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
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 ResearchMeSH KeywordsAnimalsDiabetes Mellitus, Type 2GluconeogenesisGlucoseHumansHypoglycemic AgentsMetforminConceptsGlucose-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 balance
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
2000
Mechanism of muscle glycogen autoregulation in humans
Laurent D, Hundal R, Dresner A, Price T, Vogel S, Petersen K, Shulman G. Mechanism of muscle glycogen autoregulation in humans. AJP Endocrinology And Metabolism 2000, 278: e663-e668. PMID: 10751200, DOI: 10.1152/ajpendo.2000.278.4.e663.Peer-Reviewed Original ResearchConceptsInsulin-stimulated ratesWhole body glucose oxidation ratesMuscle glycogenGlycogen loadingPlasma free fatty acid concentrationsWhole-body glucose uptakeFree fatty acid concentrationsMuscle glycogen contentGlucose oxidation ratesMuscle glycogen synthesisPlasma lactate concentrationTwofold increaseHyperinsulinemic clampGlycogen synthase activityFatty acid concentrationsLoading protocolGlucose infusionHealthy volunteersLactate concentrationGlycogen contentGlucose uptakeAnaerobic glycolysisGlycogen synthesisUnlabeled glucose infusionGlycogen
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 ResearchMeSH KeywordsDiabetes Mellitus, Type 2GlucoseGlycogenHumansHypoglycemic AgentsInsulinInsulin ResistanceLiverMagnetic Resonance SpectroscopyMusclesConceptsType 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
Efficacy and Metabolic Effects of Metformin and Troglitazone in Type II Diabetes Mellitus
Inzucchi S, Maggs D, Spollett G, Page S, Rife F, Walton V, Shulman G. Efficacy and Metabolic Effects of Metformin and Troglitazone in Type II Diabetes Mellitus. New England Journal Of Medicine 1998, 338: 867-873. PMID: 9516221, DOI: 10.1056/nejm199803263381303.Peer-Reviewed Original ResearchConceptsEndogenous glucose productionPlasma glucose concentrationPostprandial plasma glucose concentrationsPeripheral glucose disposalType 2 diabetesMetformin therapyTroglitazone therapyGlucose disposalGlucose productionHemoglobin valuesGlucose concentrationType II diabetes mellitusAdditive beneficial effectsSingle-drug therapyDiabetes mellitusGlycemic controlCombination therapyPoor responseMetabolic effectsPhysiologic effectsMetforminPatientsTherapyTroglitazoneBeneficial effects
1991
The effect of CP 68,722, a thiozolidinedione derivative, on insulin sensitivity in lean and obese Zucker rats
Bowen L, Stein P, Stevenson R, Shulman G. The effect of CP 68,722, a thiozolidinedione derivative, on insulin sensitivity in lean and obese Zucker rats. Metabolism 1991, 40: 1025-1030. PMID: 1943727, DOI: 10.1016/0026-0495(91)90124-f.Peer-Reviewed Original ResearchConceptsHepatic glucose productionInsulin-induced suppressionObese animalsObese Zucker ratsGlucose disposalInsulin sensitivityDrug treatmentFree fatty acidsZucker ratsHigher insulin infusion ratesEuglycemic hyperinsulinemic clamp techniqueInsulin-resistant animal modelsPeripheral glucose disposalHyperinsulinemic clamp techniquePeripheral glucose uptakeInsulin infusion rateInsulin clampInsulin suppressionKetone levelsInfusion rateAnimal modelsClamp techniqueEffect of CPLean animalsLipid metabolism