Regulation of ketogenesis and clinical aspects of the ketotic state

Abstract

Recent studies of the regulation of ketogenesis are reviewed. Under circumstances of relative or absolute insulin deficiency there is a mobilization of free fatty acids from adipose tissue to the liver. While an increased delivery of fatty acids to this organ is important in providing substrate for ketone body formation, it is emphasized that enhanced uptake of fatty acids by the liver is not sufficient in itself to initiate maximal ketogenesis. It appears likely that a major determinant of the rate of ketogenesis is competition for the fatty acid substrate between the β-oxidative and triglyceride synthesizing pathways. While it is widely held that the rate of triglyceride synthesis is primary and that only those fatty acids not utilized for esterification become available for oxidation, evidence for the reverse sequence is presented. It is considered likely that fatty acids are utilized for triglyceride synthesis only insofar as they escape uptake and oxidation in the mitochondria. Regardless of the mechanism, fatty acid oxidation is increased in the ketotic state with the consequence that acetyl-CoA production is accelerated. Since the utilization of acetyl-CoA for fatty acid synthesis and, to a much lesser extent, its oxidation in the Krebs cycle is impaired, the synthesis of acetoacetate and β-hydroxybutyrate is stimulated to a remarkable degree. The hepatic overproduction of ketones appears to be coupled to a limited capacity for their utilization by peripheral tissues, the combined effect of which accounts for the life-threatening acidosis seen in diabetic coma. From a clinical standpoint, newer studies relating to the treatment of diabetic ketoacidosis have been covered, with particular attention paid to the problems of late cerebral edema, paradoxical acidification of the cerebrospinal fluid during treatment, shifts of the oxygen dissociation curve due to 2,3-diphosphoglycerate depletion and initial hypokalemia. Recommendations for therapy designed to minmize complications are presented.