Major findings from the present study demonstrated that vildagliptin and sitagliptin equally improved metabolic parameters in HFD induced insulin resistant rats, (2) decreased plasma and brain oxidative stress levels in HFD induced insulin resistant rats, (3) restored brain mitochondrial function impaired by HFD, by decreasing mitochondrial ROS production, preventing mitochondrial membrane depolarization, and preventing brain mitochondrial swelling, and (4) attenuated the impairment of learning and memory behaviors in HFD induced insulin resistant rats.
We demonstrated that 12 weeks of HFD consumption caused peripheral insulin resistance and brain mitochondrial dysfunction. These findings are consistent with our previous studies (Pipatpiboon et al., 2012; Pratchayasakul et al., 2011). We also found that insulin resistance in rats induced by HFD consumption can lead to cognitive decline and an increase in oxidative stress within circulation as well as within the brain. These findings are consistent with previous studies (Greenwood and Winocur, 2005; Stranahan et al., 2008). Change in cognitive function following HFD consumption has been proposed to be due to the fact that 1) HFD consumption causes increased levels of triglyceride and cholesterol which previous evidence has shown to be correlated with cognitive performance in patients with T2DM (Perlmuter et al., 1988); 2) 12 weeks of HFD consumption induces hyperinsulinemia and increases brain oxidative stress which can create a toxic environment for neurons as suggested by a previous study showing that hyperinsulinemia in a neuronal culture can sensitize neurons to stress induced insults (Schafer and Erdo, 1991); and 3) 12 weeks of HFD consumption causes an increase in circulating and brain glucocorticoid levels as shown in our previous study (Pratchayasakul et al., 2011). It has also been shown that an increase in brain glucocorticoid levels can perturb cognitive function (Green et al., 2006).
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Vildagliptin and sitagliptin are new anti-diabetic agents classified as DPP-4 inhibitors. It has been shown that DPP-4 inhibitors improve glycemic control in insulin resistance and T2DM models (Richter et al., 2008). Consistent with this previous report, our study demonstrated that rats in the HFDVil or HFDSi groups displayed equally beneficial effects resulting in decreased peripheral insulin resistance observed as a decrease in plasma insulin levels, HOMA index, total plasma cholesterol levels, and increased plasma HDL levels. However, plasma glucose levels and LDL/VLDL levels within the HFDVil and HFDSi groups did not differ in comparison with the ND and HFDV groups. In addition, both HFDVil and HFDSi exhibited attenuated brain and circulation oxidative stress levels.
Moreover, we demonstrated that rats with high levels of plasma and brain oxidative stress induced by HFD consumption also developed brain mitochondrial dysfunction as well as impairment of cognitive function. These findings are consistent with our previous evidence showing that 12 weeks of HFD consumption in rats causes brain mitochondrial dysfunction (Pipatpiboon et al., 2012). Previous studies, as well as our findings, suggest that the cognitive impairment caused by long term HFD consumption could be related to brain mitochondrial dysfunction and oxidative stress (Chattipakorn et al., 2012; Stranahan et al., 2008; White et al., 2009; Winocur et al., 2005). Interestingly, we found that both vildagliptin and sitagliptin completely restored brain mitochondrial function and improved learning and memory behaviors in rats with HFD induced insulin resistance. The mechanism by which brain mitochondrial function is restored by treatment with vildagliptin and sitagliptin could be due to the inhibition of DPP-4 action leading to prolonged activity of GLP-1 (Baggio and Drucker, 2007; Richter et al., 2008). GLP-1 has been shown to protect against mitochondrial dysfunction in several cell types. For example, 1) it has been shown that GLP-1 is involved in the mobilization of intracellular Ca2+ and the stimulation of mitochondrial ATP synthesis in cultured Î²-cells (Tsuboi et al., 2003), and 2) the study of isolated mouse hepatocytes found that GLP-1 entered cells and acted on hepatocyte mitochondria to modulate oxidative phosphorylation and to suppress oxidative stress and ROS production in ND fed mice and diet induced obese mice (Tomas et al., 2011).
Furthermore, a recent study demonstrated that sitagliptin administration can increase active GLP-1 levels in the brain and improve memory behaviors in Alzheimerâ€™s disease mice models (D'Amico et al., 2010). Therefore, the effects of vildagliptin and sitagliptin on the improvement of learning and memory behaviors in insulin resistant rats could be due to their abilities to 1) decrease peripheral insulin resistance, 2) decrease cholesterol levels and increase HDL levels, 3) decrease plasma and brain oxidative stress levels, and 4) decrease brain mitochondrial dysfunction.
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This study demonstrated that both vildagliptin and sitagliptin exhibited similar efficacy in attenuating peripheral insulin resistance, decreasing brain and circulation oxidative stress, and restoring brain mitochondrial function, thus leading to the of prevention of learning and memory impairment in HFD induced insulin resistant rats.