2022
195-OR: A Novel 13C5 Glutamine Tracer Method (Q Flux) Reveals a Key Role of Succinyl CoA Anaplerosis in Promoting Increased Rates of Hepatic Gluconeogenesis during Hyperglucagonemia
HUBBARD B, SHULMAN G. 195-OR: A Novel 13C5 Glutamine Tracer Method (Q Flux) Reveals a Key Role of Succinyl CoA Anaplerosis in Promoting Increased Rates of Hepatic Gluconeogenesis during Hyperglucagonemia. Diabetes 2022, 71 DOI: 10.2337/db22-195-or.Peer-Reviewed Original ResearchSuccinyl CoAEndogenous glucose productionMetabolic flux analysis methodHepatic gluconeogenesisAnaplerotic pathwaysUnexpected roleHD animalsType 2 diabetes mellitusMale Sprague-Dawley ratsHigh-dose glucagonLow-dose glucagonNovel targetSprague-Dawley ratsRespective substratesPlasma glucose concentrationGlutamineMetformin, phenformin, and galegine inhibit complex IV activity and reduce glycerol-derived gluconeogenesis
LaMoia TE, Butrico GM, Kalpage HA, Goedeke L, Hubbard BT, Vatner DF, Gaspar RC, Zhang XM, Cline GW, Nakahara K, Woo S, Shimada A, Hüttemann M, Shulman GI. Metformin, phenformin, and galegine inhibit complex IV activity and reduce glycerol-derived gluconeogenesis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2022, 119: e2122287119. PMID: 35238637, PMCID: PMC8916010, DOI: 10.1073/pnas.2122287119.Peer-Reviewed Original ResearchConceptsGlucose-lowering effectPlasma glucose concentrationComplex I activityHepatic gluconeogenesisType 2 diabetes mellitusGlucose concentrationGlycerol-3-phosphate dehydrogenase activityI activityDiabetes mellitusSelective inhibitionMetforminInhibitionRelevant concentrationsGluconeogenesisPhenforminVivoMost studiesDehydrogenase activityGalegineMellitus
2020
Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance
He F, Huang Y, Song Z, Zhou HJ, Zhang H, Perry RJ, Shulman GI, Min W. Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance. Journal Of Experimental Medicine 2020, 218: e20201416. PMID: 33315085, PMCID: PMC7927432, DOI: 10.1084/jem.20201416.Peer-Reviewed Original ResearchMeSH KeywordsAdipocytesAdipose TissueAnimalsDiabetes Mellitus, Type 2Diet, High-FatEnergy MetabolismFatty LiverGene DeletionGene TargetingGluconeogenesisHomeostasisHumansHyperglycemiaInflammationInsulin ResistanceLipogenesisLiverMaleMice, Inbred C57BLMice, KnockoutMitochondriaMitophagyNF-kappa BOxidative StressPhenotypeReactive Oxygen SpeciesSequestosome-1 ProteinSignal TransductionThioredoxinsConceptsHepatic insulin resistanceWhite adipose tissueInsulin resistanceAdipose inflammationType 2 diabetes mellitusLipid metabolic disordersNF-κB inhibitorAdipose-specific deletionWhole-body energy homeostasisAltered fatty acid metabolismFatty acid metabolismT2DM progressionT2DM patientsDiabetes mellitusReactive oxygen species pathwayHepatic steatosisMetabolic disordersNF-κBP62/SQSTM1Adipose tissueHuman adipocytesEnergy homeostasisExcessive mitophagyOxygen species pathwayInflammationMechanisms by which adiponectin reverses high fat diet-induced insulin resistance in mice
Li X, Zhang D, Vatner DF, Goedeke L, Hirabara SM, Zhang Y, Perry RJ, Shulman GI. Mechanisms by which adiponectin reverses high fat diet-induced insulin resistance in mice. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 32584-32593. PMID: 33293421, PMCID: PMC7768680, DOI: 10.1073/pnas.1922169117.Peer-Reviewed Original ResearchConceptsEpididymal white adipose tissueInsulin resistanceAdiponectin treatmentAdipose tissueHigh-fat diet-induced insulin resistanceType 2 diabetes mellitusWhole-body insulin resistanceDiet-induced insulin resistanceSkeletal muscleEctopic lipid storageReverses insulin resistanceInsulin-mediated suppressionMuscle fatty acid oxidationEndogenous glucose productionMuscle insulin resistanceWhite adipose tissueLipoprotein lipase activityMuscle fat oxidationPKCε translocationInsulin-stimulated glucose uptakeFatty acid oxidationTAG uptakeDiabetes mellitusMuscle sensitivityAkt serine phosphorylationNon‐alcoholic Fatty Liver Disease and Insulin Resistance
Petersen M, Samuel V, Petersen K, Shulman G. Non‐alcoholic Fatty Liver Disease and Insulin Resistance. 2020, 455-471. DOI: 10.1002/9781119436812.ch37.Peer-Reviewed Original ResearchNon-alcoholic fatty liver diseaseHepatic insulin resistanceFatty liver diseaseInsulin resistanceLiver diseaseDevelopment of NAFLDLipid-induced muscle insulin resistanceRandle glucose-fatty acid cycleCommon chronic liver diseaseType 2 diabetes mellitusHyperinsulinemic-euglycemic clamp studiesGlucose-fatty acid cycleLiver-related deathSkeletal muscleChronic liver diseaseNon-alcoholic steatohepatitisMajor risk factorLipid-induced hepatic insulin resistanceMuscle insulin resistanceDiabetes mellitusRisk factorsClamp studiesLipoprotein lipaseDiseaseProtein kinase C
2001
Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance
Kim J, Fillmore J, Chen Y, Yu C, Moore I, Pypaert M, Lutz E, Kako Y, Velez-Carrasco W, Goldberg I, Breslow J, Shulman G. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proceedings Of The National Academy Of Sciences Of The United States Of America 2001, 98: 7522-7527. PMID: 11390966, PMCID: PMC34701, DOI: 10.1073/pnas.121164498.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlood GlucoseFatty Acids, NonesterifiedGlucagonGlucoseGlucose Clamp TechniqueGlucose Tolerance TestHeterozygoteInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceLeptinLipoprotein LipaseLiverMiceMice, KnockoutMice, TransgenicMuscle, SkeletalOrgan SpecificityPhosphatidylinositol 3-KinasesPhosphoproteinsSignal TransductionTriglyceridesConceptsInsulin resistanceFatty acid-derived metabolitesInsulin actionTriglyceride contentType 2 diabetes mellitusInsulin activationLipoprotein lipaseInsulin receptor substrate-1-associated phosphatidylinositolMuscle triglyceride contentSkeletal muscleTissue-specific insulin resistanceLiver triglyceride contentAdipocyte-derived hormoneHyperinsulinemic-euglycemic clampEndogenous glucose productionLiver-specific overexpressionTissue-specific overexpressionInsulin-stimulated glucose uptakeDiabetes mellitusTissue-specific increaseTransgenic miceGlucose productionFat metabolismGlucose uptakeInsulin
1999
Impaired Glucose Transport as a Cause of Decreased Insulin-Stimulated Muscle Glycogen Synthesis in Type 2 Diabetes
Cline G, Petersen K, Krssak M, Shen J, Hundal R, Trajanoski Z, Inzucchi S, Dresner A, Rothman D, Shulman G. Impaired Glucose Transport as a Cause of Decreased Insulin-Stimulated Muscle Glycogen Synthesis in Type 2 Diabetes. New England Journal Of Medicine 1999, 341: 240-246. PMID: 10413736, DOI: 10.1056/nejm199907223410404.Peer-Reviewed Original ResearchConceptsMuscle glycogen synthesisType 2 diabetes mellitusConcentrations of insulinNormal subjectsDiabetes mellitusGlucose metabolismGlycogen synthesisGlucose concentrationWhole-body glucose metabolismInsulin-stimulated muscle glycogen synthesisIntracellular glucose concentrationType 2 diabetesPlasma insulin concentrationGlucose transportImpaired glucose transportInterstitial fluid glucose concentrationsOpen-flow microperfusionIntramuscular glucoseInterstitial fluidGlucose-6-phosphate concentrationInsulin resistanceVivo microdialysisInsulin concentrationsHyperinsulinemic conditionsPatients