Chemically Induced (streptozotocin-alloxan) Diabetes Mellitus in the Dog. Biochemical and Ultrastructural Studies

Adult beagle dogs were infused intravenously with alloxan (50 mg/kg) and streptozotocin (30 mg/kg) in order to investigate sequential changes in plasma glucose, insulin, glucagon, and cortisol. These biochemical findings were correlated with ultrastructural alterations in pancreatic islets. Following infusion, the dogs became hyperglycemic by 2 hours, severely hypoglycemic by 6 to 14 hours, and permanently hyperglycemic by 24 hours. Plasma immunoreactive insulin increased sharply from 6 to 10 hours, then declined to nearly undetectable levels by 24 hours. Ultrastructurally, beta cells at 2 hours had clumped nuclear chromatin, vacuolated mitochondria, and dilated individual profiles of endoplasmic reticulum. Secretory granules appeared swollen but retained their internal cores. Degeneration of beta cells was severe after 10 hours, and plasma membranes of beta cells were disrupted by 24 hours. The cytoplasmic area of adjacent beta cells coalesced and had accumulations of membranous debris, lipofuscin, and autophagic vacuoles. Alpha and delta cells appeared to be unaffected. Plasma glucagon levels decreased markedly at 10 hours and were related reciprocally to changes in plasma insulin. Pancreatic islets in dogs with chronic (16 months) diabetes were small and composed primarily of granulated alpha and delta cells. Poorly granulated beta cells with degenerative changes were present in an occasional islet. The results of this investigation demonstrated that the combined administration of a single dose of alloxan and streptozotocin selectively destroyed the beta cells, while alpha and delta cells of the islets of Langerhans remained unaltered. Pathologic evidence of toxicity was not present in other organs. Chemically induced diabetes mellitus in dogs is a reproducible animal model that should prove useful in studies requiring repeated experimental manipulations or sampling of biologic fluids in order to evaluate the long-term effects of different routes of delivery or preparations of insulin to control the persistent hyperglycemia.