Abstract 368: The GLP-1 Receptor Agonist Liraglutide Improves Autophagy Impairment in the Diabetic Heart

Background: Diabetes mellitus is a well-recognized risk factor for the development of heart failure. Although studies with the glucagon-like pepide-1 analog liraglutide—an approved treatment for type 2 diabetes—have demonstrated substantial cardioprotective effects of the drug in both human and experimental diabetes, the underlying mode of action/mechanism of liraglutide remains unclear. Here, we investigate the impact of liraglutide on autophagy—an evolutionary conserved mechanism thought to play an essential role in cell survival during stress—using a rodent model of type 2 diabetes, the Goto Kakizaki (GK) rat. Methods: Thirty-two weeks old male GK rats and sex/age-matched Wistar controls were treated with liraglutide (0.2 mg/kg/day) or PBS twice daily for 8 consecutive weeks. At 40-weeks of age, cardiac structure/function were assessed by echocardiography and LV tissue samples were collected to assess the expression of inducers/markers of autophagy (mTOR, phospho-mTOR, LC3-I/II, p62, and Beclin-1). Results: Autophagy was inhibited in the heart of diabetic GK animals when compared to Wistar controls, as confirmed by a significant increase in mTOR expression/activation—a negative regulator of autophagy. This was further confirmed by an observed decrease in the LC3 II/I ratio in diabetic GK animals when compared to controls (p Conclusion: Overall, our data suggests that the cardioprotective effects of liraglutide may stem from its ability to activate autophagy in the diabetic heart and improve autophagy impairment in the setting of type 2 diabetes.