118-LB: The Antipsychotic D2 Receptor Antagonist Diphenylbutylpiperidines Improve Glycemia in Experimental Obesity by Inhibiting Succinyl-CoA—3-Ketoacid CoA transferase

Purpose: Despite significant progress in understanding the pathogenesis of type 2 diabetes (T2D) , it remains difficult to manage, hence, new therapeutic options are required. We previously observed that elevated skeletal muscle succinyl CoA:3-ketoacid CoA transferase (SCOT) activity, the rate-limiting enzyme of ketone (KB) oxidation, contributes to obesity-induced hyperglycemia. Moreover, we identified that the antipsychotic agent, pimozide, is a SCOT inhibitor with glucose-lowering actions. In silico molecular modeling determined that a wide range of DPBPs can theoretically inhibit SCOT activity, therefore, we determined whether the DPBP drug class could be repurposed for the treatment of T2D.

Methods: 8-week-old male wild-type and muscle-specific/brain-specific SCOT knockout (SCOT^MuscleKO, SCOT^BrainKO) mice were subjected to experimental obesity via consumption of a high fat, high sugar diet for 12-weeks. Lean control mice received a low fat, low sugar diet. At 8-weeks, lean and obese mice were treated with DPBPs (penfluridol, fluspirilene, pimozide (10mg/kg)) once every 2 days via oral gavage for 14-days, following which circulating KB levels and glucose homeostasis were assessed. To rule out a contribution of the canonical actions of DPBPs as dopamine 2 (D₂) receptor antagonists to DPBP-mediated glucose-lowering, obese mice were treated with the structurally unrelated D₂ receptor antagonist, lurasidone (10 mg/kg) .

Results: All tested DPBPs improved glucose homeostasis in obese mice through a mechanism dependent on the inhibition of both brain and muscle SCOT activity. Treatment with lurasidone failed to improve glycemia in obese mice, thus consistent with a SCOT-dependent mechanism of action.

Conclusions: Our findings suggest all DPBPs have glucose-lowering actions and therefore may have clinical utility in being repurposed for the treatment of T2D.