Direct Long-Term Effects of L-Asparaginase on Rat and Human Pancreatic Islets

Abstract

ABSTRACT. L-Asparaginase, an effective agent in the treatment of acute lymphoblastic leukemia, may induce a diabetic state. The pathogenesis of the diabetogenic effect was studied in cultured pancreatic islets. Mean serum concentrations in three children with acute lymphoblastic leukemia were 2.4 U/mL (range 1.4-4.5) before and 31.5 U/mL (range 18.6-51.8) immediately after an intravenous injection of 1000 U/kg L-asparaginase. Glucose-induced insulin release from pancreatic islets of rat and man was measured after 3 and 7 days of culture in media with or without clinically relevant concentrations of Escherichia coli L-asparaginase (0.01-100 U/mL). After culture, the remaining insulin, glucagon, and DNA in the islets were determined. After 7 days of culture of adult rat or human islets, both the accumulation of insulin in the medium and the content of insulin and glucagon in the islets were significantly reduced in the presence of 100 U/mL Lasparaginase compared with controls. Addition of M hydrocortisone to the culture medium enhanced this effect. In newborn rat islets a significant reduction in insulin release and content was observed already in the presence of 0.1 U/mL asparaginase, whereas the glucagon content was unchanged. Removal of the drug resulted in partial recovery of the insulin secretion. To elucidate the mechanisms of action of the drug, insulin biosynthesis was studied in islets cultured in asparagine-free medium with or without asparaginase. No difference in biosynthesis was seen between media with or without asparagine, whereas 0.1 U/ mL asparaginase caused about a 50% reduction under both conditions. These results indicate that the pancreatic Pcells are particularly sensitive to L-asparaginase, suggesting that the diabetogenic effect of the drug is exerted by a direct interaction with the pancreatic P-cell and is not due to lack of exogenous supply of asparagine. (Pediatr Res 26: 158-161,1989) L-Asparaginase is an established drug for the induction or consolidation of remission in children with acute lymphoblastic leukemia. A major side effect of L-asparaginase treatment is nonketotic hyperglycemia and glycosuria, which have been reported in 10% of children receiving 10000 IU/m2 two to four times in the induction treatment in conjunction with prednisone (1). The mechanism of the hyperglycemia is not known, but a rational approach to the treatment of this adverse effect of Lasparaginase requires clarification of the pathogenesis. Decrease in insulin synthesis (2, 3), reduction in insulin release (4), and reduction of the number of insulin receptors (5) proposed. In previous in vitro studies only acute effects were measured, and extremely high doses of the drug were used (6). The aim of our study was, therefore, to elucidate the direct longterm effect of clinically relevant concentrations of L-asparaginase on the insulin release and biosynthesis in isolated rat and human pancreatic islets in culture. MATERIALS AND METHODSAsparaginase activity in treated children. In three children with acute ...

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