Experiments were performed on 12-wk-old nonobese diabetic (NOD) mice to investigate the immunologic background of the condition, using ICR mice as controls. The results indicate the following: (1) absolute decreases in number of T lymphocytes, (2) depression of natural killer activity, (3) normal responsiveness in delayed type hypersensitivity and functional depression of killer T cells against allogeneic tumors, (4) diminished resistance to herpes virus infection, and (5) enhanced production of polyclonal antibodies to T cell-dependent antigens. These features are similar to those noted in other autoimmune diseases of man and in their experimental models in laboratory animals. Elucidation of the pathogenetic mechanism of autoimmune diabetes mellitus in NOD mice, therefore, may contribute to the diagnosis, treatment, and prevention of a wide variety of autoimmune diseases.

A clinical syndrome, characterized by acute diabetic ketoacidosis associated with a toxic neuropathy, developed in five men who intentionally ingested a recently introduced rodenticide (Vacor) containing N-3-pyridylmethyl-N'-p-nitrophenyl urea (RH-787). A 7-yr-old boy, who accidentally ingested this poison, died within 14 h. Marked insulinopenia, without a reduction in glucagon levels, suggested a specific beta-cytotoxic effect, which was supported after autopsy in three cases by histopathologic evidence of extensive beta cell destruction. Lethal effects in rats prevented investigation of RH-787's diabetogenicity in vivo; however, studies in isolated rat islets confirmed a direct inhibitory effect, which was prevented by concomitant incubation with nicotinamide, suggesting a mechanism of action similar to that of streptozotocin. We detected islet cell-surface antibodies in two of four patients studied. These findings indicate that this nongenetic, acquired form of insulinopenic diabetes, which has persisted in the surviving patients for up to 3 yr, presents a unique opportunity to test in man the concept that hyperglycemia and the accompanying metabolic consequences of insulinopenia can induced diabetic microangiopathy in the absence of genetic predisposition.

AKIRA OHNEDA, MASAO OTSUKI, HIROSHI FUJIYA, NOBUHISA YAGINUMA, TAKESHI KOKUBO, AND HARUO OHTANI SUMMARY A 55-yr-old man was admitted to the Hospital of Tohoku University in 1970, when physical examination and laboratory findings revealed malignant insulinoma with metastases to the liver. Streptozotocin treatment, totaling 79.5 g for 1 yr, improved his clinical symptoms. After discharge he was well until 1977, when he complained of palpitation and dyspnea, and he was hospitalized in September 1977 because of anorexia and a loss of body weight. Laboratory findings revealed anemia, with a decrease both in serum albumin and iron. His fasting blood glucose was 74 mg/dl and plasma insulin (IRI) 25 ^U/ml. His plasma IRI increased slightly after the stimuli of glucose, arginine, and glucagon. In contrast, his plasma glucagon (IRG) increased at fasting (3372 pg/ml) and became markedly elevated after arginine or glucose was administered. After his final admission, diazoxide improved his symptoms temporarily; streptozotocin could not be administered because of dyspnea and palpitation. On 24 January 1978, he fell suddenly into a coma and 2 days later he died. An autopsy revealed a large pancreatic tumor and metastases to the liver. Measurement of hormones from the tissues revealed a smaller amount of IRI in the pancreatic tumor and liver metastases compared with that in the uninvolved pancreas. In contrast, IRG contents had increased in the pancreatic tumor and hepatic metastases. In addition to the insulin cells, numerous cells with glucagon and somatostatin were observed in morphologic examinations. This indicated a mixed endocrine pancreatic tumor exhibiting typical symptoms of insulinoma initially and a glucagonoma syndrome later. DIABETES 28:962-969, November 1979.