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 hypoglycemic 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) 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 endogenous 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 depancreatized 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. MethodsIn the studies designed to compare the effects of ,3-hydroxybutyrate 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)

There is abundant experimental evidence indicating that adrenal glucocorticoids have a profound effect on carbohydrate metabolism (1-9). Agreement is general that they accelerate hepatic gluconeogenesis and increase liver glycogen stores (5-9), but their action on peripheral glucose utilization is still unsettled (5,6,8). Although the effects of the chronic administration of glucocorticoids are well defined and changes in carbohydrate metabolism have been recorded as early as 2 to 4 hours (10-18) after adrenocorticoid administration, the precise time of onset of glucocorticoid-induced alterations in carbohydrate metabolism has not been established. An immediate action on glucose metabolism has not been demonstrated in vivo; indeed, recent studies have suggested that the effect of adrenocorticoids on carbohydrate metabolism is delayed for at least 2 hours, beginning at a time when steroid concentrations are decreasing (10,13, 14). The changes in glucose metabolism occurring in the earliest period after glucocorticoid administration are especially * Submitted for publication July 12, 1963; accepted October 17, 1963. This work was supported in part by a U. S. Public Health Service grant (A-4236) from the National Institute of Arthritis and Metabolic Diseases, Bethesda, Md., and by grants from the Upjohn Co., Kalamazoo, Mich., and Chas. Pfizer & Co., New York, N. Y.A preliminary report of this work has been published in abstract form (The paradoxical effect of hydrocortisone on hepatic glucose output. Clin. Res. 1961, 9, 29 important to define since obscuring secondary effects are less likely to be present.The purpose of the present study was 1) to delineate the earliest detectable change in carbohydrate metabolism after acute glucocorticoid administration, 2) to characterize the early effects of glucocorticoids on hepatic glucose output, and 3) to determine whether glucocorticoids alter peripheral glucose utilization. Changes in hepatic glucose output and peripheral glucose utilization were followed during the initial 90 to 120 minutes after the intravenous injection of cortisol in dogs with chronic end-to-side portacaval shunts. This preparation was chosen because it separates the liver from the extrahepatic splanchnic circulation and therefore permits measurement of hepatic rather than splanchnic glucose balance. From the changes in hepatic glucose output and arterial glucose concentration, changes in peripheral glucose utilization can be calculated (19). MethodsThirteen studies were done on dogs with complete endto-side portacaval shunts. At least 1 month was allowed for complete recovery from the operative procedure before experiments were performed. Stable weights were maintained in these animals by a diet, supplemented with vitamins, containing 5&% of the total calories as carbohydrate, 20 to 30% as protein, and the remainder as fat.Studies were performed after a 15-hour, overnight fast with Nembutal anesthesia (25 mg per kg). Hepatic venous samples were collected through a cardiac catheter inserted deep...

No abstract