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

ABSTRACT

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).