The effects of chronic S-nitrosoglutathoine adminstration on glucose tolerance in dog animal model

The nitric oxide donor S-nitrosoglutathione (GSNO) has been used to prevent platelet activation in patients with severe pre-eclampsia. The study assesses the chronic administration of GSNO on glucose metabolism in the dog animal model. GSNO (10 mg/kg) was administered intravenously for 14 days and the blood glucose concentration was determined by the glucose oxidase method. Oral glucose tolerance tests revealed an impaired glucose tolerance in the GSNO-treated dogs as reflected by elevated postprandial blood glucose concentrations at the 1.0 hour to 2.5 hour time interval (p < 0.05). The elevated blood glucose concentration was associated with a statistically significant decrease in plasma insulin concentration. The plasma insulin concentration at 1.0 hour in captopril-treated controls was 41.00 uIU/ml compared with 27.33 uIU/ml in GSNO-treated dogs (p < 0.05). In contrast, the plasma glucagon concentration was enhanced by the chronic adminstration of GSNO, as confirmed by a concentration of 75.00 ñ 6.06 pg/ml in GSNO-treated dogs compared with 49.50 ñ 4.64 pg/ml in captopril-treated controls at the 1.0 hour time interval. Linear regression analysis of the data revealed a highly significant and positive correlation between the blood glucose concentration and the plasma glucagon concentration (r = 0.739, p < 0.01). Similarly, a positive correlation existed between the blood glucose concentration and the plasma insulin concentration (r = 0.513, p = 0.307). We conclude that chronic in vivo adminstration of GSNO impairs the parameters of carbohydrate metabolism. Patients who are on protracted treatment with GSNO could be risk for the development of diabetes mellitus.(Au)

The effect of nitric oxide released from s-nitroso-glutathoine on glucagon and insulin in dogs

Nitric oxide (NO), a potent modulator of cellular function, and NO donors have been useful tools in both experimental and clinical setting. Low molecular weight thiols such as cysteine and glutathoine were proposed to act as NO-carriers. The study was undertaken to investigate the pharmacological activity of the NO donor, S-nitrosoglutathoine (GSNO), on the plasma glucose and on the gluco-regulatory hormones, insulin and glucagon in healthy normoglycaemic dogs. Plasma glucose levels were measured by the glucose oxidase method, while the insulin and glucagon levels were determined by radioimmunoassay. In healthy normoglycaemic dogs, administration of 50 mg/kg GSNO caused an increase in post-prandial plasma glucose levels. The plasma glucose levels were significantly (p<0.05) elevated at 1.5 hr, 2.0 hr and 2.5 hr of the oral glucose tolerance test. These values were significantly higher than those obtained for the controls. The increase in glucose level was associated with a significant decrease in insulin levels and increase in glucagon levels (p<0.05). The fasting insulin level was 8.0 ñ 0.3 IU/ml in the control. The insulin level increased to a maximum of 34.0 ñ 0.3 IU/ml 1.5 hr post-prandial, and then decreased to 12.4 ñ 0.4 IU/ml after 2.5 hr. On administration of 50 mg/kg GSNO, the insulin level increased to a maximum of 23.0 ñ 0.6 IU/,l after 1.5 hr post-prandial and then decreased to 17.0 ñ 0.4 IU/ml after 2.5 hr. The blood glucagon levels increased from 40.0 ñ 0.3 pg/ml to 53.0 ñ 0.3 pg/ml after 1 hr in controls. In dogs administered with GSNO, the blood glucagon level increases to a maximum level of 80.0 ñ 0.5 pg/ml 1.5hr post-prandial. These results suggest that in healthy normoglycaemic dogs, nitric oxide released from GSNO caused a transient increase in post-prandial plasma glucose levels, inhibited glucose stimulated insulin secretion and elevated glucagon levels.(AU)

The effect of S-nitroso-glutathione on insulin receptors on erythrocytes abd mononuclear leucocytes in dogs

This study was designed to investigate differences in cellular binding of insulin in dogs administered with the nitric oxide donor, S-nitroso-glutathione (GSNO). A time course assay of insulin binding to isolated erythrocytes and mononuclear leucocytes from dogs administered with GSNO was done during the oral glucose tolerance test (OGTT). The erythrocyte receptor assay performed was the methodology used by Ghambir et al (1977). A modification was also done for mononuclear leucocyte insulin binding assay. The plasma glucose levels were measured by the glucose oxidase method, while the insulin levels were determined by radioimmunoassay. The results of these studies show the erythrocytes and mononuclear leucocytes from dogs administered with GSNO have lesser ability to bind insulin when compared to erythrocytes and mononuclear leucocytes from the controls. In dogs administered with GSNO, there was less binding of erythrocytes and mononuclear leucocytes, 44 percent and 29 percent, respectively, when compared to the bound free ratio value of the controls.(AU)

Decreased insulin binding to erythrocytes and mononuclear leucocytes in normal dogs administered with S-nitroso- glutathione

Nitric oxide is a pathogenic factor of inflammatory islet cell death in type 1 diabetes. An early event in the pathogenesis of insulin-dependent diabetes mellitus (IDDM) is intraislet accumulation of activated macrophages. Their secretory products such as nitric oxide (NO) are found to play a crucial role in islet destruction. Macrophage activity and progressive islet cell destruction persist during a long period of chronic inflammatory events preceding diabetes, suggesting the presence of nitric oxide contributing to continued immunostimulation. It has been shown previously that the nitric oxide donor, S-nitrosoglutathione (GSNO) caused persistent postprandial hyperglycaemia in normal healthy dogs at 35 and 50mg/kg. parallel with an increase in plasma nitrate concentration and decrease in insulin secretion. This study was designed to investigate differences in cellular binding of insulin in dogs administered with the GSNO. A time course assay of insulin binding, to isolate erythrocytes and mononuclear leucocytes from dog administered with GSNO, was done during the oral glucose tolerance test (OFTT). The erthrocyte receptor assay performed was the methodology used by Ghambir et al (1977). A modification was also done for mononuclear leucocytes insulin binding assay. The plasma glucose levels were measured by the glucose oxidase method, while the insulin levels were determined by radio-immunoassay. The results of these studies show that erythrocytes and mononuclear leucocytes from dogs administered with GSNO have decreased ability to bind insulin when compared to erythrocytes and mononuclear leucocytes from the controls. In dogs administered with GSNO, there was less binding of erythrocytes and mononuclear leucocytes, 44 percent and 29 percent respectively, when compared to the bound free ratio value of the controls. The data also shows that erythrocytes and mononuclear leucocytes from dogs administered with GSNO have 256 and 10.7x10 insulin receptor sites per cell, respectively, compared with 296 and 18.4x10 per cell for the control (P<0.05). Competitive inhibition studies using unlabelled insulin indicate that the affinity of insulin for its receptor on erythrocytes from dogs administered with GSNO was also significantly different from the controls, while that of mononuclear leucocytes from both group was comparable.(AU)

The hyperglycaemic effect of s-nitroso-glutathione via the release of nitric oxide - abstract

Recent evidence suggests that nitric oxide (NO) is an important factor in both inflammatory-induced and streptozotocin-induced diabetes. In this study we investigated the pharmacological activity of S-nitroso-glutathoine (GNSO), a carrier of NO, on blood glucose level in 10 mongrel dogs, and measured their plasma nitrate concentration after the administration of GSNO. S-nitroso-glutathoine elicited a dose-dependent increase in blood glucose level (15 - 102 percent) which was paralled with an increase in nitrate production. The blood glucose levels at 2.0 and 2.5 hrs in an Oral Glucose Tolerance Test were significantly higher in dogs administered with GNSO than those of the controls (p<0.05). There was also a significant increase in plasma nitrate on administration of GSNO (35 - 100 percent). The plasma nitrate concentrations from 0.5hr to 2.5hrs were significantly higher compared to the controls (p<0.05). The hyperglycaemic effect of GSNO was enhanced with the co-adminstration of ascorbic acid. This resulted in 5 - 30 percent increase in blood glucose concentration. The blood glucose levels at 2hrs in dogs after the co-administration of 35mg kg of GSNO (P<0.05). The data from this study showed that persistent hyperglycemia can be an unwanted side effect of GSNO administration and that the glucose concentration should be closely monitored when this drug is used to treat patients(AU)

The hyperglycaemic effect of S-nitroso-glutathione via the release of nitric oxide

Nitric oxide is a pathogenic factor of inflammatoryislet cell death in Type I diabetes. Insulin-Dependent Diabetes Mellitus (IDDM) is mediated by an autoimmune mechanism or inflammatory process that is characterized by destruction of beta cells. Incubation of pancreatic islet cells with activated macrophages, which release large amounts of nitric oxide, causes the death of the islet cells. When the cells are exposed to the nitric oxide donor, sodium nitroprusside, lysis of the cells occur in a concentration and time-dependent manner. In this study we investigated the pharmacological activity of S-nitroso-glutathione (GSNO), a carrier of nitric oxide on blood glucose levels in dogs, and measured the plasma nitrate/nitrite concentration in the dog serum after the administration of GSNO using an automated method. The blood glucose level was measured using the glucose oxidase assay. S-nitroso-glutathione elicited a dose-dependent increase in blood glucose levels which was paralleled with an increase in nitrate/nitrite production. The blood glucose levels at 2.0 hrs and 2.5 hrs of the Oral Glucose Tolerance Test (OGTT) were significantly higher in dogs administered with GSNO than those of the controls (p<0.05). Post-prandial blood glucose levels in dogs administered with 35 mg per kg body weight of GSNO were 7.2 + 0.9mmol/l and 7.1 + 0.7mmol/l, compared with 4.8 + 0.2mmol/l and 4.6 + 0.2mmol/l in controls. The hyperglycaemic effect was more pronounced on adminstration of 35 mg per kg body weight of GSNO and ascorbic acid. Post-prandial blood glucose levels in the dogs after administration of 50 mg per body weight, at 2.0 hrs and 2.5 hrs were 9.2 + 0.7mmol/l and 9.3 + 0.3mmol/l, respectively. The basal nitrate/nitrite concentration was 12.4 + 0.4umol. On administration of 35 mg per kg body weight of GSNO, there was a 35 - 60 percent increase in the plasma nitrate/nitrite concentration. The plasma nitrate/nitrite concentration at 2.0 hrs to 2.5 hrs ranged from 16.8 + 1.0umol. The plasma nitrate/nitrite concentration increase by 100 percent on administration of 50 mg per kg of GSNO. This study confirms that S-nitroso-glutathione is a hyperglycaemic compound which affects the blood glucose levels in dogs. The hyperglycaemic effects can be caused by the nitric oxide action on the pancreatic islet cells (AU).