Introduction and Objective: TLC-1180 (1180) is a liver-targeted mitochondrial protonophore in clinical development. Insulin resistance is a major factor in the pathogenesis of T2D and metabolic alterations associated with insulin resistance are linked to heart failure with preserved ejection fraction (HFpEF). This study aims to evaluate the effects of 1180 on tissue specific insulin resistance and exercise capacity.Methods: Male C57Bl6/J DIO mice were randomized to receive either vehicle (VEH) or 1180. Insulin-stimulated tissue specific glucose uptake was assessed using 2-Deoxy-D-Glucose (2-DG) uptake and myocardial pyruvate oxidation through the ratio of pyruvate dehydrogenase flux (VPDH) to citrate synthase flux (VCS) at the end of the hyperinsulinemic-euglycemic clamp (HEC). Cardiac fitness was evaluated using graded exercise testing.Results: Mice treated with 1180 showed lean mass-neutral weight loss and reduced plasma membrane PKCĪµ translocation in liver, skeletal muscle, visceral white adipose tissue (WAT), and myocardium. TLC-1180 improved whole-body insulin sensitivity (+140% increase in glucose infusion rate, p<0.05), predominantly driven by increased insulin-stimulated 2-DG uptake in the gastrocnemius muscle (+43%, p<0.05), heart (+96%, p<0.01) and increased suppression of endogenous glucose production during the HEC. Myocardial pyruvate oxidation improved by +84% (p<0.05) compared to VEH, approaching levels seen in lean controls. These metabolic enhancements were associated with both increased exercise duration (+31%, p<0.05) and maximal running speed (+33%, p<0.05).Conclusion: TLC-1180 reversed DIO-induced defects in liver, muscle, WAT, and myocardium as well as normalized insulin-stimulated myocardial pyruvate oxidation. These improvements were associated with enhanced exercise performance. These preclinical findings suggest that 1180 may have therapeutic potential for improving whole body insulin resistance and cardiac function in obese individuals with HFpEF.
S. Parikh: None. M. Sharma: None. R. Calais Gaspar: None. X. Huang: None. D. Zhang: None. S. Dufour: None. H.N. Morgan: None. A. Nasiri: None. J. Zheng: None. M. Kahn: None. J. Stack: None. R.P. Myers: Employee; Current; OrsoBio, Inc. G. Subramanian: Employee; Current; OrsoBio. A. Vijayakumar: Employee; Current; OrsoBio, Inc. G. Shulman: Consultant; Current; Novo Nordisk A/S. Research Support; Current; Novo Nordisk A/S. Other – collaboration; Current; Ionis Pharmaceuticals. Advisory Panel; Current; ESPERION Therapeutics, Inc. Research Support; Current; Novo Nordisk Foundation. Advisory Panel; Current; Orsobio. Research Support; Current; Orsobio. Advisory Panel; Current; Village S.S.D.
T32DK007356R01DK119968UC2DK134901P30DK045735
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