thromboxane-a2 and Hyperglycemia

Diabetic nephropathy is preceded by 'hyperfiltration' mediated by dilatation of the afferent arterioles to the glomeruli by means of IGF-1, prostaglandins, bradykinin, nitric oxide and atrial natriuretic peptide, together with constriction of the efferent arterioles by local thromboxane A2. Raised glomerular intracapillary pressures might then contribute to glomerulosclerosis, but in any case there is permeability of the vascular endothelium. AGEPs and lipid peroxides can explain this. AGEPs, or simply intermittently high levels of glucose, also account for synthesis of extracellular matrix proteins that lead to thickening of the basement membrane and glomerulosclerosis. Another glucose product, glucosamine-6-phosphate, is formed when there is hexosamine flux along with insulin resistance in tissues, and is implicated in glomerulosclerosis, since it also stimulates TGF-beta transcription. In seeking to explain proteinuria, depletion of heparan sulphates from the endothelial cells and GBM is now established as a principal cause. In addition to a high glucose reducing the synthesis of heparan sulphates, it has now been shown that high glucose may depress the synthesis of heparin sulphate proteoglycan.

Topics: Diabetic Nephropathies; Enzyme Activation; Glycosylation; Heparin; Humans; Hyperglycemia; Kidney; Protein Kinase C; Thromboxane A2

Excessive hepatic glucose production (HGP) is a major cause of fasting hyperglycemia in diabetes, and antihyperglycemic therapy takes center stage. Nonsteroidal anti-inflammatory drugs, such as acetylsalicylic acid (aspirin), reduce hyperglycemia caused by unrestrained gluconeogenesis in diabetes, but its mechanism is incompletely understood. Here, we reported that aspirin lowers fasting blood glucose and hepatic gluconeogenesis, corresponds with lower thromboxane A2 (TXA2) levels, and the hypoglycemic effect of aspirin could be rescued by TP agonist treatment. On fasting and diabetes stress, the cyclooxygenase (COX)/TXA2/thromboxane A2 receptor (TP) axis was increased in the livers. TP deficiency suppressed starvation-induced hepatic glucose output, thus inhibiting the progression of diabetes, whereas TP activation promoted gluconeogenesis. Aspirin restrains glucagon signaling and gluconeogenic gene expression (phosphoenolpyruvate carboxykinase [PCK1] and glucose-6-phosphatase [G6Pase]) through the TXA2/TP axis. TP mediates hepatic gluconeogenesis by activating PLC/IP3/IP3R signaling, which subsequently enhances CREB phosphorylation via facilitating CRTC2 nuclear translocation. Thus, our findings demonstrate that TXA2/TP plays a crucial role in aspirin's inhibition of hepatic glucose metabolism, and TP may represent a therapeutic target for diabetes.

Topics: Aspirin; Diabetes Mellitus; Glucagon; Gluconeogenesis; Glucose; Humans; Hyperglycemia; Hypoglycemic Agents; Liver; Thromboxane A2

Although aspirin treatment is useful in reducing ischaemic events in diabetic patients, recent studies suggest that it is less effective when compared with non-diabetics (ND). We sought to evaluate COX-1 sensitivity and thromboxane A(2) (TxA(2)) production in type 1 (T1DM) and type 2 diabetic (T2DM) patients under chronic aspirin treatment, and also evaluate the association between thromboxane A(2) (TxA(2)) production and markers of inflammation and metabolic control, such as high-sensitivity C-reactive protein, fasting blood glucose, and haemoglobin A1c (HbA1c).. Agonist-induced platelet aggregation (PA) and TxB(2), a stable metabolite of TxA(2), production, serum TxB(2), and platelet COX-1 and COX-2 expression were studied in T2DM patients, T1DM patients, and high-risk ND subjects, all receiving a low dose of aspirin. TxB(2) formation was studied in platelets treated in vitro with aspirin alone or with a COX-2 inhibitor (NS-398). PA, collagen-induced TxB(2) production, and serum TxB(2) were higher in T1DM and T2DM patients than in ND subjects. TxB(2) production was reduced in diabetic patients by in vitro treatment with aspirin. COX-2 was expressed in all diabetic patients but only in 46% of ND patients. In diabetic patients significant correlations were observed between TxB(2) production and both fasting plasma glucose and HbA1c.. COX-1 sensitivity and TxB(2) production is similarly reduced in both T1DM and T2DM patients under chronic aspirin treatment. The association between TxB(2) production and either fasting plasma glucose and HbA1c levels suggests that in diabetic patients hyperglycaemia is a determinant of the reduced platelet sensitivity to aspirin.

Topics: Adult; Aged; Aspirin; Blood Platelets; C-Reactive Protein; Case-Control Studies; Cyclooxygenase 1; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Resistance; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Statistics, Nonparametric; Thromboxane A2

The interaction between angiotensin-(1-7) [Ang-(1-7)] and bradykinin (BK) was studied in the isolated mesenteric arteriolar bed of control and diabetic rats perfused with either 5.5 or 22 mM of glucose. Prostanoids release after the administration of BK, Ang-(1-7) and Ang-(1-7)+BK was also studied. In control and diabetic preparations perfused with Krebs Henseleit solution with 5.5mM of glucose, Ang-(1-7) potentiates BK-induced vasodilation. On the other hand, the potentiating effect disappeared in control and diabetic preparations perfused with 22 mM of glucose. Prostaglandin F(2alpha) (PGF(2alpha)) release induced by BK and Ang-(1-7)+BK was increased in perfusates of diabetic preparations containing 22 mM of glucose. The release of thromboxane A(2) (TXA(2)) (measured as TXB(2)) or prostaglandin I(2) (PGI(2)) (measured as 6-keto-PGF(1alpha)) did not differ in control and diabetic preparations perfused with 5.5 and 22 mM of glucose. Our data allow us to suggest that hyperglycemia may be involved in the lack of potentiation in control and diabetic preparations; increase in PGF(2alpha) release, but not other cyclooxygenase products, may explain the absence of potentiation in diabetic preparations.

Topics: Angiotensins; Animals; Blood Glucose; Bradykinin; Dinoprost; Dinoprostone; Disease Models, Animal; Epoprostenol; Hyperglycemia; Male; Mesenteric Arteries; Prostaglandin-Endoperoxide Synthases; Protein Binding; Rats; Rats, Wistar; Thromboxane A2

Having developed a non-insulin-dependent diabetes mellitus (NIDDM) syndrome model in the rabbit using Wirsung duct ligation, it appeared interesting to use it to study the relationship between glycemia and the plasma levels of TXA(2)and PGI(2), and of some other biochemical parameters such as cholesterol, triglycerides, alkaline phosphatase and transaminases. A comparative study was carried out in the sham-operated rabbits (controls, C) and those having their pancreatic duct ligatured (NIDDM, D) at 15, 30, 40, 50 and 60 days post-ligation. On the 40th days, whereas in the controls, glycemia was 1.17 +/- 0.04 g.l(-1), it reached a maximum of 4.62 +/- 0.76 g.l(-1)(25.40 mM) in the NIDDMs. No significant modification was observed either in cholesterolemia or in triglyceridemia in either group. The GOT and GPT were highly increased, from 11.50 +/- 4.00 IU. l(-1)and 27.00 +/- 1.50 IU.l(-1)(C) to 37.50 +/- 5.64 IU.l(-1)(P<0. 001) and 58.50 +/- 7.50 IU.l(-1)(D) (P<0.001) in the NIDDM group, suggesting that hyperglycemia occurred simultaneously with the degeneration of the pancreatic tissue. In parallel, in D rabbits, the plasma levels of TXB(2)and 6 keto PGF(1alpha)were augmented to 68.22 +/- 6.20 pg.ml(-1)versus 22.49 +/- 5.74 pg.ml(-1)(C) (P<0.001), and 127.11 +/- 14.39 pg.ml(-1)versus 48.65 +/- 4.51 pg.ml(-1)(C) (P<0. 001) respectively. Statistical studies showed a significant correlation (P<0.05 and <0.02) between glycemia and the biosynthesis of eicosanoids under study. Moreover, 25 mM was found to be the threshold level of glucose excess essential to increase the TXA(2)and PGI(2)biosynthesis significantly. This supports the results obtained by other authors studying the action of glucose on phospholipase activity and consequent eicosanoid production.

Topics: 6-Ketoprostaglandin F1 alpha; Alkaline Phosphatase; Animals; Blood Glucose; Blood Proteins; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Epoprostenol; Hyperglycemia; Ligation; Pancreatic Ducts; Platelet Aggregation Inhibitors; Rabbits; Thromboxane A2; Thromboxane B2; Time Factors; Transaminases

The primary etiologic factor in diabetic glomerulosclerosis appears to be an overproduction of transforming growth factor-beta by mesangial cells, which in turn reflects a hyperglycemically mediated overactivation of protein kinase C (PKC) throughout the glomerulus. Membrane-active antioxidants, fish oil, and angiotensin-converting enzyme inhibitors can act to down-regulate glomerular PKC activity, via a variety of mechanisms that may include activation of diacylglycerol kinase and suppression of phosphatidate phosphohydrolase, support of endothelial nitric oxide and heparan sulfate production, inhibition of thromboxane and angiotensin synthesis/activity, and correction of glomerular hypertension. The beneficial impact of these measures on vascular endothelial function may be of more general utility in the prevention of diabetic complications such as retinopathy, neuropathy, and atherosclerosis. Adjunctive use of gamma-linolenic acid is indicated for prevention of neuropathy, and it is conceivable that bioactive chromium will have protective activity not solely attributable to improved glycemic control. Re-establishing euglycemia must clearly remain the core strategy for preventing diabetic complications, but when glycemic control remains suboptimal, practical, safe measures are at hand for decreasing risk.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Antioxidants; Diabetic Angiopathies; Diabetic Nephropathies; Enzyme Activation; Fish Oils; Heparitin Sulfate; Humans; Hyperglycemia; Kidney Glomerulus; Lipid Peroxidation; Models, Biological; Nitric Oxide; Protein Kinase C; Thromboxane A2; Transforming Growth Factor beta

The relationship between high glucose concentrations and arachidonic acid metabolism in uterine tissue from control and diabetic ovariectomized rats was evaluated. Uterine tissue from diabetic rats produced amounts of PGE2 and PGF2 alpha similar to controls, while a lower production of 6-keto-PGF1 alpha (indicating the production of prostacyclin) and a higher production of TXB2 (indicating the generation of TXA2) was found in the diabetic group. A group of diabetic rats was treated with phlorizin to diminish plasma glucose levels. Phlorizin treatment did not alter production of PGE2, PGF2 alpha, and 6-keto-PGF1 alpha in the diabetic group. A diminished production of TXB2 was found in the treated diabetic uteri when compared to the non-treated diabetic group. Moreover, a positive correlation between plasma glucose levels and uterine TXB2 generation was observed. When control uterine tissue was exposed in vitro to high concentrations of glucose (22 mM) and compared to control tissue incubated in the presence of glucose 11 mM alterations in the generation of PGE2, PGF2 alpha, and 6-keto-PGF1 alpha were not found, but a higher production of TXB2 was observed and values were similar to those obtained in the diabetic tissue. Alteration in the production of the prostanoids evaluated were not observed when diabetic tissue was incubated in the presence of high concentrations of glucose. These results provide evidence of a direct relationship between plasma glucose levels and uterine production of TXA2.

Topics: Animals; Arachidonic Acid; Blood Glucose; Dinoprost; Dinoprostone; Female; Glucose; Hyperglycemia; In Vitro Techniques; Ovariectomy; Phlorhizin; Rats; Thromboxane A2; Thromboxane B2; Uterus