P214Dipeptidyl peptidase-4 (DPP-4) inhibitor preserves cardiac function and heart rate variability and prevents cardiac mitochondrial dysfunction in high fat-induced insulin resistant rats

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Abstract

Long-term high fat diet consumption has been shown to cause insulin resistance and diabetes mellitus, leading to cardiac dysfunction and depressed heart rate variability (HRV). Although dipeptidyl peptidase-4 (DPP-4) inhibitor has been shown to have glycemic control, its cardiac effects are still unclear. We tested the hypothesis that DPP-4 inhibitor, vildagliptin, attenuates cardiac dysfunction, preserves the HRV and prevents mitochondrial dysfunction in insulin resistant rats induced by high fat consumption.

Methods

Rats were fed with either normal (ND) or high fat diet (HF) for 3 months (n = 12/group). Then, rats in each group were fed with either vildagliptin (3 mg/kg/day) or vehicle for 21 days. In each rat, plasma glucose, insulin, cholesterol, cardiac function, and HRV were determined at baseline and end of treatment. Cardiac mitochondrial function was also studied.

Results

High fat-fed rats developed insulin resistance, indicated by increased plasma insulin, cholesterol, body weight, visceral fat and HOMA index. High fat-fed rats also had increased LF/HF ratio, indicating depressed HRV. Vildagliptin improved the insulin resistant condition, and completely restored the HRV (Figure). Vildagliptin also improved end-diastolic pressure, end-systolic pressure, and stroke volume in high fat-fed rats, compared to the vehicle group. Moreover, vildagliptin attenuated cardiac mitochondrial dysfunction caused by high fat consumption, by decreasing ROS production and preventing mitochondrial membrane potential changes (Δψm) (Figure).

Conclusions

In high fat-induced insulin resistant rats, depressed HRV and cardiac dysfunction could be markedly improved by DPP-4 inhibitor vildagliptin. This cardioprotection was due to its prevention of mitochondrial dysfunction caused by high fat consumption.

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