We studied the effect of suppression of lipolysis on ketogenesis in rats with established diabetic ketoacidosis (DKA) using 16, 16-dimethylprostaglandin E2 (DMPGE2) as an antilipolytic agent.

DMPGE2 produced a dose-related reduction in plasma free fatty acid (FFA) levels and a reduction in plasma glycerol levels after an intravenous injection of up to 2 μg/kg body weight in animals with streptozotocin-induced DKA. In contrast, doses of PGE2 varying from 2 to 500 μg/kg body weight intravenously failed to suppress lipolysis and some doses were lipolytic. In nondiabetic rats, DMPGE2 produced a fall in the FFA and glycerol levels and a concomitant reduction in the plasma ketone levels.

When DMPGE2, 2 μg/kg body weight, was administered intravenously every 30 min for 4 h to rats with DKA, the plasm FFA level fell from 2.86 ± 0.36 meq/L at time 0 to 0.78 ± 0.07 meq/L at 4 h; the final value was lower than that found in fed, nondiabetic, nonketotic rats studied under the same conditions. However, the plasma ketone levels remained elevated in response to DMPGE2 (8.36 ± 0.46 mM at time 0; 7.19 ± 0.17 mM at 4 h). In contrast, insulin produced a rapid and marked fall in both the FFA and the ketone levels in comparable animals.

When DMPGE2 was administered together with insulin to rats with DKA, the plasma FFA level fell to the same low level achieved with insulin alone. Nevertheless, DMPGE2 impaired the effect of insulin on the total plasma ketone level. When both agents were given concurrently, the total plasma ketone level fell from 10.26 ± 0.99 mM at time 0 to 5.32 ± 1.67 mM at 4 h; with insulin alone, the total plasma ketone level fell from 8.47 ± 0.84 mM at time 0 to 0.78 ± 0.23 mM at 4 h. DMPGE2 also interfered with the response of the plasma glucose level to insulin.

Conclusions: (1) DMPGE2 is a potent antilipolytic agent in vivo, as well as in vitro. This efficacy contrasts with the absence of an antilipolytic effect of PGE2 in vivo, although both substances suppress lipolysis in vitro. This discrepancy may be explained by the fact that DMPGE2, unlike PGE2, is not rapidly metabolized in the pulmonary circulation. (2) DMPGE2 has an effect on ketogenesis, in addition to its antilipolytic effect, in animals with DKA but not in normal animals. This may be enhancement of hepatic ketogenesis, interference with the peripheral disposal Of ketones, or both.

This content is only available via PDF.