Comparative efficacy of Dipeptidyl peptidase-4 (DPP-4) inhibitors on cardiac function, heart rate variability, and cardiac mitochondrial function in obese-insulin resistant rats

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 758-779-Cardiometabolic Risk & Vascular Biology
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-762
Nattayaporn Apaijai*, Hiranya Pintana, Siriporn C Chattipakorn and Nipon Chattipakorn
Chiang Mai University, Chiang Mai, Thailand
Obesity from long-term high-fat diet (HFD) consumption is known to cause insulin resistance and left ventricular (LV) dysfunction (1).  Although both vildagliptin and sitagliptin, which are drugs in the dipeptidyl peptidase-4 (DPP-4) inhibitor class, have been shown to exert cardioprotection (1-3), their effects on the heart as well as therapeutic efficacy under insulin resistant condition induced by high-fat diet consumption are still unclear.  In the present study, 36 male Wistar rats were divided into 2 groups and fed either normal diet (ND) or HFD for 12 weeks.  Then, rats in each group were divided into 3 subgroups to receive vehicle (V), vildagliptin (3 mg/kg), or sitagliptin (30 mg/kg) via gavage feeding for 21 days (n=6/subgroup).  Plasma insulin, glucose, cholesterol, plasma and cardiac malondialdehyde (MDA), heart rate variability (HRV), and LV function were determined.  Moreover, cardiac mitochondrial function and morphology in all hearts were studied.  Our results showed that all HFD-fed rats developed insulin resistance which was characterized by increased body weight and visceral fat, hyperinsulinemia with euglycemia, increased HOMA index, increased total cholesterol level.  They also had increased plasma and cardiac MDA levels, depressed HRV indicated by increased low-frequency to High-frequency (LF/HF) ratio, and LV dysfunction shown by decreased end-systolic pressure and stroke volume, with increased end-diastolic pressure.  Cardiac mitochondrial dysfunction was also found indicated by increased ROS production, mitochondrial depolarization and mitochondrial swelling.  Electron microscopy revealed a mitochondrial morphology change indicated by increased unfolded cristae in cardiac mitochondria in the HFD group.  Treatment with both vildagliptin and sitagliptin significantly improved metabolic parameters, decreased LF/HF ratio to physiological level, improved LV function, improved mitochondrial function, and morphology.  However, body weight and visceral fat were unaffected by both drugs.  Our findings suggest that vildagliptin and sitagliptin exert equal cardioprotective efficacy in improving insulin resistance, restoring cardiac autonomic balance, and effectively preventing LV dysfunction in obese insulin resistant rats.  These benefits of DPP-4 inhibitors could be mainly due to their prevention of cardiac mitochondrial dysfunction.

1. Apaijai N, Pintana H, Chattipakorn SC, Chattipakorn N 2012 Cardioprotective effects of metformin and vildagliptin in adult rats with insulin resistance induced by a high-fat diet. Endocrinology 153:3878-3885 2. Chinda K, Palee S, Surinkaew S, Phornphutkul M, Chattipakorn S, Chattipakorn N 2012 Cardioprotective effect of dipeptidyl peptidase-4 inhibitor during ischemia-reperfusion injury. Int J Cardiol 2012 (E-published ahead of print) 3. Lenski M, Kazakov A, Marx N, Bohm M, Laufs U 2011 Effects of DPP-4 inhibition on cardiac metabolism and function in mice. J Mol Cell Cardiol 51:906-918

Nothing to Disclose: NA, HP, SCC, NC

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Sources of Research Support: Thailand Research Fund grants: TRF-RTA 5580006(NC), TRF-BRG5480003 (SC) and Thailand National Research Foundation grant (NC, SC)