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At baseline levels, the body weight, food intake, plasma glucose levels, insulin levels, total cholesterol levels, and plasma MDA levels did not differ between ND fed rats and HFD fed rats (Table 1). After 12 weeks, HFD fed rats had significantly increased body weight, plasma insulin levels, HOMA index, plasma cholesterol levels, and plasma MDA levels in comparison with ND fed rats (Table 1). These findings indicate that HFD fed rats developed peripheral insulin resistance characterized by increased plasma insulin levels and HOMA index without an increase in plasma glucose levels.
After 21 days of either vildagliptin or sitagliptin treatment in ND fed rats, the metabolic parameters, including body weight, food intake, visceral fat, plasma insulin levels, plasma glucose levels, plasma cholesterol levels, plasma MDA levels, HOMA index, and plasma HDL levels were not significantly different from those of the vehicle-treated rats (NDV) (Table 2). Vehicle-treated HFD fed rats (HFDV) also showed the characteristics of peripheral insulin resistance including increased body weight, visceral fat, plasma cholesterol levels, plasma insulin levels, and HOMA index as well as decreased plasma HDL levels in comparison with vehicle-treated ND rats (NDV) (Table 2). However, HFD fed rats treated with vildagliptin (HFDVil) and with sitagliptin (HFDSi) displayed significantly decreased HOMA index, plasma insulin levels, and plasma cholesterol levels as well as decreased plasma HDL levels in comparison with the HFDV group. However, neither vildagliptin nor sitagliptin altered the body weight, food intake, visceral fat, or plasma glucose levels in comparison with the HFDV group (Table 2).
We also found that both plasma and brain MDA levels within the HFDV group were significantly increased in comparison with the NDV group (Table 2). However, plasma and brain oxidative stress levels within the HFDVil group and HFDSi group were significantly decreased in comparison with the HFDV group (Table 2). These findings suggest that HFD consumption induces not only peripheral insulin resistance, but also leads to oxidative stress in the plasma and brain. The administration of either vildagliptin or sitagliptin reduces peripheral insulin resistance, peripheral oxidative stress, and brain oxidative stress induced by HFD consumption.
Vildagliptin and sitagliptin improved cognitive behaviors in HFD fed rats assessed by the Morris Water Maze (MWM) test
Locomotive activity was measured via the open-field test. We found that the number of lines that the rats crossed during the test at the end of week 12 was not significantly different between the ND group (41.67Â±3.91) and the HFD group (42.33Â±2.54). These findings indicate that the locomotive activity of all rats before pharmacological treatment did not differ between the two diet groups.
In the MWM test, before pharmacological treatment, we found that the time needed to reach the platform during the acquisition test, performed on days 4 and 5, in the HFD group was significantly increased in comparison with the NDV group (Figure 1A). During the probe test, the time that the rats spent in the target quadrant was significantly decreased within the HFD group in comparison with the ND group (Figure 1B). These findings indicate that rats fed with the HFD for 12 weeks display significantly impaired learning and memory behaviors.
After 21 days of pharmacological treatment, we found that the HFDVil and HFDSi groups required significantly less time to reach the platform during the acquisition test in comparison with the HFDV group (Figure 1C). In the probe test, the HFDVil and HFDSi groups spent significantly more time in the target quadrant in comparison with the HFDV group (Figure 1D). These findings suggest that vildagliptin and sitagliptin equally attenuate the impairment of learning and memory behaviors in HFD induced insulin resistant rats.
Vildagliptin and sitagliptin attenuated brain mitochondrial dysfunction and decreased brain oxidative stress levels in HFD fed rats
To assess brain mitochondrial function, we measured the changes in brain mitochondrial ROS production after H2O2 stimulation, ïÂ„ïÂ™m after H2O2 stimulation, and brain mitochondrial swelling. We found that 12 weeks of HFD consumption caused brain mitochondrial dysfunction as indicated by increased brain mitochondrial ROS production, brain mitochondrial membrane depolarization, and brain mitochondrial swelling in comparison with the ND group (Figure 2). In HFD rats, treatment with either vildagliptin or sitagliptin significantly decreased brain mitochondrial ROS production (Figure 2A), attenuated brain mitochondrial depolarization (Figure 2B), and decreased brain mitochondrial swelling (Figure 2C) in comparison with the HFDV group. We also showed that vildagliptin and sitagliptin significantly reduced brain MDA levels in comparison with the HFDV group (Table 2). All of these findings suggest that vildagliptin and sitagliptin have equally beneficial effects resulting in decreased brain mitochondrial dysfunction and brain oxidative stress levels in HFD induced insulin resistant rats.