Correction of Ketosis by Suppression of Lipolysis with 5-Methylpyrazole-3-Carboxylic Acid in Rats with Established Diabetic Ketoacidosis

Abstract

Because the presence of an elevated plasma free fatty acid (FFA) concentration is not always sufficient to promote ketogenesis, we examined the contribution of circulating FFAs to ketogenesis in established diabetic ketoacidosis. We studied the effects of suppression of lipolysis on ketogenesis in rats with established streptozotocininduced diabetic ketoacidosis using 5-methylpyrazole-3-carboxylic acid (5-methylpyrazole) as an antilipolytic agent. In response to this substance, plasma FFA fell from 2.42 ± 0.15 meq/L to 0.56 ± 0.06 meq/L in four hours. There was a concomitant fall in total plasma ketone from 12.17 ± 0.60 mM to 2.62 ± 0.54 mM. The fall in total plasma ketone was due predominantly to a fall in the beta-hydroxybutyrate concentration but also to a fall in the acetoacetate concentration. Although the agent slowed the rise of plasma glucose in these diabetic animals, the concentration was markedly elevated (573 ± 22 mg/dl) at four hours. Studies were performed in comparable rats with diabetic ketoacidosis to exclude the possibility that 5-methylpyrazole interferes with hepatic ketogenesis. When the plasma FFA concentration was raised by administration of a lipid emulsion and heparin (after plasma FFA and total plasma ketone had fallen in response to 5-methylpyrazole), total plasma ketone also rose despite the presence of 5-methylpyrazole. When the plasma FFA concentration was maintained at a high level by administration of a lipid emulsion and heparin from the start of the experiment, 5-methylpyrazole failed to affect the total plasma ketone concentration. Thus, availability of substrate (plasma FFAs) reversed or prevented the correction of ketosis by 5-methylpyrazole. These findings indicate that circulating FFAs are rate limiting for the maintenance of the ketotic state in established diabetic ketoacidosis and support the view that the absence of ketosis in the usual patient with hyperosmolar nonketotic diabetic coma is a result of inadequate availability of plasma FFAs for ketogenesis. 5-Methylpyrazole converts an experimental model of diabetic ketoacidosis into one resembling hyperosmolar nonketotic diabetic coma.