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

Abstract

The effects of alterations in carbohydrate metabolism induced by starvation and insulin deprivation on hepatic ketone production and peripheral ketone utilization have been the subject of intensive investigation (1-12). Only scant attention, however, has been paid to the effects that hyperketonemia, in turn, might have on carbohydrate and fat metabolism. The conflicting results from such studies (13-17) have been reviewed recently (18). Studies in this laboratory, designed to define the effects of induced hyperketonemia on carbohydrate and fat metabolism (18, 19), showed that iv infusions of ,8-hydroxybutyric acid, acetoacetic acid, or their sodium salts produced the following immediate changes in glucose and nonesterified fatty acid (NEFA) metabolism: 1) blood glucose concentration fell promptly, at times to distinctly hypo-glycemic levels, 2) hepatic glucose output decreased sharply to less than 50% of control values, a reduction accounting entirely for the decrease in arterial glucose concentration, and 3) these changes in glucose metabolism were accompanied simultaneously by a greater than 50% fall in arterial plasma NEFA concentration. The qualitative similarity between ketone infusion and the slow iv administration of insulin (20) not t During tenure of U. S. Public Health Service post-doctoral fellowship (APD-17,224) of the National Institute for Arthritis and Metabolic Diseases. t During tenure of a predoctoral fellowship. only on blood glucose concentration and hepatic glucose output but also on plasma NEFA concentration suggested the possibility that ketones produce these effects via stimulation of endoge-nous insulin secretion. The present studies were designed specifically to determine whether ketone bodies stimulate the pancreatic 8-cells, directly or indirectly, to secrete increased amounts of insulin. Two types of studies were performed: in the first group, the effects of hyperketonemia produced by infusions of 8-hydroxybutyrate and acetoacetate on blood glucose concentrations were compared in depan-creatized dogs and in dogs with alloxan diabetes; in the second group of studies, the changes in pancreatic venous insulin concentrations were determined by immunoassay during infusions of ketones either into a femoral vein or into a branch of the pancreatic artery. Methods In the studies designed to compare the effects of ,3-hy-droxybutyrate and acetoacetate on the arterial glucose concentration of totally diabetic depancreatized and partially diabetic alloxanized dogs, experiments were performed at least 2 weeks after alloxanization (21) or. total pancreatectomy to permit complete recovery. Pan-createctomy was performed and postoperative treatment carried out according to the technique of Markowitz, Archibald, and Downie (22). The diabetic state was controlled in both groups with NPH insulin, which was discontinued 12 to 20 hours before study. The time allowed to elapse after discontinuation of maintenance insulin in both the alloxanized and depancreatized groups was varied in an effort to obtain similar starting blood glucose concentrations in both groups so that a po-tentiating effect of ketones on administered insulin could be observed if it occurred in the depancreatized dogs. After an overnight fast the dogs were anesthetized with Nembutal (sodium pentobarbital). Arterial blood samples were obtained through an indwelling Cournand 408