2022
Metformin, 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
2021
Validation of a Gas Chromatography-Mass Spectrometry Method for the Measurement of the Redox State Metabolic Ratios Lactate/Pyruvate and β-Hydroxybutyrate/Acetoacetate in Biological Samples
Wijngaard R, Perramón M, Parra-Robert M, Hidalgo S, Butrico G, Morales-Ruiz M, Zeng M, Casals E, Jiménez W, Fernández-Varo G, Shulman GI, Cline GW, Casals G. Validation of a Gas Chromatography-Mass Spectrometry Method for the Measurement of the Redox State Metabolic Ratios Lactate/Pyruvate and β-Hydroxybutyrate/Acetoacetate in Biological Samples. International Journal Of Molecular Sciences 2021, 22: 4752. PMID: 33946157, PMCID: PMC8125771, DOI: 10.3390/ijms22094752.Peer-Reviewed Original ResearchInsulin-stimulated endoproteolytic TUG cleavage links energy expenditure with glucose uptake
Habtemichael EN, Li DT, Camporez JP, Westergaard XO, Sales CI, Liu X, López-Giráldez F, DeVries SG, Li H, Ruiz DM, Wang KY, Sayal BS, González Zapata S, Dann P, Brown SN, Hirabara S, Vatner DF, Goedeke L, Philbrick W, Shulman GI, Bogan JS. Insulin-stimulated endoproteolytic TUG cleavage links energy expenditure with glucose uptake. Nature Metabolism 2021, 3: 378-393. PMID: 33686286, PMCID: PMC7990718, DOI: 10.1038/s42255-021-00359-x.Peer-Reviewed Original ResearchConceptsTUG cleavageGlucose uptakeProtein degradation pathwaysGLUT4 glucose transportersCoactivator PGC-1αC-terminal cleavage productInsulin-stimulated glucose uptakeAte1 arginyltransferaseGene expressionPhysiological relevanceWhole-body energy expenditureGlucose transporterPeroxisome proliferator-activated receptorCell surfacePGC-1αProtein 1Proliferator-activated receptorDegradation pathwayEffect of insulinCleavage pathwayAdipose cellsCleavage productsPathwayCleavageEnergy expenditureTherapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH
Goedeke L, Shulman GI. Therapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH. Molecular Metabolism 2021, 46: 101178. PMID: 33545391, PMCID: PMC8085597, DOI: 10.1016/j.molmet.2021.101178.Peer-Reviewed Original ResearchConceptsFatty liver diseaseLiver diseaseSmall molecule mitochondrial uncouplersTherapeutic potentialMitochondrial uncouplerNon-human primate studiesType 2 diabetesWide therapeutic indexSystemic toxicity concernsTreatment of MetabolicCell-specific effectsInsulin resistanceTherapeutic indexMetabolic diseasesNonalcoholic hepatosteatosisSustained increaseToxicity concernsPrimate studiesDiseaseTherapeutic developmentMitochondrial inefficiencyNutrient oxidationATP productionTreatmentTissue
2020
Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease
Luukkonen PK, Dufour S, Lyu K, Zhang XM, Hakkarainen A, Lehtimäki TE, Cline GW, Petersen KF, Shulman GI, Yki-Järvinen H. Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 7347-7354. PMID: 32179679, PMCID: PMC7132133, DOI: 10.1073/pnas.1922344117.Peer-Reviewed Original ResearchMeSH KeywordsBody CompositionCitrate (si)-SynthaseDiet, KetogenicFatty AcidsFatty Acids, NonesterifiedFatty LiverFemaleHumansInsulinInsulin ResistanceLipoproteins, VLDLLiverMaleMiddle AgedMitochondriaNon-alcoholic Fatty Liver DiseaseObesityOverweightOxidation-ReductionPyruvate CarboxylaseTriglyceridesConceptsNonalcoholic fatty liver diseaseFatty liver diseaseIntrahepatic triglyceridesKetogenic dietHepatic insulin resistanceNonesterified fatty acidsInsulin resistanceLiver diseaseOverweight/obese subjectsHepatic mitochondrial redox stateSerum insulin concentrationsHepatic mitochondrial metabolismProton magnetic resonance spectroscopyStable isotope infusionKD dietObese subjectsFatty acidsPlasma leptinHepatic steatosisInsulin concentrationsNEFA concentrationsBody weightTriiodothyronine concentrationsIsotope infusionWeight lossGlucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis
Perry RJ, Zhang D, Guerra MT, Brill AL, Goedeke L, Nasiri AR, Rabin-Court A, Wang Y, Peng L, Dufour S, Zhang Y, Zhang XM, Butrico GM, Toussaint K, Nozaki Y, Cline GW, Petersen KF, Nathanson MH, Ehrlich BE, Shulman GI. Glucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis. Nature 2020, 579: 279-283. PMID: 32132708, PMCID: PMC7101062, DOI: 10.1038/s41586-020-2074-6.Peer-Reviewed Original ResearchConceptsHepatic steatosisType 2Nonalcoholic fatty liver diseaseDiet-induced hepatic steatosisFatty liver diseasePlasma glucagon concentrationsHepatic adipose triglyceride lipaseHepatic acetyl-CoA contentHepatic glucose productionRatio of insulinHepatic glucose metabolismInositol triphosphate receptorAdipose triglyceride lipaseMitochondrial oxidationMitochondrial fat oxidationGlucose intoleranceLiver diseaseGlucagon concentrationsInsulin resistancePortal veinAcetyl-CoA contentHepatic lipolysisGlucagon biologyGlucose metabolismKnockout mice
2014
Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase
Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DT, Albright RA, Prigaro BJ, Wood JL, Bhanot S, MacDonald MJ, Jurczak MJ, Camporez JP, Lee HY, Cline GW, Samuel VT, Kibbey RG, Shulman GI. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 2014, 510: 542-546. PMID: 24847880, PMCID: PMC4074244, DOI: 10.1038/nature13270.Peer-Reviewed Original Research
2013
Direct assessment of hepatic mitochondrial oxidative and anaplerotic fluxes in humans using dynamic 13C magnetic resonance spectroscopy
Befroy DE, Perry RJ, Jain N, Dufour S, Cline GW, Trimmer JK, Brosnan J, Rothman DL, Petersen KF, Shulman GI. Direct assessment of hepatic mitochondrial oxidative and anaplerotic fluxes in humans using dynamic 13C magnetic resonance spectroscopy. Nature Medicine 2013, 20: 98-102. PMID: 24317120, PMCID: PMC3947269, DOI: 10.1038/nm.3415.Peer-Reviewed Original Research
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
2000
Assessment of mitochondrial energy coupling in vivo by 13C/31P NMR
Jucker B, Dufour S, Ren J, Cao X, Previs S, Underhill B, Cadman K, Shulman G. Assessment of mitochondrial energy coupling in vivo by 13C/31P NMR. Proceedings Of The National Academy Of Sciences Of The United States Of America 2000, 97: 6880-6884. PMID: 10823916, PMCID: PMC18769, DOI: 10.1073/pnas.120131997.Peer-Reviewed Original ResearchConceptsUCP3 mRNA
1999
Determination of the rate of the glutamate/glutamine cycle in the human brain by in vivo 13C NMR
Shen J, Petersen K, Behar K, Brown P, Nixon T, Mason G, Petroff O, Shulman G, Shulman R, Rothman D. Determination of the rate of the glutamate/glutamine cycle in the human brain by in vivo 13C NMR. Proceedings Of The National Academy Of Sciences Of The United States Of America 1999, 96: 8235-8240. PMID: 10393978, PMCID: PMC22218, DOI: 10.1073/pnas.96.14.8235.Peer-Reviewed Original ResearchConceptsGlutamate/glutamine cycleGlutamine cycleCerebral cortexMin/Rat cerebral cortexVivo 13C NMR spectraGlucose oxidation ratesHuman brainGlucose oxidationGlutamatergic activityRat modelTricarboxylic acid cycle rateParietal lobeHuman cortexCortexTime courseBrainGlutamine synthesisMajor metabolic fluxCycle rateTricarboxylic acid cycleHigh levelsInfusionRatsAcid cycle