Abstract 606: DPP-4 Inhibition Improves Diastolic dysfunction in obese mice fed a Western Diet

Abstract

Background and rationale: Obesity and diabetes are associated with insulin resistance, salt sensitive hypertension and cardiovascular dysfunction. Pharmacological inhibition of dipeptidylpeptidase-4 (DPP-4) to increase the bioavailability of glucagon like peptide-1 (GLP-1) is a contemporary therapy for control of glycemia in Type2 diabetes patients. Whether DPP-4 inhibition lowers blood pressures and improves pre-diabetic cardiomyopathy in a diet induced obesity (DIO) mouse model has not been examined in detail. Methods: C57Bl/6 mice were fed high fat/high sucrose (Western diet, WD) for 16wks starting at ∼4 wks of age and treated with MK-0626 (10mg/kg/day, Merck). Results: When compared to normal chow-fed mice, Western diet-fed (DIO) mice manifested increased MAP (15-20mmHg), heart (50%) and body weight (33%), increased blood sugars (FBS) and sodium retention (urine sodium 6.9μmol/day/gBW vs. 2.3μmol/day/gBW, respectively). In addition to correcting FBS, MK-0626 lowered MAP and increased sodium excretion and corrected cardiac diastolic dysfunction ( Table ). Indeed, echocardiographic indices of diastolic function, including tissue doppler E’/A’ ratio, estimates of LV filling pressure (E/E’), isovolemic relaxation time and the Tei index, all abnormal in mice fed a WD, were improved by MK-0626. Contemporaneous with these cardiac functional abnormalities, the mTOR/S6K and ERK1/2 growth signaling pathways were activated in DIO mice and improved by 16 wks of MK-0626 treatment. Conclusion: These studies suggest that MK-0626 increases cardiac and renal bioavailability of GLP-1 and improves myocardial GLP-1R signaling, myocardial remodeling resulting in increased renal sodium excretion and improvements in cardiac diastolic function in pre-diabetic insulin resistant DIO mice. Table: Summary of 2D M-Mode, pulse wave and tissue doppler Echo measurements on 20 wk old mice on control diet (CD), Western diet (WD), or Western Diet with MK-0626 (WD-MK). Values are mean ± SE. Numbers in parentheses are sample sizes. Paired t-tests: *p<0.05 CD vs WDC; † P<0.05 WDC vs WD-MKE, velocity of early mitral flow; E’, peak velocity of septal annulus; E/E’ index of LA filling pressure; Vp, flow propogation velocity; E/Vp, index of LV filling pressure; IVRT, isovolumic relaxation time; MPI, myocardial performance index.