Hypoglycemic Action of Orinase. Effect on Output of Glucose by Liver

Abstract

A simple method for gauging changes in the output of glucose by the liver was described. Throughout postabsorption, there are present in hepatic venous blood aperiodic fluctuations in glucose which are reflected throughout the major peripheral arterial tree. Under the influence of the drug, these fluctuations at both sites promptly disappear. The quantitated changing rate of output of glucose by the liver after l-butyl-3p-tolylsulfonylurea (Orinase) (33% fall in 10 minutes) is drastic. A small dose of glucagon by vein immediately reverses this trend with a return in exaggerated form of the normal postabsorptive fluctuations. As a corollary one may infer that long use of the drug does not impair liver glycogen deposition. It is suggested that the site of action of Orinase is proximal to the phosphorylase enzyme systems and takes the form of a suppression of glucagon production at source with a resulting reduction of glucose output by the liver. After 70 days of intensive exposure to the drug in the normal dog, acute signs and symptoms of toxicity are present but no histopathologic changes in the liver, kidneys, thyroid, adrenals or pancreas (including alpha-beta cell ratios). No evidence was found to suggest that the drug works by destruction of the alpha cells of the pancreas.