8-epi-prostaglandin-f2alpha and Glucose-Intolerance

In coronary artery disease patients, enhanced external counterpulsation (EECP) improves peripheral arterial function and nitric oxide (NO) bioavailability, which have been implicated in the pathogenesis of abnormal glucose tolerance (AGT). We sought to evaluate the effects of EECP on outcomes of arterial function, glucose tolerance, and skeletal muscle morphology in subjects with AGT.. 18 subjects with AGT were randomly (2:1 ratio) assigned to receive either 7 wk (35 1-h sessions) of EECP (n = 12) or 7 wk of standard care (control; n = 6). Peripheral vascular function, biochemical assays, glucose tolerance, and skeletal muscle morphology were evaluated before and after EECP or control. EECP increased normalized brachial artery (27%) and popliteal artery (52%) flow-mediated dilation. Plasma nitrite/nitrate (NOx) increased (30%) and 8-isoprostane-PGF-F(2α), a marker of lipid peroxidation in the plasma, decreased (-23%). Fasting plasma glucose declined (-16.9 ± 5.4 mg/dl), and the homeostasis model assessment of insulin resistance (HOMA-IR) decreased (31%) following EECP. Plasma glucose 120 min after initiation of oral glucose tolerance testing decreased (-28.3 ± 7.3 mg/dl), and the whole body composite insulin sensitivity index (C-ISI) increased (21%). VEGF concentrations increased (75%), and vastus lateralis skeletal muscle biopsies demonstrated improvements in capillary density following EECP. No change was observed in cellular signaling pathways, but there was a significant increase GLUT-4 protein expression (47%) following EECP.. Our findings provide novel evidence that EECP has a beneficial effect on peripheral arterial function and glucose tolerance in subjects with AGT.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Blood Pressure; Brachial Artery; Capillaries; Coronary Artery Disease; Counterpulsation; Dinoprost; Glucose; Glucose Intolerance; Glucose Tolerance Test; Glucose Transporter Type 4; Glycemic Index; Humans; Insulin; Middle Aged; Muscle, Skeletal; Neovascularization, Pathologic; Nitric Oxide; Oxidation-Reduction; Phosphorylation; Popliteal Artery; Regional Blood Flow; Signal Transduction; Vascular Endothelial Growth Factor A; Vasodilation

The effect of glucose excursions on oxidative stress is an important topic in diabetes research. We investigated this relationship by analyzing markers of oxidative stress and glycemic data from a continuous glucose monitoring system (CGMS) in 30 individuals with normal glucose regulation (NGR), 27 subjects with impaired glucose regulation (IGR), and 27 patients with newly diagnosed type 2 diabetes (T2DM). We compared the mean amplitude of glycemic excursion (MAGE), mean postprandial glucose excursion (MPPGE), and mean postprandial incremental area under the curve (IAUC) with plasma levels of oxidative stress markers 8-iso-PGF2α, 8-OH-dG, and protein carbonyl content in the study subjects. Patients with T2DM or IGR had significantly higher glucose excursions and plasma levels of oxidative stress markers compared to normal controls (P < 0.01 or 0.05). Multiple linear regression analyses showed significant relationships between MAGE and plasma 8-iso-PGF2α, and between MPPGE and plasma 8-OH-dG in patients with IGR or T2DM (P < 0.01 or 0.05). Furthermore, 2h-postprandial glucose level and IAUC were related to plasma protein carbonyl content in the study cohort including T2DM and IGR (P < 0.01). We demonstrate that glucose excursions in subjects with IGR and T2DM trigger the activation of oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Biomarkers; Blood Glucose; Cohort Studies; Deoxyguanosine; Diabetes Complications; Diabetes Mellitus, Type 2; Dinoprost; Female; Glucose Intolerance; Humans; Hyperglycemia; Hypoglycemia; Male; Middle Aged; Monitoring, Ambulatory; Oxidative Stress; Postprandial Period; Protein Carbonylation

Insulin resistance is associated with hypertension by mechanisms likely involving the kidney. To determine how the major apical sodium transporter of the thick ascending limb, the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) is regulated by high-fat feeding, we treated young male, Fischer 344 X Brown Norway (F344BN) rats for 8 wk with diets containing either normal (NF, 4%) or high (HF, 36%) fat, by weight, primarily as lard. HF-fed rats had impaired glucose tolerance, increased urine excretion of 8-isoprostane (a marker of oxidative stress), increased protein levels for NKCC2 (50-125%) and the renal outer medullary potassium channel (106%), as well as increased natriuretic response to furosemide (20-40%). To test the role of oxidative stress in this response, in study 2, rats were fed the NF or HF diet plus plain drinking water, or water containing N(G)-nitro-l-arginine methyl ester (l-NAME), a nitric oxide synthase inhibitor (100 mg/l), or tempol, a superoxide dismutase mimetic (1 mmol/l). The combination of tempol with HF nullified the increase in medullary NKCC2, while l-NAME with HF led to the highest expression of medullary NKCC2 (to 498% of NF mean). However, neither of these drugs dramatically affected the elevated natriuretic response to furosemide with HF. Finally, l-NAME led to a marked increase in blood pressure (measured by radiotelemetry), which was significantly enhanced with HF. Mean arterial blood pressure at 7 wk was as follows (mmHg): NF, 100 +/- 2; NF plus l-NAME, 122 +/- 3; and HF plus l-NAME, 131 +/- 2. Overall, HF feeding increased the abundance of NKCC2. Inappropriately high sodium reabsorption in the thick ascending limb via NKCC2 may contribute to hypertension with insulin resistance.

Topics: Animals; Antioxidants; Biomarkers; Blood Pressure; Blotting, Western; Crosses, Genetic; Cyclic N-Oxides; Dietary Fats; Dinoprost; Enzyme Inhibitors; Furosemide; Glucose Intolerance; Hypertension; Insulin Resistance; Kidney Medulla; Male; Natriuresis; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Potassium Channels, Inwardly Rectifying; Rats; Rats, Inbred BN; Rats, Inbred F344; Sodium Potassium Chloride Symporter Inhibitors; Sodium-Potassium-Chloride Symporters; Sodium-Potassium-Exchanging ATPase; Solute Carrier Family 12, Member 1; Spin Labels; Telemetry; Time Factors; Up-Regulation

There is evidence that acarbose reduces the risk for development of diabetes and cardiovascular complications. The mechanism underlying the vasculoprotective effect is however not known. We hypothesized that vasculoprotection observed by acarbose may be the consequence of a diminished generation of oxidative stress.. Lean and obese Zucker rats received a diet containing 10% sucrose for 7 days. A part of the rats was treated with acarbose (15 mg/kg/day in chow). Blood glucose, plasma insulin, lipid peroxides, and as a more specific marker of oxidative stress, 8-isoprostanes, were analyzed. As cellular markers of oxidative stress we determined the activities of mitochondrial aconitase and NADPH-oxidase in aorta, heart, and kidney. In addition, poly(ADP-ribose) polymerase activity (PARP) was measured in aorta.. Sucrose feeding of obese Zucker rats resulted in increased blood glucose levels, plasma insulin, lipid peroxides and 8-isoprostanes. Mitochondrial aconitase was reduced; the activities of NAPDH-oxidase and PARP were enhanced. Treatment of obese Zucker rats with acarbose largely prevented these changes, whereas it had no effect in lean sucrose fed rats.. Specifically in obese Zucker rats sucrose feeding is associated with an increased oxidative stress. The data provide IN VIVO evidence that mitochondria play a role in the generation of reactive oxygen species (ROS) in insulin resistant, hyperglycaemic states. Activation of PARP by ROS may be an important mediator of vascular dysfunction in insulin resistance. Treatment with acarbose is helpful to prevent the increase in oxidative stress and vascular dysfunction induced by hyperglycemia.

Topics: Acarbose; Aconitate Hydratase; Aging; Animals; Aorta; Dinoprost; Glucose Intolerance; Lipid Peroxidation; Lipid Peroxides; Male; Mitochondria; NADPH Oxidases; Obesity; Organ Specificity; Oxidative Stress; Poly(ADP-ribose) Polymerases; Rats; Rats, Zucker; Thinness

To measure oxidative stress, endothelial dysfunction and insulin resistance in Indian Mauritians at different stages of development of Type II (non-insulin-dependent) diabetes mellitus.. Plasma total 8-epi-PGF2alpha, an indicator of oxidative stress, was determined in age-matched subjects with normal glucose metabolism (n = 39), impaired glucose tolerance (n = 14), newly diagnosed diabetes (n = 8) and established diabetes (n = 14). Plasma glucose and insulin were measured at baseline and 2 h following an oral glucose tolerance test. Endothelial function was assessed by non-invasive digital pulse wave photoplethysmography.. Plasma 8-epi-PGF2alpha increased in subjects with impaired glucose tolerance (p < 0.05) compared with control subjects, and was even higher in newly diagnosed diabetic patients (p < 0.01) and established (p < 0.01) diabetic patients. A tendency towards reduced endothelial function in subjects with impaired glucose tolerance became significant in patients with newly diagnosed and established diabetes (p < 0.01), and was correlated with 8-epi-PGF2alpha (r = 0.36, p < 0.01). Insulin resistance (homeostasis model assessment) did not change in subjects with impaired glucose tolerance compared with control subjects, but increased in newly diagnosed (p < 0.01) and established (p < 0.001) diabetic subjects. The 8-epi-PGF2alpha was correlated with fasting glucose (r = 0.50, p < 0.001), triglycerides (r = 0.40, p < 0.001) and insulin resistance (r = 0.35, p < 0.001).. Oxidant stress is an early event in the evolution of Type II diabetes and could precede the development of endothelial dysfunction and insulin resistance.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dinoprost; Endothelium, Vascular; F2-Isoprostanes; Fasting; Female; Glucose; Glucose Intolerance; Humans; India; Insulin Resistance; Male; Mauritius; Middle Aged; Oxidative Stress; Reference Values; Triglycerides