Despite significant progress in understanding the path-ogenesis of type 2 diabetes (T2D), the condition remains difficult to manage. Hence, new therapeutic options tar-geting unique mechanisms of action are required. We have previously observed that elevated skeletal muscle succinyl CoA:3-ketoacid CoA transferase (SCOT) activ-ity, the rate-limiting enzyme of ketone oxidation, con-tributes to the hyperglycemia characterizing obesity and T2D. Moreover, we identified that the typical anti-psychotic agent pimozide is a SCOT inhibitor that can alleviate obesity-induced hyperglycemia. We now ex-tend those observations here, using computer-assisted in silico modeling and in vivo pharmacology studies that highlight SCOT as a noncanonical target shared among the diphenylbutylpiperidine (DPBP) drug class, which in-cludes penfluridol and fluspirilene. All three DPBPs tested (pimozide, penfluridol, and fluspirilene) improved glycemia in obese mice. While the canonical target of the DPBPs is the dopamine 2 receptor, studies in obese mice demon-strated that acute or chronic treatment with a structurally unrelated antipsychotic dopamine 2 receptor antagonist, lurasidone, was devoid of glucose-lowering actions. We further observed that the DPBPs improved glycemia in a SCOT-dependent manner in skeletal muscle, sug-gesting that this older class of antipsychotic agents may have utility in being repurposed for the treatment of T2D.
|Original language||English (US)|
|Number of pages||9|
|State||Published - Jan 2023|
Bibliographical noteFunding Information:
Acknowledgments. The in silico modeling studies required access to the Compute Canada and SHARCNET online servers. Funding. This work was supported by a Canadian Institutes of Health Research project grant (to J.R.U.). J.R.U. is a Tier 2 Canada Research Chair (Pharmacotherapy of Energy Metabolism in Obesity). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. S.A.T.D., A.A.G., K.Y., R.A.F., C.T.S., K.G., J.S.F.C., J.J.C., F.E., C.L., and R.A. performed the experiments. S.A.T.D., C.A.V.-M., P.A.C., J.N.M.G., R.A., and J.R.U. reviewed and edited the manuscript. S.A.T.D., R.A., and J.R.U. designed the experiments. S.A.T.D. and J.R.U. analyzed the data and wrote the manuscript. All authors read and approved the manuscript for submission. J.R.U. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
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