Background: TLC-6740, a liver-targeted mitochondrial uncoupler, and TLC-3595, a selective ACC2 inhibitor, are in development for obesity and diabetes. By enhancing substrate oxidation, 6740 and 3595 have complementary mechanisms to GLP-1R agonists. Here, we assessed effects of 6740, 3595, and SEMA monotherapy (mono) and combinations (combos) in db/db mice.

Methods: Male db/db mice (fasting glucose, FG>180mg/dL) were treated for 4 wk with vehicle (Veh), 6740, 3595, or SEMA mono or dual/triple combos. At 3 wk, an oral glucose tolerance test (oGTT) was performed and incremental AUC (iAUC) of glucose was calculated normalizing for glycemia before glucose bolus.

Results: FG was lower in all groups vs Veh with the greatest reductions in 6740+3595, 6740+SEMA, and 6740+3595+SEMA combos (-42 to -56%) (Fig). While HbA1c was lower with all monos vs Veh (-0.6 to -1.0%), combos had the greatest effect (-1.4 to -1.7%). Food intake was lower in all SEMA groups, but only SEMA+3595 caused weight loss (-11%). oGTT iAUC was reduced vs Veh with only ‘6740 mono (-26%) and SEMA combos with 6740 (-40%), 3595 (-31%), and 6740+3595 (-41%).

Conclusions: In db/db mice, 6740 improved glucose tolerance, FG, and HbA1c similarly to SEMA. Addition of 6740 and/or 3595 to SEMA improved glycemic parameters, supporting evaluation of combinations with GLP-1R agonists for diabetes.

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Disclosure

A. Vijayakumar: Employee; OrsoBio, Inc. N. Sroda: Employee; OrsoBio, Inc. E. Murakami: Employee; OrsoBio, Inc. S. Weng: Employee; OrsoBio, Inc. R.P. Myers: Employee; OrsoBio, Inc. M. Subramanian: Board Member; OrsoBio, Inc. G.I. Shulman: None.

© 2024 by the American Diabetes Association
2024
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