Background: Exenatid (Exe) failed to reduce heart failure hospitalization in patients with type II diabetes mellitus (T2DM) in EXSCEL. However, there is evidence to improve heart failure with preserved ejection fraction (HFpEF). T2DM is associated with cellular alterations that interplay with cardiac dysfunction. In this context, membrane expression of glucose transporter (GLUT) 4 is decreased. Exe was shown to induce GLUT4 expression under normal conditions. However, this potency in diabetes as well as mitochondrial respiration and cardiac function have not been investigated. In this study, we analyzed exe treatment in diet-induced obesity (DIO) mice about cardiac function, GLUT4 expression and mitochondrial respiration.

Methods: Mice were treated with high-fat diet for a duration of 24 weeks. Starting from week 12, the exe group was additionally treated with exenatid injection every two days (1 mmol/kg bodyweight). After completion of treatment, efficacy of exe was supervised by glucose tolerance test, basal glucose levels and body weight. Cardiac functions were assessed by precise murine echocardiography (VEVO® Visualsonics) including structural diameters, diastolic and systolic function as well as longitudinal and circumferential global strain. GLUT4 expression was evaluated by western blot analyses of cardiac tissue. Effects on mitochondrial respiration were measured by OROBOROS® respirometry.

Results: As expected, exe treated mice showed lower basal glucose levels (DIO 210.5±40.22 mg/dl vs. DIO+Exe 156.7±31.60 mg/dl, p=0.0072), an improved glucose tolerance and lower body weight (DIO 53.03±3.1 g vs. DIO+Exe 46.71±4.7 g, p=0.0029). Diastolic function was improved in Exe treated DIO mice compared to non-treated DIO controls (E/E’ DIO -37.34±9.1 vs. DIO+Exe -13.11±3.8, p<0.0001; E/A DIO 1.28±0.1 vs. DIO+Exe 1.4±0.1, p= 0.0054). Exe mice had smaller myocardial mass (LV Mass Corrected DIO 156.7±25.5 mg vs. DIO+Exe 123.8±28.1 mg). In systolic function, contractility was improved shown by reduction in end-systolic volume (ESV) and fractional shortening (FS) (ESV: DIO 31.59±7.3 µl vs DIO+Exe 24.90±4.5 µl, p=0.0083; FS: 13.44±5.2% vs. DIO+Exe 18.99±5.1%, p=0.0187) whereby ejection fraction, stroke volume and cardiac output were equal. Global longitudinal (GLS) and -circumferential strain (GCS) were similar as well. On a cellular level, GLUT4 expression was increased in cardiac tissue (DIO 0.6298± 0.36 vs. DIO+Exe 2.28±0.74 level of expression). Additionally, exe intensified mitochondrial respiration shown by increased physiological, ATP linked and maximum respiration.

Conclusion: In the model of diet induced obesity, mice treated with Exe showed improved cardiac diastolic function, contractility and reduced myocardial mass. These results are associated with increased GLUT4 expression and mitochondrial respiration in cardiac tissue. Future studies based on this pathway are needed to clarify use of exe in diabetic patients with diastolic dysfunction.