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
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
2020
Cellular and Molecular Mechanisms of Metformin Action
LaMoia TE, Shulman GI. Cellular and Molecular Mechanisms of Metformin Action. Endocrine Reviews 2020, 42: 77-96. PMID: 32897388, PMCID: PMC7846086, DOI: 10.1210/endrev/bnaa023.Peer-Reviewed Original ResearchConceptsGlucose-lowering effectType 2 diabetesMetformin actionHepatic gluconeogenesisFirst-line therapyDosage of metforminRedox-dependent mechanismMechanism of actionMolecular mechanismsSafety profileMetformin inhibitsComplex I inhibitionMetformin concentrationsGlucose metabolismMetforminClinical settingPleotropic effectsDiscrepant effectsDiabetesAMPK activationCurrent literatureRelevant concentrationsI inhibitionRecent studiesRedox balanceMitochondrial Dysfunction, Insulin Resistance, and Potential Genetic Implications
Sangwung P, Petersen KF, Shulman GI, Knowles JW. Mitochondrial Dysfunction, Insulin Resistance, and Potential Genetic Implications. Endocrinology 2020, 161: bqaa017. PMID: 32060542, PMCID: PMC7341556, DOI: 10.1210/endocr/bqaa017.Peer-Reviewed Original ResearchConceptsInsulin resistanceWhole-body insulin resistanceMitochondrial functionEctopic lipid depositionBody insulin resistanceType 2 diabetesWhite adipose tissuePrediabetic individualsVivo metabolic studiesInsulin-responsive tissuesLipid depositionAdipose tissueType 2Skeletal muscleMitochondrial dysfunctionPotential mechanismsMetabolic studiesHuman genetic studiesTissueEnvironmental determinantsMitochondrial malfunctionCellular energy balanceRecent insightsCritical roleDiabetesMechanistic Links between Obesity, Insulin, and Cancer
Perry RJ, Shulman GI. Mechanistic Links between Obesity, Insulin, and Cancer. Trends In Cancer 2020, 6: 75-78. PMID: 32061306, PMCID: PMC7214048, DOI: 10.1016/j.trecan.2019.12.003.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus Statements
2019
The integrative biology of type 2 diabetes
Roden M, Shulman GI. The integrative biology of type 2 diabetes. Nature 2019, 576: 51-60. PMID: 31802013, DOI: 10.1038/s41586-019-1797-8.Peer-Reviewed Original ResearchConceptsType 2 diabetesInsulin resistanceFrequent metabolic disorderWhite adipose tissueRelevant animal modelsCommon underlying abnormalityAdequate substrate supplyInflammatory pathwaysUnderlying abnormalityMetabolic disordersAnimal modelsAdipose tissueEnergy intakeHepatic gluconeogenesisDiabetesObesityAbnormalitiesTissue communicationRecent studiesEnergy imbalanceDysfunctionPathwayInsulinIntakeBrainNonalcoholic Fatty Liver Disease, Insulin Resistance, and Ceramides
Samuel VT, Shulman GI. Nonalcoholic Fatty Liver Disease, Insulin Resistance, and Ceramides. New England Journal Of Medicine 2019, 381: 1866-1869. PMID: 31693811, DOI: 10.1056/nejmcibr1910023.Peer-Reviewed Original Research
2016
Mitochondrial Protonophores For Treatment of NAFLD/NASH and Type 2 Diabetes
Shulman G. Mitochondrial Protonophores For Treatment of NAFLD/NASH and Type 2 Diabetes. The FASEB Journal 2016, 30 DOI: 10.1096/fasebj.30.1_supplement.257.2.Peer-Reviewed Original ResearchType 2 diabetesInsulin resistanceLipid-induced insulin resistanceNAFLD/NASHSkeletal muscleAdipose tissue inflammationEctopic lipid depositionNon-alcoholic steatohepatitisAmerican Diabetes AssociationEctopic lipid depositsAlcoholic steatohepatitisDiabetes AssociationTissue inflammationRecent studiesLipid depositionType 2Lipid depositsHepatic gluconeogenesisCellular mechanismsMitochondrial protonophoreDiabetesMitochondrial inefficiencyLiverMuscleMolecular triggers
2014
Leptin reverses diabetes by suppression of the hypothalamic-pituitary-adrenal axis
Perry RJ, Zhang XM, Zhang D, Kumashiro N, Camporez JP, Cline GW, Rothman DL, Shulman GI. Leptin reverses diabetes by suppression of the hypothalamic-pituitary-adrenal axis. Nature Medicine 2014, 20: 759-763. PMID: 24929951, PMCID: PMC4344321, DOI: 10.1038/nm.3579.Peer-Reviewed Original ResearchThe role of hepatic lipids in hepatic insulin resistance and type 2 diabetes
Perry RJ, Samuel VT, Petersen KF, Shulman GI. The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature 2014, 510: 84-91. PMID: 24899308, PMCID: PMC4489847, DOI: 10.1038/nature13478.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsType 2 diabetesHepatic insulin resistanceNon-alcoholic fatty liver diseaseFatty liver diseaseInsulin resistanceLiver diseaseHepatic lipidsHealth care costsInflammatory signalingTherapeutic approachesMortality rateDiabetesRelated epidemicsProtein kinase CεDiseaseCellular modificationsEpidemicLipid speciesMorbidityLipidsDiacylglycerol activationMice
2003
Mitochondrial Dysfunction in the Elderly: Possible Role in Insulin Resistance
Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW, Shulman GI. Mitochondrial Dysfunction in the Elderly: Possible Role in Insulin Resistance. Science 2003, 300: 1140-1142. PMID: 12750520, PMCID: PMC3004429, DOI: 10.1126/science.1082889.Peer-Reviewed Original ResearchMeSH KeywordsAdipose TissueAdolescentAdultAgedAged, 80 and overAgingBlood GlucoseBody Mass IndexFemaleHumansInsulinInsulin ResistanceLiverMaleMiddle AgedMitochondriaMitochondrial DiseasesMuscle, SkeletalNuclear Magnetic Resonance, BiomolecularOxidation-ReductionOxygen ConsumptionPhosphorylationTriglyceridesConceptsInsulin resistanceInsulin-stimulated muscle glucose metabolismType 2 diabetesMuscle glucose metabolismLean body massElderly study participantsAge-associated declineMitochondrial function contributesFat massFat accumulationGlucose metabolismYoung controlsStudy participantsLiver tissueFunction contributesMitochondrial dysfunctionYounger participantsPossible roleMitochondrial oxidativeBody massMagnetic resonance spectroscopyParticipantsDiabetesDysfunctionPathogenesis
2001
Glucose toxicity and the development of diabetes in mice with muscle-specific inactivation of GLUT4
Kim J, Zisman A, Fillmore J, Peroni O, Kotani K, Perret P, Zong H, Dong J, Kahn C, Kahn B, Shulman G. Glucose toxicity and the development of diabetes in mice with muscle-specific inactivation of GLUT4. Journal Of Clinical Investigation 2001, 108: 153-160. PMID: 11435467, PMCID: PMC353719, DOI: 10.1172/jci10294.Peer-Reviewed Original ResearchMeSH KeywordsAdipose TissueAge of OnsetAnimalsDepression, ChemicalDiabetes Mellitus, Type 2Disease Models, AnimalGlucoseGlucose Transporter Type 4HyperglycemiaInsulinInsulin Infusion SystemsInsulin ResistanceKidney TubulesLiverMaleMiceMice, KnockoutMonosaccharide Transport ProteinsMuscle ProteinsMuscle, SkeletalPhlorhizinPrediabetic StateProtein TransportConceptsDevelopment of diabetesMuscle glucose uptakeKO miceHepatic glucose productionInsulin-stimulated glucose uptakeGlucose toxicityMuscle-specific inactivationGlucose uptakeAdipose tissueInsulin-stimulated muscle glucose uptakeGlucose productionWhole-body glucose uptakeSkeletal muscle glucose uptakeAdipose tissue glucose uptakeSuppress hepatic glucose productionTissue glucose uptakeHyperinsulinemic-euglycemic clampMuscle glucose transportInsulin resistanceTransgenic miceDiabetes phenotypeInsulin actionPhloridzin treatmentInsulin's abilityDiabetesUncoupling Protein-2 Negatively Regulates Insulin Secretion and Is a Major Link between Obesity, β Cell Dysfunction, and Type 2 Diabetes
Zhang C, Baffy G, Perret P, Krauss S, Peroni O, Grujic D, Hagen T, Vidal-Puig A, Boss O, Kim Y, Zheng X, Wheeler M, Shulman G, Chan C, Lowell B. Uncoupling Protein-2 Negatively Regulates Insulin Secretion and Is a Major Link between Obesity, β Cell Dysfunction, and Type 2 Diabetes. Cell 2001, 105: 745-755. PMID: 11440717, DOI: 10.1016/s0092-8674(01)00378-6.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAnimalsBlood GlucoseBody WeightDiabetes MellitusDiabetes Mellitus, Type 2Disease Models, AnimalGene TargetingHomeostasisHumansHyperglycemiaInsulinInsulin SecretionIon ChannelsIslets of LangerhansMaleMembrane Transport ProteinsMiceMice, KnockoutMice, ObeseMitochondrial ProteinsModels, BiologicalObesityProteinsRNA, MessengerThermogenesisUncoupling AgentsUncoupling Protein 2ConceptsOb/ob miceInsulin secretionOb miceCell dysfunctionFirst-phase insulin secretionIslet ATP levelsGlucose-stimulated insulin secretionLevel of glycemiaSerum insulin levelsBeta-cell dysfunctionType 2 diabetesObesity-induced diabetesΒ-cell dysfunctionBeta-cell glucose sensingProtein 2UCP2-deficient miceInsulin levelsPathophysiologic significanceBeta cellsType 2SecretionMiceObesityATP levelsDiabetesAdipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver
Abel E, Peroni O, Kim J, Kim Y, Boss O, Hadro E, Minnemann T, Shulman G, Kahn B. Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature 2001, 409: 729-733. PMID: 11217863, DOI: 10.1038/35055575.Peer-Reviewed Original ResearchConceptsInsulin-stimulated glucose uptakeType 2 diabetesInsulin resistanceGlucose uptakeAdipose tissueGLUT4 expressionInsulin-resistant statesDownregulation of GLUT4Glucose intoleranceGlucose transportAdipose massIntracellular storage sitesGlucose homeostasisInsulin actionDiabetesPhosphoinositide-3-OH kinaseImpaired activationSkeletal muscleMuscleMicePlasma membrane4Early defectsLiverMain siteAdipocytes
2000
Mechanism of Insulin Resistance in A-ZIP/F-1 Fatless Mice*
Kim J, Gavrilova O, Chen Y, Reitman M, Shulman G. Mechanism of Insulin Resistance in A-ZIP/F-1 Fatless Mice*. Journal Of Biological Chemistry 2000, 275: 8456-8460. PMID: 10722680, DOI: 10.1074/jbc.275.12.8456.Peer-Reviewed Original ResearchConceptsType 2 diabetesInsulin resistanceFatless miceInsulin actionTriglyceride contentA-ZIP/FDevelopment of diabetesLiver triglyceride contentHyperinsulinemic-euglycemic clampAccumulation of triglyceridesMuscle/liverWild-type littermatesInsulin receptor substrate-1Receptor substrate-1Partitioning of fatSubsequent impairmentDiabetesFat metabolismMiceFat tissueLiverInsulin signalingMuscleLatter tissueSubstrate-1Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice
Gavrilova O, Marcus-Samuels B, Graham D, Kim J, Shulman G, Castle A, Vinson C, Eckhaus M, Reitman M. Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. Journal Of Clinical Investigation 2000, 105: 271-278. PMID: 10675352, PMCID: PMC377444, DOI: 10.1172/jci7901.Peer-Reviewed Original ResearchConceptsA-ZIP/FLipoatrophic diabetesAdipose tissueNear-physiological amountsMuscle insulin sensitivityLack of fatLipoatrophic miceInsulin levelsHepatic steatosisInsulin resistanceInsulin sensitivitySevere formFFA levelsDiabetesDonor fatTransplantationBeneficial effectsEndocrine communicationSubcutaneous sitesMiceSurgical implantationAdipose physiologyHyperglycemiaFatTissue
1999
Cellular mechanisms of insulin resistance in humans
Shulman G. Cellular mechanisms of insulin resistance in humans. The American Journal Of Cardiology 1999, 84: 3-10. PMID: 10418851, DOI: 10.1016/s0002-9149(99)00350-1.Peer-Reviewed Original ResearchConceptsType 2 diabetesInsulin resistanceMuscle glycogen synthesisFree fatty acidsGlucose productionHepatic gluconeogenesisInsulin-stimulated glucose metabolismInsulin-stimulated muscle glycogen synthesisBetter glucose controlCellular mechanismsHepatic glucose productionLiver glycogen concentrationGlycogen synthesisPathophysiologic defectsCombination therapyGlucose controlInsulin secretionInsulin receptor substrateHyperinsulinemic clampingPeripheral tissuesGlucose clearanceFFA levelsGlucose metabolismThiazolidinedione troglitazoneDiabetes
1998
Disruption of IRS-2 causes type 2 diabetes in mice
Withers D, Gutierrez J, Towery H, Burks D, Ren J, Previs S, Zhang Y, Bernal D, Pons S, Shulman G, Bonner-Weir S, White M. Disruption of IRS-2 causes type 2 diabetes in mice. Nature 1998, 391: 900-904. PMID: 9495343, DOI: 10.1038/36116.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlood GlucoseCloning, MolecularDiabetes Mellitus, Type 2FemaleGene TargetingHumansInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceIntracellular Signaling Peptides and ProteinsIslets of LangerhansLiverMaleMiceMice, Inbred C57BLMuscle, SkeletalPhosphatidylinositol 3-KinasesPhosphoproteinsPhosphorylationReceptor, InsulinRecombination, GeneticSignal TransductionConceptsType 2 diabetesInsulin resistanceHuman type 2 diabetesPancreatic β-cell functionInsulin secretion increasesSingle molecular abnormalityΒ-cell compensationIRS-2-deficient miceΒ-cell functionHuman type 2Insulin secretionInsulin receptor substrateGlucose homeostasisSecretion increasesInsulin actionType 2DiabetesMolecular abnormalitiesProgressive deteriorationSkeletal muscleIRS-2Insulin signalingIRS-1Mild resistanceMice
1997
Human IAPP/amylin overproducing transgenic mice: Characterization of an animal model to study the role of IAPP in the pathogenesis of Type 2 diabetes
Höppener J, Oosterwijk C, Shulman G, Jiménez-Chillarón J, Guinovart J, Chico S, Gómez-Foix A, Ahrén B, Lips C. Human IAPP/amylin overproducing transgenic mice: Characterization of an animal model to study the role of IAPP in the pathogenesis of Type 2 diabetes. Experimental And Clinical Endocrinology & Diabetes 1997, 105: 69-69. DOI: 10.1055/s-0029-1211891.Peer-Reviewed Original Research