The objective of the study was to investigate the effects of different intensity exercise and 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure on glucose metabolism in Sprague Dawley (SD) rats, as well as the action of insulin receptor substrate (IRS)/phosphatidylinositol-3-kinases (PI3K)/protein kinase (AKT) signaling pathway in it. Besides that, we explored whether exercise can alleviate the toxicity induced by TCDD. Sixty male SD rats (8 weeks old) were randomly divided into non-exercise group, none-exercise toxic group, moderate-intensity exercise group, moderate-intensity exercise toxic group, high-intensity exercise group, high-intensity exercise toxic group. The toxic groups were intraperitoneally injected with TCDD, which the dose was 6.4 µg/kg· BW for the first week, then 21% of the above week dose for continuous 8 weeks. The 8-week treadmill running of moderate intensity (15 m/min, 60 min/day) and high intensity (26 m/min, 35 min/day) were implemented separately in exercise groups five times a week. After detecting the concentration of fasting serum glucose, insulin and C-peptide, the index of the homeostasis model assessment of insulin resistance (HOMA-IR) and islet β-cell secretion (HOMA-β) were calculated. We measured the hepatic mRNA expression levels of IRS2, phosphatidylinositol-3-kinases catalytic subunit alpha (PIK3CA), AKT by real-time PCR. The protein expression of total IRS2 (tIRS2), phosphorylated IRS2 at Ser731 (pSer731), total PIK3CA (tPIK3CA), total Akt (tAkt), phosphorylated Akt at Thr308 (pThr308) in liver were analyzed by western blot. We observed that compared to the non-exercise group, insulin and HOMA-IR index were significantly higher in the none-exercise toxic group (p < 0.05), while glucose, insulin, C-peptide and HOMA-IR index were significantly lower in the moderate-intensity exercise group (p < 0.05). In the high-intensity exercise group, the HOMA-IR index was significantly lower and the gene expression of IRS2 was significantly higher than in the non-exercise group (p < 0.05). Besides that, the HOMA-β index in the moderate-intensity exercise toxic group was significantly higher compared to the none-exercise toxic group and moderate-intensity exercise group (p < 0.05). The level of IRS2mRNA was significantly lower in the high-intensity exercise toxic group than in the high-intensity exercise group (p < 0.05). Our results demonstrated that 8-week TCDD exposure could induce insulin resistance in rats, while exercise could improve insulin sensitivity in which moderate intensity was more obvious than high intensity exercise. Meanwhile, both intensity exercise could not effectively alleviate the insulin resistance induced by TCDD, but high intensity exercise could promote compensatory insulin secretion to maintain glucose homeostasis. Although the gene expression of IRS2 was changed in high-intensity exercise groups, the mediation role of the hepatic IRS2/PI3K/AKT pathway in the effects of exercise and TCDD exposure on glucose metabolism remains very limited.

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