15-keto-13-14-dihydroprostaglandin-e2 and Diabetic-Ketoacidosis

Nonketotic diabetes mellitus (DM) is associated with increased platelet production of thromboxane (TX) A2 and decreased endothelial production of prostacyclin (prostaglandin [PG]I2), but measurements of stable derivatives of these substances in the circulation have yielded discordant results. We studied the relationship between the severity of nonketotic DM and the plasma levels of 13,14-dihydro-15-keto-PGE2, 6-keto-PGF1 alpha, and TXB2 (stable derivatives of PGE2, PGI2, and TXA2, respectively) in rats, using three commonly employed doses of streptozotocin (40, 50, and 60 mg/kg body weight) to induce nonketotic DM of varying severity. Small differences in the severity of DM were associated with considerable differences in the plasma levels of 13,14-dihydro-15-keto-PGE2 and 6-keto-PGF1 alpha but not TXB2. Each eicosanoid responded differently to variations in the severity of DM. The plasma 13,14-dihydro-15-keto-PGE2 level was significantly lower than normal in the rats given 40 mg/kg streptozotocin, was unchanged from normal in the rats given 50 mg/kg and was significantly higher than normal in the rats given 60 mg/kg. The plasma 6-keto-PGF1 alpha level was significantly increased in rats given 40 mg/kg and 60 mg/kg, but was unchanged in those given 50 mg/kg. The plasma TXB2 level was not significantly different from normal in any one of the three groups of rats with nonketotic DM. The effect of severity on the plasma levels of the PGE2 and PGI2 derivatives is unexplained, but may reflect the origin of these derivatives from diverse organs and tissues, and the differing effects of abnormal metabolic factors (eg, fatty acids, glucose, insulin, pH) on the synthesis of these derivatives.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetic Ketoacidosis; Dinoprostone; Epoprostenol; Keto Acids; Male; Prostaglandins E; Rats; Rats, Inbred Strains; Regression Analysis; Thromboxane B2

Plasma levels of 13,14-dihydro-15-keto-PGE2, a stable derivative of PGE2, are elevated in rats with diabetic ketoacidosis (DKA) and decrease in response to insulin therapy. In patients with insulin-dependent diabetes mellitus type I (IDDM) the plasma levels of this derivative also rise in response to insulin withdrawal and then fall in response to insulin replacement. We wished to determine whether the level of this substance is elevated acutely when patients present with DKA and to determine whether the levels fall during treatment. We also wished to identify the origin of the circulating 13,14-dihydro-15-keto-PGE2 in patients with DKA and in normal fasting subjects. We measured the plasma level of 13,14-dihydro-15-keto-PGE2 in five patients with DKA and in six normal subjects during a 24-h fast. In the patients with DKA before treatment, the plasma 13,14-dihydro-15-keto-PGE2 level was threefold above normal. During therapy, the 13,14-dihydro-15-keto-PGE2 level fell toward normal. There was a significant direct correlation between the plasma free fatty acid (FFA) level and the plasma 13,14-dihydro-15-keto-PGE2 level before and during treatment. In addition, the inverse correlation between the plasma free-insulin level and the plasma 13,14-dihydro-15-keto-PGE2 level approached significance (P = .06). In contrast, in the normal fasting subjects the plasma FFA level rose to values comparable to those observed in the patients with DKA, but there was no significant increase in the plasma 13,14-dihydro-15-keto-PGE2 level.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adipose Tissue; Adolescent; Adult; Aged; Blood Glucose; Diabetic Ketoacidosis; Dinoprostone; Fasting; Fatty Acids, Nonesterified; Female; Humans; Insulin; Ketone Bodies; Lipolysis; Male; Middle Aged; Prostaglandins E

Insulin therapy was withdrawn from 15 well-controlled type I diabetic subjects for no longer than 18 h to examine the sequence with which 13,14-dihydro-15-keto-PGE2 (PGE-m), glucagon, norepinephrine, and epinephrine increased in circulating blood in diabetic subjects becoming ketoacidotic. Fourteen of 15 patients had increments in PGE-m; 12/12, 12/15, and 13/15 had increments in glucagon, norepinephrine, and epinephrine, respectively. Six of the 15 patients developed mild diabetic ketoacidosis (DKA) by 12-18 h; all had nonmeasurable C-peptide levels. This DKA group had significantly greater increments of PGE-m (835 +/- 130 versus 276 +/- 111 pg/ml, mean +/- SEM, P less than 0.01) but not glucagon, norepinephrine, or epinephrine compared with the 9 non-DKA patients. In the DKA group, there were significant PGE-m and glucagon increments in the circulation by 3 h, significant norepinephrine increments by 9 h, and epinephrine increments in 5/6 patients by 12 h (not statistically significant) of insulin withdrawal. These studies document that (1) PGE-m accumulates in the circulation during DKA, (2) PGE-m and glucagon increase before catecholamines, and (3) PGE-m, glucagon, and catecholamine levels promptly return to normal levels when insulin therapy is reinstituted. It is suggested that elevated PGE-m levels early in the onset of DKA may represent a host-defense mechanism.

Topics: Adult; Diabetic Ketoacidosis; Dinoprostone; Epinephrine; Female; Glucagon; Humans; Insulin; Male; Norepinephrine; Prostaglandins E

We studied the effects of two structurally unrelated inhibitors of the fatty acid cyclooxygenase and of alpha and beta adrenergic blockade on the elevated plasma levels of 13,14-dihydro-15-keto-prostaglandin (PG)E2, 6-keto-PGF1 alpha and thromboxane (TX)B2, the stable derivatives of PGE2, PGI2 (prostacyclin) and TXA2, respectively, in rats with streptozotocin-induced diabetic ketoacidosis (DKA). Meclofenamic acid and indomethacin each produced a significant decrease in the elevated plasma levels of 13,14-dihydro-15-keto-PGE2, 6-keto-PGF1 alpha and TXB2. Phentolamine significantly reduced the plasma level of TXB2 but had no effect on the elevated circulating levels of glucose, free fatty acids, total ketones, 13,14-dihydro-15-keto-PGE2 or 6-keto-PGF1 alpha. Propranolol significantly reduced the elevated circulating levels of glucose, free fatty acids and total ketones but had no effect on the levels of the three prostaglandin derivatives. The ability of meclofenamic acid and indomethacin to reduce the plasma levels of 13,14-dihydro-15-keto-PGE2, 6-keto-PGF1 alpha and TXB2 confirms that the plasma levels of these three derivatives are elevated in rats with DKA. Since abnormalities in the production of PGI2 and perhaps other cyclooxygenase derivatives may contribute to the pathogenesis of certain important hemodynamic and gastrointestinal features of DKA, cyclooxygenase inhibitors may play a role in the management of selected patients with this disorder. Alpha adrenergic activity is essential for the maintenance of the elevated plasma TXB2 level in rats with DKA. The fall in the plasma TXB2 level during alpha adrenergic blockade appears to reflect inhibition of platelet aggregation and platelet TXA2 production, but other sources of the elevated plasma TXB2 level in DKA are not excluded. Beta adrenergic activity contributes to the maintenance of elevated circulating levels of glucose, free fatty acids and total ketones in experimental DKA but not to the elevated plasma levels of the prostaglandin derivatives.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Glucose; Cyclooxygenase Inhibitors; Diabetes Mellitus, Experimental; Diabetic Ketoacidosis; Dinoprostone; Fatty Acids, Nonesterified; Indomethacin; Ketone Bodies; Male; Meclofenamic Acid; ortho-Aminobenzoates; Phentolamine; Propranolol; Prostaglandins; Prostaglandins E; Rats; Rats, Inbred Strains; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetic Ketoacidosis; Dinoprostone; Fatty Acids, Nonesterified; Insulin; Ketones; Male; Prostaglandins; Prostaglandins E; Pyrazoles; Rats; Rats, Inbred Strains; Thromboxane B2