The Hypoglycemic Action of Ketones. II. Evidence for a Stimulatory Feedback of Ketones on the Pancreatic Beta Cells *

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Abstract
Seventeen experiments were performed on dogs to determine whether the hypoglycemic effect of ketones could be ascribed to an increased secretion of endogenous insulin. The failure of ketone infusions to lower blood glucose concentration in completely depancreatized dogs coupled with a fall in blood glucose in alloxanized dogs indicated that the pancreas is necessary for this hypoglycemic action. Intravenous infusions of [beta]-hydroxybutyrate and acetoacetate resulted in a 200% increase in the concentration of insulin in the pancreatic venous blood. Much smaller amounts of ketones infused directly into the pancreatic artery produced an eightfold increase in insulin secretion, indicating that ketones have a direct stimulatory effect on the beta cells. We suggest that during fasting, with its characteristic hyperketonemia, to beta cell stimulation by ketones may represent a feedback for insulin secretion which then modulate NEFA release and ketone production and thereby prevent fatal ketoacidosis during prolonged starvation. The role of hyperketonemia in decreasing peripheral glucose utilization and conserving glucose for use by the central nervous system during the new steady state that characterizes starvation is also discussed.