6-ketoprostaglandin-f1-alpha and Insulin-Resistance

Insulin sensitivity is decreased by prostaglandin E2 (PGE2), a major product of cyclooxygenase (COX). As shown in erythrocytes, PGE2 formation is inhibited by annexin A7. The present study defined the role of annexin A7 in glucose metabolism. Gene-targeted mice lacking annexin A7 (annexin7 (-/-)) were compared to wild-type mice (annexin7 (+/+)). The serum 6-Keto-prostaglandin-F1α (6-Keto-PGF1α) concentration was measured by ELISA and hepatic COX activity determined by an enzyme assay. Expression of COX-1, COX-2, prostaglandin E synthase, GLUT-4, and insulin receptor was determined by Western blotting. Glucose and insulin serum concentrations were analyzed following an intraperitoneal glucose load and glucose serum levels after intraperitoneal injection of insulin. Experiments were done without and with pretreatment of the mice with COX-inhibitor aspirin. The serum 6-Keto-PGF1α level and hepatic COX activity were significantly higher in annexin7 (-/-) than in annexin7 (+/+) mice. Hepatic COX-1 expression was higher in annexin7 (-/-) mice. Glucose tolerance was decreased in annexin7 (-/-) mice. Intraperitoneal insulin injection decreased the serum glucose level in both genotypes, an effect significantly less pronounced in annexin7 (-/-) mice. Glucose-induced insulin secretion was higher in annexin7 (-/-) mice. GLUT-4 expression in skeletal muscle from annexin7 (-/-) mice was reduced. Aspirin pretreatment lowered the increase in insulin concentration following glucose injection in both genotypes and virtually abrogated the differences in serum insulin between the genotypes. Aspirin pretreatment improved glucose tolerance in annexin7 (-/-) mice. In conclusion, annexin A7 influences insulin sensitivity of cellular glucose uptake and thus glucose tolerance. These effects depend on COX activity.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Annexin A7; Cyclooxygenase 1; Cyclooxygenase 2; Glucose; Glucose Transporter Type 4; Insulin; Insulin Resistance; Intramolecular Oxidoreductases; Liver; Mice; Muscle, Skeletal; Prostaglandin-E Synthases; Receptor, Insulin

The work was designed to study levels of serum prostaglandin F1a (6-keto-PGF1a), thromboxane B2, and leukotriene B4 (LTB4)--stable products of cyclooxygenase and lipogenase-catalyzed reactions of arachidonic acid, in patients with metabolic syndrome (MS) differing in glucose homeostasis. It was shown that MS is associated with excess production of anti-inflammatory oxilipines (LTB4) regardless of the presence or absence of insulin resistance. LTB4 are known to influence inflammatory processes due to compensatory synthesis of vasodilating eicosanoids (6-keto-PGF1a) that antagonize vasoconctriction and inflammation. Combination of MS with insulin resistance in patients with elevated LTB4 and 6-keto-PGF1a levels is associated with enhanced synthesis of thromboxane A2 responsible for vasoconstriction, platelet formation, and development of endothelial dysfunction. The study suggests disturbed synthesis of eicosanoids in patients with MS and their important role in pathogenesis of this condition.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Eicosanoids; Female; Humans; Insulin Resistance; Leukotriene B4; Male; Metabolic Syndrome; Middle Aged; Thromboxane B2; Young Adult

To investigate insulin resistance and the effects of intravenous acute saline load on renal production of prostaglandin I(2) (PGI(2)) and thromboxane A(2) (TXA(2)) in salt-sensitive hypertensive patients.. The 24-hour excretion of urinary 6-keto-prostaglandin F (PGF) 1alpha and thromboxane B(2) were measured before and after intravenous acute saline load in 53 hypertensive patients whose salt sensitivity had been determined. Oral glucose tolerance test and insulin release test were performed in all the subjects.. after intravenous acute saline load, the 24-hour excretions of urinary 6-keto PGF 1alpha were significantly lower in salt-sensitive (SS) hypertensive patients than that in non-salt-sensitive (NSS) ones (316+/-57 pg/min vs 371+/-68 pg/min, P<0.01), and the decrease from baseline was much greater in SS group than that in NSS group (197+/-99 pg/min vs 136+/-101 pg/min, P<0.01). Both 24 hour urinary excretion of TXA(2) and the increase in urinary excretion of TXA(2) were significantly greater in SS hypertensive patients than those in NSS ones after salt loading (394+/-32 pg/min vs 359+/-44 pg/min, P<0.01, and 80+/-47 pg/min vs 47+/-45 pg/min, P<0.01, respectively). The plasma glucose and insulin concentrations in every time point were much higher in SS hypertensive subjects than that in NSS ones, and the former group had lower insulin sensitivity index than the latter (0.013+/-0.003 vs 0.018+/-0.004, P<0.01). Saline load produces significantly different effects on renal production of PGI(2) and TXA(2) in SS and NSS hypertensive patients, and these changes may be related to the pathophysiology of SS hypertensive patients after acute salt loading. Insulin resistance is greater in SS hypertensive patients than in NSS ones.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Epoprostenol; Female; Humans; Hypertension; Injections, Intravenous; Insulin Resistance; Kidney; Male; Middle Aged; Sodium Chloride; Thromboxane A2; Thromboxane B2

Although insulin-mediated vasodilation is impaired in insulin resistance, the mechanisms of this are unknown. We investigated factors mediating vasoactive responses to insulin in control and insulin-resistant rats. Responses to insulin in small mesenteric arteries from control and insulin-resistant rats were investigated after blocking endothelin-A receptors, cyclooxygenase, nitric oxide synthase, and potassium channels. In addition, insulin's effect on prostacyclin production in small mesenteric blood vessels was assessed by enzyme immunoassay. Insulin induced a concentration-dependent vasodilation in control arteries that was absent in arteries from insulin-resistant rats. However, in the presence of BQ610, an endothelin-A receptor antagonist, the response to insulin was normalized in insulin-resistant arteries. In control arteries, insulin-induced vasodilation was completely inhibited by indomethacin, meclofenamate, glibenclamide, or potassium chloride. In contrast, neither n-nitro-L-arginine nor the combination of charybdotoxin and apamin altered vasodilation to insulin. In insulin-resistant arteries in the presence of BQ610, vasodilation was also inhibited by indomethacin, glibenclamide, and potassium chloride. Insulin increased prostacyclin production in small mesenteric blood vessels from both groups of rats to a similar degree. Insulin-induced vasodilation in small rat mesenteric arteries is mediated through prostacyclin- and ATP-dependent potassium channels. However, insulin-resistant arteries do not vasodilate to insulin unless endothelin-A receptors are blocked. Thus, impaired relaxation to insulin in insulin-resistant rats is due to enhanced vasoconstriction by endothelin, which offsets a normal vasodilatory response to insulin.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelins; Glyburide; In Vitro Techniques; Indomethacin; Insulin; Insulin Resistance; Male; Mesenteric Artery, Superior; Oligopeptides; Potassium Chloride; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Vasodilation