Studies on Ketone Metabolism in Man. II. The Effect of Glucose, Insulin, Cortisone and Hypoglycemia on Splanchnic Ketone Production1

Abstract

We have previously described a technique which utilizes hepatic venous catheterization for the estimation of net splanchnic ketone body production (NSKP) in man (1). In a series of subjects without metabolic abnormality, a small but significant endogenous NSKP was detected in the postabsorptive state, and upon the intravenous administration of a ketone body precursor, sodium octanoate, the NSKP was increased fivefold. The present report concerns the application of this technique to the study of the effects of glucose, insulin, cortisone and hypoglycemia on ketone body production in man. METHODSTwenty-seven mildly ill male hospital patients between the ages of 23 and 58 years, without metabolic abnormality, were used as subjects and studied after a 12 to 14 hour fast. The criteria of selection and management of subjects, technique of hepatic venous catheterization, methods of chemical analysis, and calculations are identical to those previously reported (1). The 16 normal males in the study will serve as the control series, designated "1955 series," for the present experiments.The subjects of the present experiments were divided into four groups and studied in a manner similar to the "1955 series" except for the specific metabolic alterations noted below for each group under "Results." The general plan of study for all groups was as follows: After mild phenobarbital sedation, inlying femoral arterial and forearm venous needles and the hepatic venous catheter were inserted. An intravenous infusion of bromsulphalein was started and maintained throughout the period of study. A control study was made on each subject during which femoral arterial and hepatic venous bloods were each sampled four times at five minute intervals for the subsequent determination of bromsulphalein, glucose and total ketone concentrations. A 500 ml. infusion of a 1.5 per cent solution of sodium octanoate was then administered intravenously at a constant rate over a one hour period, during which time blood sampling was repeated four times at 15 minute intervals. Blood sampling for oxygen content and saturation was interspersed at appropriate intervals during each period. The estimated hepatic blood flow (EHBF) was determined by the technique of Bradley, Ingelfinger, Bradley and Curry (2). The net splanchnic glucose production (NSGP) and net splanchnic ketone production (NSKP) are the products of the hepatic blood flow and the hepatic venous-arterial blood glucose and ketone differences, respectively. The net splanchnic oxygen consumption (SPO.) was calculated by multiplying the arterial-hepatic venous blood oxygen differences by the EHBF.

The Role of the Endocrine Glands in Ketosis. Ii. Ketonemia Following Insulin Hypoglycemia*

“…The results of this study confirm and extend those obtained in man (10) and are similar to our findings in fasting ketosis (1), with one exception. Cortisone inhibited fasting ketosis but did not modify insulin hypoglycemic ketosis either in man or in the rat.…”

“…In contrast, ketone levels initially fell 2 hours after injection of insulin followed by a rise to levels over 12 mg per 100 ml at 4 and 6 hours, an increment of 6.6 mg per 100 ml above the fasting ketonemia. Cortisone pretreatment suppresses ketosis during fasting and cold stress in rats (9), but does not prevent the increase in ketonemia and net splanchnic ketone body production following insulin hypoglycemia in either man (10) or the rat (Table I). Despite several different steroid regimens, the increments in ketonemia at 4 and 6 hours were of the same order as in normals.…”

“…McPherson, Werk, Myers and Engel studied the effects of glucose and insulin on net splanchnic ketone production in man during an infusion of sodium octanoate (10). Arterial blood ketone levels were lower when insulin and glucose were infused than with glucose alone, despite comparable net splanchnic ketone production.…”

Carbohydrate Metabolism of the Liver in Normal Man under Varying Dietary Conditions

“…The estimation of glucose production showed a wide variation from 0.47-1.36 mmoymin (4,18,20,25,26,39,40,42). The reason for this variation was probably due to the varying conditions of the individual subjects as well as a lack of standardization of the diet prior to the examination and different emotional reactions to the investigation (27).…”

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

“…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)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Only scant attention, however, has been paid to the effects that hyperketonemia, in turn, might have on carbohydrate and fat metabolism.…”