Elsevier

Toxicology Letters

Volume 182, Issues 1–3, 10 November 2008, Pages 42-47
Toxicology Letters

Effect of the organophosphorus pesticide diazinon on glucose tolerance in type 2 diabetic rats

https://doi.org/10.1016/j.toxlet.2008.08.004Get rights and content

Abstract

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) (2 g/(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 (β-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.

Introduction

Organophosphorus pesticides (OPs) are widely used to improve crop productivity and hygienic environments in many developed countries. Sales of diazinon (DZN), one of the OPs, have been legally limited in the United States from December 31 2004, due to its toxicity for human health. However, DZN is commonly used to control a range of crop pests and is also used as a veterinary ecotoparasiticide in Asia, including Japan. Indeed, annual production of DZN-related compounds in Japan between 2003 and 2005 is presented to be about 10 million tons (Nouyaku-Youran, 2006). Although it is well known that primary target of OPs including DZN is acetylcholine esterase (AChE), they have several toxicological effects such as delayed neurotoxicity and/or polyneuropathy caused by inhibition of neuropathy target esterase (Lotti and Moretto, 2005, Quistad et al., 2002, Casida and Quistad, 2004) and hyperglycemia (Seifert, 2001).

Diabetes mellitus (DM) is a chronic metabolic disorder representing an increase in blood glucose levels due to an absolute or relative deficiency of insulin and/or an increase in insulin resistance. A report of Japanese Ministry of Health, Labor and Welfare in 2002 has claimed that 7.4 million of Japanese populations are strongly suspected to suffer from DM. It is reported that DM might modify drug pharmacokinetics by changing hepatic drug-metabolizing enzyme activity (Dixon et al., 1961, Thummel and Schenkman, 1990). We have recently found the possibility that DZN causes high toxicity in streptozotocin-induced type 1 diabetic model rats due to the overproduction of DZN-oxon, which is a major DZN metabolite and a potent inhibitor of AChE, as a result of up-regulation of hepatic CYP1A2 (Ueyama et al., 2007). However, there is no detailed information about the ill-effect of DZN on type 2 diabetic model rats.

It has been reported that DZN induces hyperglycemia (Seifert, 2001) and pancreatitis (Frick et al., 1987) in experimental animals. In the present study, to verify the hypothesis that DZN alters the glucose tolerance in control and diabetic model rats, we investigated the effect of DZN on type 2 diabetic mellitus using Goto-Kakizaki (GK) rats, which are a spontaneous animal model of non-insulin-dependent diabetes (NIDDM) without obesity (Goto et al., 1988).

Section snippets

Chemicals

Glucose and DZN (the purity is 99%) were purchased from Wako Pure Chemical Industries Ltd. (Osaka, Japan). Citric acid and sodium carboxymethylcellulose (CMC) were purchased from Yoneyama Yakuhin Kogyo Co., Ltd. (Osaka, Japan). Blood glucose level monitor system GLUTEST NEO was kindly donated from Sanwa Kagaku Kenkyusho Co., Ltd. (Mie, Japan). N-Histofine Simple Stain Rat MAX PO (M) was purchased from Nichirei Biosciences (Tokyo, Japan). 5,5′-Dithio-bis-2-nitrobenzoic acid (DTNB),

Biochemical data

Biochemical data are summarized in Table 1. DZN significantly decreased plasma triglyceride levels in both Wistar and GK rats, and decreased plasma total cholesterol levels in Wistar rats, but not GK rats. DZN had no effect on the body weight, total protein, amylase activity and HDL-cholesterol in both rats.

Effect of DZN on OGTT in Wistar and GK rats

Plasma concentration–time curves of glucose in Wistar and GK rats before and after oral administration of glucose are shown in Fig. 1A. There were no significant differences in the fasting

Discussion

We have recently demonstrated that toxicological effect of DZN is enhanced in streptozotocin-induced diabetic model rats due to overproduction of DZN-oxon by increased hepatic drug-metabolizing enzyme activity (Ueyama et al., 2007). GK rats are used as a valuable tool for understanding the pathogenesis of type 2 diabetes and for development of new drugs (Bisbis et al., 1993, Ikeda and Sugiyama, 2001). The novel findings obtained in this study are that DZN impaired glucose tolerance in the type

Acknowledgments

This work was supported in part by a Health and Labor Sciences Research Grant (Research on Risk of Chemical Substances) from the Ministry of Health, Labor and Welfare of Japan, and a Grant-in-Aid for Scientific Research (19790404, 17310033) from the Japan Society for the Promotion of Science.

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