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The present study was undertaken to determine oxidative/nitrosative stress in aqueous humor of alloxan-induced hyperglycemic rabbits and to investigate the effects of two oral antidiabetic drugs, pioglitazone from peroxisome proliferator-activated receptor gamma (PPARγ) agonists and repaglinide from nonsulfonylurea K(ATP) channel blockers. Ascorbic acid (AA), glutathione (GSH), total antioxidant status (TAS), lipid peroxidation products (LPO), total nitrites (NO(2)), advanced oxidized protein products (AOPP), and protein carbonyl groups (PCG) were determined using respective colorimetric and ELISA methods. In our hyperglycemic animals, AA decreased by 77%, GSH by 45%, and TAS by 66% as compared to control animals. Simultaneously, LPO increased by 78%, PCG by 60%, AOPP by 84%, and NO(2) by 70%. In pioglitazone-treated animals, AA and TAS increased above control values while GSH and PCG were normalized. In turn, LPO was reduced by 54%, AOPP by 84%, and NO(2) by 24%, in relation to hyperglycemic rabbits. With repaglinide, AA and TAS were normalized, GSH increased by 20%, while LPO decreased by 45%. Our results show that pioglitazone and repaglinide differ significantly in their ability to ameliorate the parameters like NO(2), PCG, and AOPP. In this area, the multimodal action of pioglitazone as PPARγ agonist is probably essential.

The lungs are involved in diabetes in the cause of the complex phenomena diabetes generates. In the present study, hyperglycemia inhibited pulmonary antioxidants, including superoxide dismutase, catalase, glutathione peroxidase, and glutathione. These effects were accompanied by significant elevation of lipid peroxidation, total nitrites, and nitrotyrosine levels. The study investigated the effects of 2 oral antidiabetics, pioglitazone and repaglinide, on the mentioned parameters. It is concluded that pioglitazone exerts protective effect in the lung by inhibiting nitrosative stress and normalizing the nitrites and nitrotyrosine levels. Administration of repaglinide prevents oxidative and, to a smaller extent, nitrosative changes.

In hyperglycemia a reduction of the antioxidant power and an increased production of nitric oxide (NO) have been reported. Because nitrotyrosine (NT) is a stable end-product of nitrosative stress, assessment of its concentration is considered a useful marker of NO-dependent damages. The level of nitrotyrosine and four antioxidant parameters were evaluated in pancreas, kidney, heart, and testis of alloxan-induced hyperglycemic rabbits after 6 and 10 weeks of persistent hyperglycemia. In hyperglycemic groups, the level of nitrotyrosine was elevated by 44 and 39%, 92 and 95%, and by 155 and 138% in pancreas, kidney, and heart, respectively, while the testicular level of NT was unaffected. The pancreatic activities of glutathione peroxidase (GPX) and catalase (CAT) increased by 64% and 50%, and by 49 and 70%, while the level of glutathione (GSH) and the activity of glutathione reductase (GR) decreased by 37 and 38%, and by 57 and 42%. In the kidney the significant changes occurred as decreases in GR activity and GSH level by 36 and 35%, and by 28 and 23%, respectively. In the heart, a significant increase in CAT activity by 90 and 23% was observed. In the testis, the CAT, GPX, and GR activities were increased by 67 and 77%, 72 and 27%, and 33 and 28%, respectively, while the level of GSH was increased by 22 and 17%. These results confirm that tissues from hyperglycemic animals differ in neutralizing nitrosative stress. This may be due to different adaptive responses of their glutathione redox cycle.

The aim of this study was to analyze the antioxidative effect of repaglinide in the heart of alloxan-induced diabetic rabbits. The activities of superoxide dismutase (Cu,Zn-SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R), glutathione (GSH), ascorbic acid (AA), products of lipid peroxidation (LPO) and protein carbonyl groups (PCG) were estimated after 4 and 8 weeks of repaglinide treatment (1 mg daily). At significance level p<0.05, in diabetic heart the activities of Cu,Zn-SOD and CAT were elevated as compared to control values (by 60.7% and 55.3% for Cu,Zn-SOD, and by 89.7% and 77.4% for CAT after 4 and 8 weeks, respectively). The level of AA was diminished by 52.5% and 41.5% while GSH-Px and GSSG-R activities were decreased after 4 weeks of experiment (by 11.5% and 14.4%, respectively). GSH level was diminished by 33.2% after 8 weeks. Simultaneously, in diabetic heart the levels of LPO and PCG were elevated as compared to control values (by 51.6% and 111.3% for LPO, and by 72.0% and 132.9% for PCG after 4 and 8 weeks, respectively). In diabetic animals, repaglinide normalized GSH-Px activity and GSH level. It modified the activities of Cu,Zn-SOD, CAT and AA as compared to diabetic non-treated animals. In diabetic-treated rabbits the level of LPO was diminished as compared to diabetic non-treated animals, while the level of PCG was not affected. In the present study, repaglinide did not affect blood glucose and plasma insulin concentrations in diabetic rabbits. Nevertheless, the drug showed some beneficial antioxidative properties in the heart tissue.

Oxidative stress, defined as an imbalance between the production of reactive oxygen species (ROS) and antioxidant defense, is considered to be an important pathogenic factor in diabetes mellitus and its complications. In diabetic state, ROS might also be implicated in promoting a state of systemic inflammation. Recently, it was demonstrated that antioxidant therapy could be used to stop the initiation and propagation of this inflammatory response. Repaglinide is a new oral antidiabetic agent with a possible antioxidant activity. Therefore, in the present study, a possible therapeutic value of repaglinide in ameliorating the oxidative and inflammatory processes was tested in diabetic animals. In the study, the levels of total antioxidant status (TAS), ascorbic acid (AA), protein carbonyl groups (PCG) and interleukin-6 (IL-6) were determined in plasma of diabetic rabbits after 4 and 8 weeks of repaglinide treatment (1mg daily). Ex vivo analysis revealed that there were significant differences in these markers between hyperglycemic and control animals (P<0.05). Some of these parameters were ameliorated by repaglinide treatment. In diabetic rabbits treated with repaglinide, protein oxidation was diminished by 17.8% after 8 weeks of experiment. The level of AA in plasma of diabetic treated animals was higher than in non-treated diabetic groups (by 9.4 and 22.6% after 4 and 8 weeks, respectively). In diabetic treated animals, the TAS level was also significantly increased (by 23.6 and 16.7%). However, in diabetic rabbits, repaglinide did not affect the concentration of IL-6.

In this study, the antioxidative properties of repaglinide were examined in tissues of alloxan-induced diabetic rabbits. Glutathione (GSH), glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R) and protein carbonyl groups (PCG) were measured after 4 and 8 weeks treatment with repaglinide (0.3 mg/kg daily). In liver, diabetic versus control values (mean +/- S.E.M., p<0.05) for GSH-Px were 181.0 +/- 5.4 mU/mg protein versus 203.1 +/- 1.9 mU/mg protein and 187.4 +/- 6.6 mU/mg protein versus 240.9 +/- 18.8 mU/mg protein. The respective values for GSH were 33.7 +/- 0.4 nmol/mg protein versus 49.0 +/- 1.6 nmol/mg protein and 37.7 +/- 1.0 nmol/mg protein versus 41.2 +/- 0.7 nmol/mg protein. In diabetic kidney, GSSG-R activity (20.6 +/- 1.6 mU/mg protein versus 32.4 +/- 1.5 mU/mg protein and 23.6 +/- 0.6 mU/mg protein versus 36.3 +/- 0.3 mU/mg protein) and GSH level (16.6 +/- 0.5 nmol/mg protein versus 23.2 +/- 0.9 nmol/mg protein and 17.9 +/- 0.5 nmol/mg protein versus 23.2 +/- 0.6 nmol/mg protein) were reduced compared to control. PCG level was elevated in diabetic liver (0.58 +/- 0.02 nmol/mg protein versus 0.16 +/- 0.03 nmol/mg protein at 4 weeks and 0.64 +/- 0.04 nmol/mg protein versus 0.16 +/- 0.03 nmol/mg protein at 8 weeks) and in diabetic kidney (0.32 +/- 0.03 nmol/mg protein versus 0.11 +/- 0.02 nmol/mg protein and 0.35 +/- 0.03 nmol/mg protein versus 0.16 +/- 0.03 nmol/mg protein). Repaglinide did not affect the glucose level but reduced to some extent the oxidative stress enhanced by chronic hyperglycemia. In diabetic kidney, it restored to control values GSSG-R activity (45.4 +/- 2.0 mU/mg protein at 4 weeks and 41.1 +/- 0.07 mU/mg protein at 8 weeks), GSH level (27.0 +/- 0.8 and 26.8 +/- 0.9 nmol/mg protein), and partly PCG level (0.17 +/- 0.02 nmol/mg protein at 8 weeks). The treatment partly affected GSH-Px activity (262.7 +/- 17.6 mU/mg protein) and GSH level (40.4 +/- 1.4 nmol/mg protein) in diabetic liver. This study shows that repaglinide produces measurable antioxidative effects at therapeutic dose.

Hyperglycemia not only generates reactive oxygen species but also attenuates antioxidant mechanisms creating a state of oxidative stress. Oxidative stress is thought to play a crucial role in pathogenesis of chronic diabetic complications. Pioglitazone is a new oral antidiabetic agent, a potent inhibitor of glycation and potent antioxidant. In the present study, normoglycemic and alloxan-induced diabetic rabbits were treated with pioglitazone (1 mg/kg daily) for 4 and 8 weeks. At the end, glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R), glutathione (GSH) and protein carbonyl groups (PCG) were evaluated in homogenates of liver and kidney. Chronic hyperglycemia caused a marked increase in oxidative processes and some changes in activity of antioxidants. In liver, diabetic vs. control values (mean+/-S.E.M; P<0.05) for GSH-Px were 181.0+/-5.4 vs. 203.1+/-1.9 and 187.4+/-6.6 vs. 240.9+/-18.8mU/mg protein. Pioglitazone treatment for 8 weeks affected GSH-Px activity in diabetic liver (261.5+/-7.3 mU/mg protein). In diabetic kidney, GSSG-R activity (20.6+/-1.6 vs. 32.4+/-1.5 and 23.6+/-0.6 vs. 36.3+/-0.3 mU/mg protein) and GSH level (16.6+/-0.5 vs. 23.2+/-0.9 and 17.9+/-0.5 vs. 23.2+/-0.6 nmol/mg protein) were diminished, while PCG level (0.32+/-0.03 vs. 0.11+/-0.02 and 0.35+/-0.03 vs. 0.16+/-0.03 nmol/mg protein) was elevated. In diabetic kidney, pioglitazone restored to control values GSSG-R activity (34.4+/-1.4 and 30.6+/-0.1 mU/mg protein) as well as GSH (25.5+/-1.2 and 21.6+/-0.5 nmol/mg protein) and PCG (0.16+/-0.01 and 0.19+/-0.02 nmol/mg protein) levels. The present study showed that pioglitazone reduced to some extent the oxidative stress enhanced by chronic hyperglycemia.

The study was undertaken to analyze the effect of pioglitazone on superoxide dismutase (Cu, Zn-SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R), glutathione (GSH), ascorbic acid (AA), lipid peroxidation products (LPO) and protein carbonyl groups (PCG) in the heart of alloxan-induced diabetic rabbits after 4 and 8 weeks of pioglitazone treatment. In diabetic animals, Cu, Zn-SOD and CAT were elevated by 60 and 55%, and 90 and 77% as compared to controls at 4 and 8 weeks, respectively. GSH-Px, GSSG-R and GSH were diminished by 11, 14 and 33% as compared to controls at 4 or 8 weeks. AA was diminished by 52 and 41%. At P <0.05, pioglitazone normalized the activities of Cu, Zn-SOD, GSH-Px and GSSG-R. The activity of CAT was modified as compared to diabetic non-treated rabbits. After pioglitazone treatment, GSH and AA were increased as compared to diabetic non-treated animals. In diabetic rabbits, LPO was elevated by 52 and 111% and normalized by pioglitazone treatment. PCG was elevated by 72 and 133% and diminished as compared to diabetic non-treated animals at 8 weeks. The study shows that pioglitazone reduces oxidative stress in the heart of diabetic rabbits. In therapy, similar action can improve the cardiovascular system of diabetic patients.

Impaired homeostasis under diabetic conditions is connected with the increased production of free radicals and deficiency of antioxidative systems. The aim of this study was to analyze the effect of new oral antidiabetic drug-pioglitazone on activity of antioxidant factors and lipid peroxidation in vivo. The liver and kidney of alloxan-induced diabetic rabbits were examined after 4 and 8 weeks of treatment. After 4 weeks of diabetes the superoxide dismutase (Cu,Zn-SOD) activity in the liver was diminished while the catalase (CAT) activity and the level of ascorbic acid (AA) were elevated in comparison with the control group. Pioglitazone treatment during 4 weeks decreased the catalase activity in relation to the control diabetic animals. After 8 weeks of diabetes the CAT activity in the liver was elevated in comparison with the control group. Pioglitazone treatment during 8 weeks decreased the CAT activity and the level of lipid peroxidation products (LPO), and increased the Cu,Zn-SOD activity in relation to control diabetic animals. After 4 weeks of diabetes in the kidney the Cu,Zn-SOD activity and the level of ascorbic acid (AA) were diminished while the CAT activity and the LPO level were elevated in comparison with the control group. Pioglitazone treatment during 4 weeks increased the AA and decreased the LPO levels in relation to non-treated diabetic animals. After 8 weeks of disease the Cu,Zn-SOD activity in the kidney was diminished in comparison with the control group. Pioglitazone during 8 weeks decreased the LPO level in relation to non-treated diabetic animals. This study shows that diabetic animals undergo an important oxidative stress, which is partially corrected by pioglitazone treatment.

Objectives: Hyperglycaemia can result in oxidative stress which may affected as cellular tissue damage., Design and Methods: After 3, 6, 12 and 24 weeks of hyperglycaemia oxidative stress related parameters were measured in lung tissue of diabetic and control rabbits., Results: Decreased activities of antioxidative compounds and intensification of lipid peroxidation process were found in diabetic lung., Conclusions: The data obtained suggest that hyperglycaemia induces oxidative stress in lung tissue which may play an important role in pathogenesis of diabetic complications.

The present study was designed to evaluate the oxidative stress-related parameters in alloxan-induced diabetes in rabbits. After 3, 6, 12 and 24 weeks of hyperglycaemia the enzymatic and non-enzymatic factors were measured in heart tissue of diabetic and control groups. Superoxide dismutase and glutathione peroxidase activities and the contents of total sulfhydryl compounds significantly increased at all time intervals. Catalase activity increased initially (after 3 and 6 weeks), decreased after 12 weeks and increased again at the 24th week of the experiment. Glutathione reductase activity increased initially (at 3rd week), decreased below control level after 6 and 12 weeks, then increased again. Ascorbic acid concentration decreased after 3 and 6 weeks, and increased at the 12th and 24th weeks. The level of lipid peroxidation products was reduced after 3, 6 and 12 weeks of the experiment. After 24 weeks it was significantly elevated. These data suggest that hyperglycaemia induces oxidative stress in the heart but the defense mechanisms in the heart tissue are fairly efficacious against oxidative injury.