the effect of ketones and insulin not only on hepatic glucose output and blood glucose levels but also on nonesterified fatty acid concentration suggests that ketones act via stimulation of endogenous insulin secretion. The data also suggest that during starvation or carbohydrate deprivation hepatic ketone production may be regulated via a feedback of ketones on the pancreatic islets and in this manner prevent the development of progressive ketonemic acidosis.