Streptozotocinによるインスリン産生膵島腫瘍の発生過程における病態生理に関する研究

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This study was performed to examine the oncogenic action of streptozotocin on the endocrine pancreas in male Wistar rats and to clarify physiologic responses in the course of and after the tumor induction. In addition, induced tumors were examined histologically and measurements of pancreatic hormones in tumors were done using radioimmunoassay. Young male Wistar rats were injected intravenously with 65mg/kg of streptozotocin alone, or with streptozotocin, 65mg/kg, preceded by 15 min. by a single intraperitoneal injection of nicotinamide, 500mg/kg, or of picolinamide, 250mg/kg. The administration of streptozotocin alone resulted in gross intolerance to glucose with flat and depressed plasma insulin response, whereas the diabetogenic action of the nitrosourea compound was partially prevented by pretreatment with nicotinamide or picolinamide. Although those animals pretreated with nicotinamide or picolinamide did not show any signs of overt diabetes, slightly abnormal glucose tolerance was found one week after treatment. Serial oral glucose tolerance tests in rats treated with streptozotocin and nicotinamide showed that the elevation of blood glucose levels after glucose loading was depressed significantly 7 months after treatment. Plasma insulin responses were distinctly elevated 9 months following treatment. The mean insulinogenic index increased from 0.34 at one week after treatment to 1.01 at the 5th month and was 1.65 and 2.87 at 7 and 9 months following treatment, respectively. These results suggest that islet cell tumors had already been induced within 7 months. Induced neoplasms were capable of secreting large amounts of insulin 9 months following the injection. Nine to 26 months after the various treatment schedules, 110 pancreatic islet cell tumors were induced in 11 out of 19 (58%), in 25 out of 30 (83%), and in 13 out of 16 rats (81%) treated with streptozotocin alone, or with streptozotocin and nicotinamide or picolinamide. Blood glucose levels - less than 100mg/100ml even after glucose load -were low, and plasma insulin levels rose markedly following glucose load in tumor-bearing rats. Thus, insulinogenic responses were much greater as compared to those of tumor-free rats. No significant difference was observed among the rats with tumors induced by streptozotocin alone, or by streptozotocin with nicotinamide or picolinamide with regard to their blood glucose and plasma insulin responses to an oral glucose load. These findings suggest that pancreatic islet cell tumors induced by streptozotocin with and without nicotinamide or picolinamide are insulin-secreting, and that streptozotocin itself has oncogenic effects on the rat endocrine pancreas. While pancreatic tissue from tumor-free rats contained 14 U/g wet weight of insulin, mean insulin concentrations in islet cell tumors amounted to 401 U/g wet weight, indicating that insulin-secreting tumors induced by streptozotocin have large stores of insulin. In addition, pancreatic glucagon was demonstrated immunochemically in some tumors, suggesting that these neoplasms consisted of at least more than one type of pancreatic endocrine cell. Pancreatic islet cell tumors measuring up to 0.9cm were round, well-delineated, and were frequently observed in the splenic segment. They had a thin fibrous capsule and their cells stained, in general, with aldehyde-fuchsin. Ultrastructurally, most tumors examined consisted of granulated B cells, although the number of secretory granules appeared to be less than that of non-neoplastic B cells. The units of rough-surfaced endoplasmic reticulum appeared prominent. Cells whose secretory granules were similar to those of pancreatic A cells were encountered, while those characteristics of D cells were not encountered in the tumors examined. Neither macroscopic nor microscopic abnormalities were observed in livers of tumor-bearing rats.
日本内分泌学会の論文

著者

鹿住敏
神戸大学医学部内科学第2講座

Streptozotocinによるインスリン産生膵島腫瘍の発生過程における病態生理に関する研究

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