FUNCTIONAL AND MORPHOLOGIC STUDIES ON THE EFFECT OF ORINASE ON THE PANCREAS1,2

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Abstract
The effect of Orinase on the blood sugar concentration of rabbits and partially pancreatectomized dogs treated with adrenal steroids and/or growth hormone was correlated with the morphologic alterations in the pancreas. Concomitant with increasing severity and duration of the diabetic state increasing numbers of animals failed to show significant hypoglycemia after a test dose of the sulfonylurea. It was also found, with one exception, that in those diabetic animals, whose beta cells were completely degranulated, no hypoglycemia was observed after Orinase. Furthermore, dogs with metahypophyseal diabetes also failed to respond. When complete beta cell degranulation occurs in diabetes, produced by experimentally increasing the demand for insulin, it can be assumed that the pancreas is putting out insulin at maximal capacity, and has lost its insulinogenic reserve. On the other hand, metahypophyseal diabetes is an insulin deficiency syndrome due to degenerative changes in beta cells. The ineffectiveness of Orinase under these conditions support the viewpoint that the hypoglycemic action of the drug is mediated by stimulation of the beta cells to increased insulin output. However, certain data which was obtained suggested additional extrapancreatic actions, probably on the liver and central nervous system. These observations included, a hypoglycemic response to Orinase in an animal with complete beta cell degranulation; as well as, a marked rapid blood sugar elevation in hormone-treated rabbits, after rapid intravenous Orinase injection, usually followed by death of the animals. The clinical implications of these experiments in relation to the effectiveness of the sulfonylureas in various types of diabetic patients are discussed.