Prevention of diabetes in the spontaneously diabetic BB rat by the glutamine antimetabolite acivicin.
The autoimmune syndrome of the BB rat is associated with a marked increase in glutamine (Gln) metabolism in immune system cells of both diabetes-prone (BBdp) and diabetic (BBd) rats. To test whether inhibition of Gln metabolism prevents diabetes, 17 BBdp received acivicin (1 mg/kg) and 17 received saline subcutaneously every 2 days from age 48 days until diabetes onset or age 186 days. Twenty-seven non-diabetes-prone (BBn) rats served as controls. Acivicin caused some growth effects and a macrocytic anemia, but no other clinical or biochemical side effects. Only one acivicin-treated BBdp became diabetic (age 158 days), compared with saline-treated rats, of which 10 became diabetic and 2 became glucose intolerant (p < 0.001). Insulitis was moderate to severe in 88% of the saline-treated BBdp rats, but minimal in most acivicin-treated BBdp rats. Liver glutamine and glutamate tended to be higher in acivicin- than saline-treated BBdp rats. Acivicin caused no change in the proportions of T or B lymphocytes, NK cells, or macrophage phenotypes in spleen or blood; all BBdp rats were typically lymphopenic. Mitogenic responses of splenocytes in vitro were not affected. The results are consistent with the hypothesis that acivicin, by interfering with Gln metabolism, "targets" activated cells of the immune system and thereby attenuates the process and prevents overt diabetes, without major disturbance of Gln levels or generalized immunosuppression. This prevention is not due to a nutritional-growth retardation effect, as diabetes was prevented in females that showed no such effect.
Misra
M
M
McGill Nutrition and Food Science Centre, Royal Victoria Hospital, Montréal, QC, Canada.
Duguid
W P
WP
Marliss
E B
EB
D000818:Animals; D001772:Blood Cell Count; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005951:Glucose Tolerance Test; D018698:Glutamic Acid / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D015759:Ionomycin / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D016131:Lymphocyte Subsets / Q000187:drug effects; D008297:Male; D051381:Rats; D011913:Rats, Inbred BB; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D007555:Isoxazoles; D005973:Glutamine; D018698:Glutamic Acid; D015759:Ionomycin; D005723:gamma-Glutamyltransferase; D013755:Tetradecanoylphorbol Acetate; C006303:acivicin