Effect of the organophosphorus pesticide diazinon on glucose tolerance in type 2 diabetic rats.
We have reported that the toxicity of the organophosphorus pesticide diazinon (DZN) and its metabolites is increased in streptozotocin-induced diabetic rats (type 1 diabetic rats). In the present study, we have investigated the effect of DZN on glucose tolerance in genetic type 2 diabetic rats, Goto-Kakizaki (GK) rats. Oral glucose tolerance test (OGTT) (2g/(5 ml kg)) was assessed before, and 1 and 2 weeks after intraperitoneal injection of DZN (6.5 mg/kg) in Wistar and GK rats. DZN significantly increased the levels of glucose in plasma at designated blood sampling points in GK rats. The activity of hepatic drug-metabolizing enzymes and expression of hepatic cytochrome P450 (CYP) 1A2, CYP3A2 and CYP2D1, which oxidize DZN to DZN-oxon, a potent ChE inhibitor, were measured before DZN injection. There were no significant differences in the activity and expression of CYPs between both rat groups, indicating that the ability of metabolic activation might be almost the same in Wistar and GK rats. DZN dramatically decreased the activity of cholinesterase (ChE) in plasma by approximately 40% in both Wistar and GK rats. However, no significant differences in the activity of ChE in plasma were observed between Wistar and GK rats for 5 days after DZN injection. No massive necrotic and apoptotic areas, leukocyte infiltration and immunoreactive insulin-positive cells (beta-cells) were observed in pancreas 2 weeks after DZN injection. Moreover, DZN might not affect plasma insulin levels in Wistar and GK rats. These results suggest that DZN deteriorates the glucose tolerance in GK rats. It is unlikely that this phenomenon is due to differences in ChE activity and/or DZN-oxon production levels between Wistar and GK rats.
Ueyama
Jun
J
Department of Medicinal Informatics, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan.
Kamijima
Michihiro
M
Asai
Kazumi
K
Mochizuki
Aiko
A
Wang
Dong
D
Kondo
Takaaki
T
Suzuki
Toshiaki
T
Takagi
Kenji
K
Takagi
Kenzo
K
Kanazawa
Hiroaki
H
Miyamoto
Ken-ichi
K
Wakusawa
Shinya
S
Hasegawa
Takaaki
T
D000109:Acetylcholine / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003976:Diazinon / Q000633:toxicity*; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4 / Q000096:biosynthesis / Q000235:genetics; D007306:Insecticides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar
D051275:Glucose Transporter Type 4; D007306:Insecticides; C495694:Slc2a4 protein, rat; D003577:Cytochrome P-450 Enzyme System; D000109:Acetylcholine; D003976:Diazinon