The Effects of Long-term Administration of Sulfonylureas on the Carbohydrate Metabolism in Normal and Alloxanized Rats; Have Sulfonylureas a Diabetogenic Action ?

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Abstract
The effects of long-term administration of sulfonylureas on glucose tolerance was studied in normal rats and alloxanized rats which showed no decreased glucose tolerance. Sulfonylureas were administered daily through a stomach tube in doses of 200 mg./ kg of body weight (carbutamide or tolbutamide) and 100 mgAg. of body weight (chlorpropamide) for 4 to 6 months. The fasting blood sugar levels did not exceed 200 mg/dj. in either normal or alloxanized animals, except in one rat belonging to the normal rat group which received chlorpropamide. The fasting blood sugar level in this rat increased to 257 mg/dl 5 days after the administration of chlorpropamide. Lobar pneumonia in the left upper lobe and abscess formation in the occipital cranial fossa were observed at autopsy but the beta cells in the islets of the pancreas were not degranulated. Glucose tolerance was decreased 1 to 3 months after the administration of the sulfonylurea drugs in the normal rat groups but improved gradually thereafter. A more notable decrease in glucose tolerance, however, was observed in 40% of the alloxanized rats compared with the normal rats. No differences in the decreased glucose tolerance test were found among the sulfonylurea drugs. The mean response indices to the sulfonylureas were not changed in any of the groups 4 to 6 months after the administration of sulfonylureas. The free acetone in the blood did not increase in the normal groups, while it increased in alloxanized rat groups which were administered tolbutamide or chlorpropamide. The glycogen content of the liver decreased markedly in both the normal and alloxanized groups. The mean glucose-6-phosphatase activity of the liver decreased in both the normal and alloxanized groups compared with that of each control group. The glucose uptake of the isolated diaphragm did not decrease in any group except in the alloxanized group which was administered chlorpropamide. The mean weight of the adrenal gland did not increase in any group. The diabetogenic action of the sulfonylureas and the mechanism which induces decreased glucose tolerance after the administration of sulfonylureas are discussed.