| Background：The prevalence of diabetes mellitus is increasing in recent years anddiabetes has become one of the most severe public health issues. The pathologicalmechanisms of diabetes mellitus include decreased β cell mass and insulin resistance.Malfunction of insulin signaling is the cause and major pathological mechanism ofinsulin resistance. Skeletal muscles account for more than80%glucose consumptionstimulated by insulin, thus, skeletal muscles play crucial roles in the development ofinsulin resistance. Epidemiologic and experimental data show that organophosphatesexposure can increase the morbidity and mortality of diabetes mellitus. Omethoate isan organophosphate with high toxicity, fast action and low residue. Omethoate wasadministered to Wistar male rats for60day, the components in insulin signaling weredetermined to investigate the effects of omethoate on insulin signaling of rats exposedto omethoate.Objectives：To explore the effects of omethoate on the levels of glucose, insulin,inflammatory factors and endoplasmic reticulum stress of rats exposed to omethoatefor60days, to investigate whether omethoate can produce effects on insulin signalingand its related mechanisms.Methods：1. Healthy8–week old Wistar male rats were divided into four groups, controlgroup rats received saline at the dosage of0.42ml/Kg, low dosage group rats receivedomethoate at the dose of5mg/Kg, medium dosage group rats received omethoate atthe dose of10mg/Kg, high dosage group rats received omethoate at the dose of20mg/Kg. Omethoate was dissolved in40%oil. Saline and omethoate wereadministered to the rats through gastric injection for consecutive60days. Rats hadfree access to water. Body weight of the rats were measured every3days to track thechanges of body weight. 2. Glucose meter was used to determine the glucose levels andradioimmunospectremeter was used to assay the insulin levels.3. The levels of serum IL-6and TNF-α, the AGEs levels in kidney and retinawere determined by ELISA.4. EMSA was used to detect the activities of NF-κB5. Western blot was used to determine the expression of p-p38MAPK,p38MAPK, BiP, PERK, IRE1α, p-eIF2α, eIF2α, InsR, IRS-1, p-IRS-1Ser307andp-IRS-1Tyr612.Results：1. Body weight changes. The body weight of rats from LD, MD and HD groupswas significantly lower than that of rats from control group（P<0.05）. There was nosignificant difference in body weight of rats between LD group and MD group. Thebody weight of rats from HD group was significantly higher than that of rats from LDand MD groups (P<0.05).2. FBG, serum FINS. There was no significant difference in FBG and serumFINS of rats among groups.3. Level of serum IL-6and TNF-α. The level of serum IL-6and TNF-α of ratsfrom control group was significantly higher than that of rats exposed to omethoate（P<0.05）。The level of serum IL-6and TNF-α of rats from MD and HD groups wassignificantly higher than that of rats from LD group（P<0.05）；and the level of serumIL-6and TNF-α of rats from HD group was significantly higher than that of rats fromMD group（P<0.05）。4. Level of kidney and retina AGEs. The level of kidney and retina AGEs of ratsexposed to omethoate was significantly higher than that of rats from control group（P<0.05）。The level of serum IL-6and TNF-α of rats from LD and MD groups wassignificantly lower than that of rats from HD group（P<0.05）。There was nosignificant difference in kidney and retina AGEs of rats between LD group and MDgroup.5. Activity of NF-κB in skeletal muscles. The activity of skeletal muscles NF-κB of rat exposed to omethoate was significantly higher than that of rats from controlgroup（P<0.05）. The activity of skeletal muscles NF-κB of rats from HD group wassignificantly higher than that of rats from LD and MD groups（P<0.05）.6. Expression level of p-p38MAPK/p38MAPK in skeletal muscles. Theexpression level of p-p38MAPK/p38MAPK in skeletal muscles of rats exposed toomethoate was significantly higher than that of rats from control group（P<0.05）. Theexpression level of p-p38MAPK/p38MAPK in skeletal muscles of rats from MD andHD groups was significantly higher than that of rats from control group（P<0.05）.7. Expression level of BiP, PERK, IRE1α, p-eIF2α and eIF2α in skeletal muscles.The expression level of BiP, PERK, IRE1α, p-eIF2α and eIF2α in skeletal muscles ofrats exposed to omethoate was significantly higher than that of rats from controlgroup（P<0.05）. The expression level of BiP, PERK, IRE1α, p-eIF2α and eIF2αinskeletal muscles of rats from MD and HD groups was significantly higher than that ofrats from LD group（P<0.05）. The expression level of BiP, PERK, IRE1α, p-eIF2αand eIF2α in skeletal muscles of rats from HD group was significantly higher thanthat of rats from MD group（P<0.05）. The level of p-eIF2α/eIF2α in skeletal musclesof rats exposed to omethoate was significantly higher than that of rats from controlgroup（P<0.05）. The level of p-eIF2α/eIF2α in skeletal muscles of rats from HDgroup was significantly higher than that of rats from LD and MD groups（P<0.05）.There was no significant difference in p-eIF2α/eIF2α in skeletal muscles of ratsbetween LD group and MD group.8. Expression level of InsR, IRS-1, p-IRS-1Ser307and p-IRS-1Tyr612inskeletal muscles. There was no significant difference in InsR, IRS-1, p-IRS-1Ser307and p-IRS-1Tyr612in skeletal muscles of rats among groups. The level of p-IRS-1Ser307in skeletal muscles of rats exposed to omethoate was significantly higher thanthat of rats from control group（P<0.05）. The level of p-IRS-1Ser307in skeletalmuscles of rats from HD group was significantly higher than that of rats from LD andMD groups（P<0.05）. The level of p-IRS-1Ser307in skeletal muscles of rats fromHD group was significantly higher than that of rats from MD group（P<0.05）. Thelevel of p-IRS-1Tyr612in skeletal muscles of rats exposed to omethoate was significantly lower than that of rats from control group（P<0.05）. The level of p-IRS-1Tyr612in skeletal muscles of rats from HD group was significantly lower than that ofrats from LD and MD groups（P<0.05）. The level of p-IRS-1Tyr612in skeletalmuscles of rats from HD group was significantly lower than that of rats from MDgroup（P<0.05）.Conclusion：1. Exposed to omethoate, rats can develop high level of inflammatory factors.2. Exposed to omethoate increase impression of protein related with endoplasmicreticulum stress in rats.3. Omethoate is likely to increase phosphorylation of insulin receptor substance1in site Ser307and decrease phosphorylation in site Tyr612, and it can induceabnormalities in insulin signaling through oxidative stress and endoplasmic reticulumstress. |
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