2024
899-P: Combinations of the Mitochondrial Protonophore TLC-6740 and/or the ACC2 Inhibitor TLC-3595 Provide Additive Glycemic Benefits to Semaglutide (SEMA) in db/db Mice
VIJAYAKUMAR A, SRODA N, MURAKAMI E, WENG S, MYERS R, SUBRAMANIAN M, SHULMAN G. 899-P: Combinations of the Mitochondrial Protonophore TLC-6740 and/or the ACC2 Inhibitor TLC-3595 Provide Additive Glycemic Benefits to Semaglutide (SEMA) in db/db Mice. Diabetes 2024, 73 DOI: 10.2337/db24-899-p.Peer-Reviewed Original ResearchOral glucose tolerance testGLP-1R agonistsDb/db miceIncremental AUCGlucose tolerance testMale db/db miceImproved glucose toleranceSemaglutide groupGlycemic parametersSemaglutideTolerance testFood intakeGlucose toleranceGLP-1RLiver-targeted mitochondrial uncouplerDb/dbMiceGlucose bolusVEHAgonistsEvaluation of combinationsHbA1cDiabetesMitochondrial uncouplingAssess effects1886-LB: Safety, PK, and Preliminary Efficacy of the Liver-Targeted Mitochondrial Protonophore TLC-6740—A Phase 1 Study
GANE E, HUSS R, SUR J, MURAKAMI E, WENG S, KIRBY B, SHAH A, SHULMAN G, SUBRAMANIAN M, VIJAYAKUMAR A, MYERS R. 1886-LB: Safety, PK, and Preliminary Efficacy of the Liver-Targeted Mitochondrial Protonophore TLC-6740—A Phase 1 Study. Diabetes 2024, 73 DOI: 10.2337/db24-1886-lb.Peer-Reviewed Original ResearchTreatment of obesityAdverse eventsSteady-state half-lifeEvaluate food effectsPhase 1 studyDose-dependent improvementDose-dependent reductionProportion of subjectsUnrelated to treatmentDose-dependent mannerMAD cohortsLab abnormalitiesSerum totalLDL-CFood effectHealthy subjectsClinical useWeight lossImpact of foodBody weightPreliminary efficacyObesityHalf-lifeTreatmentMitochondrial uncoupling
2022
Sex‐ and strain‐specific effects of mitochondrial uncoupling on age‐related metabolic diseases in high‐fat diet‐fed mice
Goedeke L, Murt KN, Di Francesco A, Camporez JP, Nasiri AR, Wang Y, Zhang X, Cline GW, de Cabo R, Shulman GI. Sex‐ and strain‐specific effects of mitochondrial uncoupling on age‐related metabolic diseases in high‐fat diet‐fed mice. Aging Cell 2022, 21: e13539. PMID: 35088525, PMCID: PMC8844126, DOI: 10.1111/acel.13539.Peer-Reviewed Original ResearchConceptsControlled-release mitochondrial protonophoreAge-related metabolic diseasesHepatocellular carcinomaMetabolic diseasesHigh-fat diet-fed miceProtein kinase C epsilon activationDiet-induced obese miceWhole-body energy expenditureC57BL/6J male miceDiet-fed miceHigh-fat dietHepatic lipid peroxidationHepatic lipid contentMitochondrial uncouplingHepatic insulin resistanceHigh therapeutic indexHepatic mitochondrial biogenesisStrain-specific effectsSex-specific mannerCRMP treatmentHFD feedingUnwanted side effectsObese miceInsulin resistanceChronic ingestion