Direct long-term effects of L-asparaginase on rat and human pancreatic islets

TY - JOUR

T1 - Direct long-term effects of L-asparaginase on rat and human pancreatic islets

AU - Clausen, Niels

AU - Nielsen, Jens Høiriis

PY - 1989/8

Y1 - 1989/8

N2 - 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 L-asparaginase compared with controls. Addition of 10(-6) 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 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.(ABSTRACT TRUNCATED AT 250 WORDS)

AB - 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 L-asparaginase compared with controls. Addition of 10(-6) 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 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.(ABSTRACT TRUNCATED AT 250 WORDS)

KW - Animals

KW - Animals, Newborn

KW - Asparaginase

KW - Cells, Cultured

KW - DNA

KW - Glucagon

KW - Humans

KW - Hydrocortisone

KW - Insulin

KW - Islets of Langerhans

KW - Rats

U2 - 10.1203/00006450-198908000-00019

DO - 10.1203/00006450-198908000-00019

M3 - Journal article

C2 - 2671905

SN - 0031-3998

VL - 26

SP - 158

EP - 161

JO - Pediatric Research

JF - Pediatric Research

IS - 2

ER -