Abstract 15417: Dual Ampk Activator/mtor Inhibitor Improves Metabolic Parameters in T2d Mice and Protects Cardiomyocytes Against Ischemic Injury

Abstract

Background: Type 2 diabetes (T2D) is a major metabolic disorder associated with increased morbidity and mortality, predominantly due to heart failure resulting from superimposed ischemic heart disease. Dual AMPK activation/mTOR inhibition (NovoMedix compound, NMX2) has been shown to attenuate adverse cardiac remodeling and fibrosis in a pressure-overload mouse model of heart failure. Given the importance of AMPK signaling in T2D, we investigated the beneficial effects of chronic treatment with NMX2 in T2D mice. Methods & Results: Adult male db/db T2D mice were treated daily with NMX2 (50 mg/kg, p.o.) or equal volume of vehicle (7% DMSO, as control) for 15 weeks. Increase in body weight was significantly attenuated along with reduction in insulin levels with NMX2 treatment as compared to control ( A-B ). NMX2 treatment improved glucose homeostasis (glucose and insulin tolerance tests) and reduced adiposity (fat mass percentage, measured by body composition analysis) ( C-G ). Respiratory exchange ratio (RER) measured by indirect calorimetry analysis (Phenomaster, TSE) was significantly improved in NMX2-treated mice, which indicates increased glucose utilization as compared to control mice ( H & I ). Cardiomyocytes isolated from control and NMX2-treated db/db mice were subjected to simulated ischemia/reoxygenation (SI/RO, 40 minutes SI and 1 hour RO). NMX2 significantly reduced necrosis (trypan blue staining, J ), apoptosis (TUNEL assay, K ) and activation of the NLRP3 inflammasome (apoptosis speck-like protein, ASC aggregation by immunofluorescence staining, L & M ) in cardiomyocytes compared to control. Conclusion: Chronic treatment with NMX2 improves glucose homeostasis and RER and reduces adiposity and body weight in diabetic mice. NMX2 also protects cardiomyocytes from diabetic mice against ischemic injury by reducing sterile inflammation, which supports the development of this treatment modality for T2D and its related cardiac complications.