title: 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.
authors.affiliation: Cardiac Electrophysiology Research and Training CenterFaculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.|Cardiac Electrophysiology UnitDepartment of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.|Center of Excellence in Cardiac Electrophysiology ResearchChiang Mai University, Chiang Mai, Thailand.
authors.forename: Pongpan
authors.initials: P
authors.lastname: Tanajak
authors.affiliation: Cardiac Electrophysiology Research and Training CenterFaculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.|Cardiac Electrophysiology UnitDepartment of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.|Center of Excellence in Cardiac Electrophysiology ResearchChiang Mai University, Chiang Mai, Thailand.
authors.forename: Hiranya
authors.initials: H
authors.lastname: Pintana
authors.affiliation: Cardiac Electrophysiology Research and Training CenterFaculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.|Cardiac Electrophysiology UnitDepartment of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.|Center of Excellence in Cardiac Electrophysiology ResearchChiang Mai University, Chiang Mai, Thailand.
authors.forename: Natthaphat
authors.initials: N
authors.lastname: Siri-Angkul
authors.affiliation: Cardiac Electrophysiology Research and Training CenterFaculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.|Cardiac Electrophysiology UnitDepartment of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.|Center of Excellence in Cardiac Electrophysiology ResearchChiang Mai University, Chiang Mai, Thailand.
authors.forename: Juthamas
authors.initials: J
authors.lastname: Khamseekaew
authors.affiliation: Cardiac Electrophysiology Research and Training CenterFaculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.|Cardiac Electrophysiology UnitDepartment of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.|Center of Excellence in Cardiac Electrophysiology ResearchChiang Mai University, Chiang Mai, Thailand.
authors.forename: Nattayaporn
authors.initials: N
authors.lastname: Apaijai
authors.affiliation: Cardiac Electrophysiology Research and Training CenterFaculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.|Center of Excellence in Cardiac Electrophysiology ResearchChiang Mai University, Chiang Mai, Thailand.|Department of Oral Biology and Diagnostic SciencesFaculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Siriporn C
authors.initials: SC
authors.lastname: Chattipakorn
authors.affiliation: Cardiac Electrophysiology Research and Training CenterFaculty of Medicine, Chiang Mai University, Chiang Mai, Thailand nchattip@gmail.com.|Cardiac Electrophysiology UnitDepartment of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.|Center of Excellence in Cardiac Electrophysiology ResearchChiang Mai University, Chiang Mai, Thailand.
authors.forename: Nipon
authors.initials: N
authors.lastname: Chattipakorn
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D031204:Caloric Restriction; D002316:Cardiotonic Agents / Q000494:pharmacology*; D059305:Diet, High-Fat; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000502:physiology; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011236:Prediabetic State / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016277:Ventricular Function, Left / Q000187:drug effects* / Q000502:physiology; D000077597:Vildagliptin
chemical_list: D001786:Blood Glucose; D002316:Cardiotonic Agents; D009570:Nitriles; D011759:Pyrrolidines; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D000077597:Vildagliptin; D000218:Adamantane
keywords: DPP-4 inhibitor; FGF21 sensitivity; apoptosis; caloric restriction; cardiac function; fatty acid β-oxidation; insulin resistance; mitochondria; obesity