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 effects
2023
Hepatocyte CYR61 polarizes profibrotic macrophages to orchestrate NASH fibrosis
Mooring M, Yeung G, Luukkonen P, Liu S, Akbar M, Zhang G, Balogun O, Yu X, Mo R, Nejak-Bowen K, Poyurovsky M, Booth C, Konnikova L, Shulman G, Yimlamai D. Hepatocyte CYR61 polarizes profibrotic macrophages to orchestrate NASH fibrosis. Science Translational Medicine 2023, 15: eade3157. PMID: 37756381, PMCID: PMC10874639, DOI: 10.1126/scitranslmed.ade3157.Peer-Reviewed Original ResearchConceptsNonalcoholic steatohepatitisLiver inflammationNonalcoholic fatty liver diseaseProgression of NASHCysteine-rich angiogenic inducer 61Fatty liver diseaseLiver-specific knockout miceImproved glucose toleranceType 2 diabetesGlucose toleranceLiver diseaseNASH progressionProfibrotic macrophagesProinflammatory propertiesReduced fibrosisCardiovascular diseaseProfibrotic phenotypeFibrotic developmentKnockout miceNF-κBMetabolic diseasesNASH dietPDGFB expressionFibrosisProfibrotic program
2021
Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis
Jiang Z, Zhao M, Voilquin L, Jung Y, Aikio MA, Sahai T, Dou FY, Roche AM, Carcamo-Orive I, Knowles JW, Wabitsch M, Appel EA, Maikawa CL, Camporez JP, Shulman GI, Tsai L, Rosen ED, Gardner CD, Spiegelman BM, Svensson KJ. Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis. Cell Metabolism 2021, 33: 1836-1852.e11. PMID: 34348115, PMCID: PMC8429235, DOI: 10.1016/j.cmet.2021.07.010.Peer-Reviewed Original ResearchConceptsFatty liver diseaseAdipose glucose uptakeGlucose toleranceLiver diseaseHepatic steatosisGlucose uptakeDiet-induced obese miceImpaired glucose toleranceInsulin-like growth factor receptorType 2 diabetesHepatic lipid synthesisIsthmin 1Growth factor receptorObese miceInsulin sensitivityTherapeutic dosingMouse modelGlucoregulatory functionGlucose regulationUnmet needTherapeutic potentialDiabetesLipid accumulationPI3K-AktFactor receptor
2016
Insulin Resistance in Type 2 Diabetes
Roden M, Petersen K, Shulman G. Insulin Resistance in Type 2 Diabetes. 2016, 174-186. DOI: 10.1002/9781118924853.ch13.Peer-Reviewed Original ResearchType 2 diabetesNon-alcoholic fatty liver diseaseInsulin resistanceInflammatory pathwaysAdipose tissueHepatic mitochondrial oxidative capacityLipid-mediated insulin resistanceFatty liver diseaseImpaired glucose toleranceDiabetes-related complicationsEctopic lipid accumulationΒ-cell dysfunctionFatty acid availabilityAction of insulinMitochondrial oxidative capacityAtherogenic dyslipidemiaMultiple deleterious effectsGlucose toleranceLiver diseaseCarbohydrate ingestionEctopic storagePostprandial hyperglycemiaSystemic abnormalitiesInhibits lipolysisFree fatty acids
2001
Syntaxin 4 heterozygous knockout mice develop muscle insulin resistance
Yang C, Coker K, Kim J, Mora S, Thurmond D, Davis A, Yang B, Williamson R, Shulman G, Pessin J. Syntaxin 4 heterozygous knockout mice develop muscle insulin resistance. Journal Of Clinical Investigation 2001, 107: 1311-1318. PMID: 11375421, PMCID: PMC209300, DOI: 10.1172/jci12274.Peer-Reviewed Original ResearchMeSH KeywordsAdipocytesAdipose Tissue, BrownAnimalsBiological TransportGlucoseGlucose Clamp TechniqueGlucose Tolerance TestGlucose Transporter Type 4GlycogenGlycolysisHeterozygoteInsulin ResistanceLiverMembrane ProteinsMiceMice, KnockoutMonosaccharide Transport ProteinsMuscle ProteinsMuscle, SkeletalQa-SNARE ProteinsConceptsHeterozygous knockout miceInsulin-stimulated glucose uptakeGlucose uptakeKnockout miceNormal insulin-stimulated glucose uptakeWhole-body glucose uptakeHyperinsulinemic-euglycemic clamp procedureInsulin-stimulated glucose metabolismInsulin-stimulated GLUT4 translocationSkeletal muscleGLUT4 vesicle traffickingImpaired glucose toleranceMuscle insulin resistanceEarly embryonic lethalitySkeletal muscle glucose transportMuscle glucose transportCritical physiological roleGlucose toleranceInsulin resistanceClamp procedureVesicle traffickingSyntaxin 4Embryonic lethalityGlucose metabolismAnimal models
1990
Effect of metformin treatment on insulin action in diabetic rats: In vivo and in vitro correlations
Rossetti L, DeFronzo R, Gherzi R, Stein P, Andraghetti G, Falzetti G, Shulman G, Klein-Robbenhaar E, Cordera R. Effect of metformin treatment on insulin action in diabetic rats: In vivo and in vitro correlations. Metabolism 1990, 39: 425-435. PMID: 2157941, DOI: 10.1016/0026-0495(90)90259-f.Peer-Reviewed Original ResearchConceptsInsulin receptor tyrosine kinase activityDiabetic ratsMetformin treatmentReceptor tyrosine kinase activityTyrosine kinase activitySupernormal levelsGlucose disposalInsulin-mediated whole-body glucose disposalTotal body insulin-mediated glucose disposalInsulin actionNeonatal streptozotocin diabetic ratsTotal body glucose uptakeInsulin-mediated glucose disposalWhole-body glucose disposalGlucose uptakeDeficient insulin responseNormalized glucose toleranceInsulin clamp studiesStreptozotocin-diabetic ratsVivo insulin actionHepatic glucose productionMuscle glycogen synthesisGlycogen synthesisSynthetic rateGlucose tolerance