An electron microscopic study was carried out on the pancreatic islets of cortisone-alloxan pretreated rabbits in which protracted severe diabetes was produced by the subsequent administration of a subdiabetogenic dose of 1 mg. per kilogram of cortisone acetate. In the nondiabetic control rabbits, receiving cortisone-alloxan treatment alone, the beta cells were ultramicroscopically riddled with membranous sacs which either were empty or contained variable amounts of a diffuse electron-dense material. There were but few typical granules present. Occasional atypical granules were irregularly shaped and in some instances were eccentrically located. There were no other changes present. By light microscopy the beta cells appeared, by the aldehyde fuchsin method, well granulated. The cortisonealloxanized rabbits which were rendered severely diabetic for up to 105 days by subsequent treatment with 1 mg./kg. of cortisone, showed marked degranulation and loss of the membranous sacs. There was prominence of the various organelles of beta cells, particularly the endoplasmic reticulum which was frequently arranged in a concentric array, often giving a fingerprint-like appearance. These changes were considered expressions of marked cellular hyperactivity. In addition, there was glycogen deposition in beta cells as well as significant dilatation of the intercellular spaces and undulation of the plasma cell membranes. The alpha and delta cells were unchanged. These studies suggest that the beta cells of rabbits after cortisonealloxan administration develop a defect which makes them incapable of meeting the metabolic stress of a subdiabetogenic dose of cortisone which normal animals are able to cope with readily. These findings make it necessary to re-evaluate the concept of normal pancreatic islet and beta cell morphology in cases of human maturity-onset diabetes. These patients, as do the cortisone-alloxan treated rabbits, may have readily apparent beta cell pathology at the ultrastructural level, which is not visualized by light microscopy.

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