Vildagliptin and caloric restriction for cardioprotection in pre-diabetic rats

Abstract

Long-term high-fat diet (HFD) consumption causes cardiac dysfunction. Although calorie restriction (CR) has been shown to be useful in obesity, we hypothesized that combined CR with dipeptidyl peptidase-4 (DPP-4) inhibitor provides greater efficacy than monotherapy in attenuating cardiac dysfunction and metabolic impairment in HFD-induced obese-insulin resistant rats. Thirty male Wistar rats were divided into 2 groups to be fed on either a normal diet (ND, n = 6) or a HFD (n = 24) for 12 weeks. Then, HFD rats were divided into 4 subgroups (n = 6/subgroup) to receive just the vehicle, CR diet (60% of mean energy intake and changed to ND), vildagliptin (3 mg/kg/day) or combined CR and vildagliptin for 4 weeks. Metabolic parameters, heart rate variability (HRV), cardiac mitochondrial function, left ventricular (LV) and fibroblast growth factor (FGF) 21 signaling pathway were determined. Rats on a HFD developed insulin and FGF21 resistance, oxidative stress, cardiac mitochondrial dysfunction and impaired LV function. Rats on CR alone showed both decreased body weight and visceral fat accumulation, whereas vildagliptin did not alter these parameters. Rats in CR, vildagliptin and CR plus vildagliptin subgroups had improved insulin sensitivity and oxidative stress. However, vildagliptin improved heart rate variability (HRV), cardiac mitochondrial function and LV function better than the CR. Chronic HFD consumption leads to obese-insulin resistance and FGF21 resistance. Although CR is effective in improving metabolic regulation, vildagliptin provides greater efficacy in preventing cardiac dysfunction by improving anti-apoptosis and FGF21 signaling pathways and attenuating cardiac mitochondrial dysfunction in obese-insulin-resistant rats.

Comparisons of cardioprotective efficacy between fibroblast growth factor 21 and dipeptidyl peptidase‐4 inhibitor in prediabetic rats

“…Finally, the %FS was determined using the LV function study mode. An increase in %FS was considered to be an indicator of LV function …”

“…An admittance P‐V catheter (Transonic Scisense, Ontario, Canada) was inserted and advanced into the LV chamber through the right common carotid artery and then connected to the recording system. LV function parameters including heart rate (HR), end‐systolic pressure (ESP), end‐diastolic pressure (EDP), dP/dt max , dP/dt min , and stroke volume (SV) were determined and analyzed using LabScribe 2 software (iWorx System, Dover, NH, USA) . Moreover, the protocols for blood pressure measurement, HRV assessment, cardiac mitochondrial function measurements, plasma and cardiac lipid peroxidation assessment and cardiac tissue proteins expression were described in the .…”

“…In this study, the fresh LV apex was used to determine the FGF21 signaling pathway, apoptotic pathway, and myocardial FAO pathway. The general procedures of protein preparation and Western blot analysis are described in previous studies . The samples were loaded onto the 10% SDS‐polyacrylamide gels .…”

“…The samples were loaded onto the 10% SDS‐polyacrylamide gels . Then, proteins were transferred to nitrocellulose membranes in a glycine/methanol transfer buffer in a Wet/Tank blotting system (Bio‐Rad Laboratories, CA, USA) . Membranes were blocked in either 5% skim milk or 5% bovine serum albumin in Tris‐buffered saline and Tween (TBST) buffer.…”

“…8,9 FAO change was also found in caloric restriction and vildagliptin interventions which can reduce cardiac FGF21 resistance, and improved cardiac FAO that may contribute to the improvement of cardiac function in obese-insulin resistant rats. 10 Although our previous study has demonstrated that long-term FGF21 therapy reduced metabolic dysfunction, inflammation, apoptosis signaling pathways, restored heart rate variability (HRV), and improved myocardial FAO signaling pathways and left ventricular (LV) function in HFD-induced obese-insulin resistant rats, 11 there is a lack of evidence that directly compares the efficacy of FGF21 and antidiabetic drug DDP4-i on these parameters in obese-insulin resistant rats.…”