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
323-OR: SGLT2 Inhibition Promotes Myocardial Ketone Utilization in the Normal and Failing Heart
GOEDEKE L, LEE J, MA Y, HU X, ZHANG J, DONG J, GALSGAARD K, GUERRERA N, HAEDERSDAL S, ZHANG X, PERRY R, CLINE G, YOUNG L, SHULMAN G. 323-OR: SGLT2 Inhibition Promotes Myocardial Ketone Utilization in the Normal and Failing Heart. Diabetes 2021, 70 DOI: 10.2337/db21-323-or.Peer-Reviewed Original ResearchPlasma glucose concentrationDAPA treatmentHeart failureAwake male Sprague-Dawley ratsMajor adverse cardiovascular eventsMale Sprague-Dawley ratsRecent clinical outcome studiesAdverse cardiovascular eventsHeart failure ratsType 2 diabetesClinical outcome studiesSprague-Dawley ratsGlucose concentrationΒOHB levelsCardiovascular eventsCardiovascular benefitsVehicle treatmentPermanent ligationSGLT2 inhibitorsCoronary arteryControl ratsKetone utilizationDawley ratsAcute effectsFailing Heart
2020
Sodium-glucose cotransporter-2 inhibitors: Understanding the mechanisms for therapeutic promise and persisting risks
Perry RJ, Shulman GI. Sodium-glucose cotransporter-2 inhibitors: Understanding the mechanisms for therapeutic promise and persisting risks. Journal Of Biological Chemistry 2020, 295: 14379-14390. PMID: 32796035, PMCID: PMC7573269, DOI: 10.1074/jbc.rev120.008387.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsSodium-glucose cotransporter 2SGLT2 inhibitorsEuglycemic ketoacidosisGlucose reabsorptionTherapeutic promiseSGLT2 inhibitor therapyLower plasma glucose concentrationsModest weight lossGlucose-lowering agentsRenal glucose reabsorptionType 2 diabetesType 1 diabetesPlasma glucose concentrationGlucose concentrationBlood glucose concentrationHeart failureInhibitor therapyAtrial fibrillationCardiovascular diseaseCotransporter 2Preclinical studiesHealthy personsClinical utilityDiabetes managementProximal tubules
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 conditionsPatientsEffects of free fatty acids on glucose transport and IRS-1–associated phosphatidylinositol 3-kinase activity
Dresner A, Laurent D, Marcucci M, Griffin M, Dufour S, Cline G, Slezak L, Andersen D, Hundal R, Rothman D, Petersen K, Shulman G. Effects of free fatty acids on glucose transport and IRS-1–associated phosphatidylinositol 3-kinase activity. Journal Of Clinical Investigation 1999, 103: 253-259. PMID: 9916137, PMCID: PMC407880, DOI: 10.1172/jci5001.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultFatty Acids, NonesterifiedFemaleGlucoseGlucose Clamp TechniqueGlucose-6-PhosphateGlycerolGlycogenHumansHyperinsulinismInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceLipid MetabolismMagnetic Resonance SpectroscopyMaleMuscle, SkeletalPhosphatidylinositol 3-KinasesPhosphoproteinsConceptsFree fatty acidsIRS-1-associated phosphatidylinositolLipid infusionInsulin resistanceGlycerol infusionPlasma free fatty acidsWhole-body glucose uptakeFive-hour infusionLipid/heparinHyperinsulinemic-euglycemic clampGlucose concentrationGlucose transportMuscle glycogen synthesisDiminished glucose transportMuscle biopsy samplesHuman skeletal muscleRate of insulinGlucose-6-phosphate concentrationFatty acidsHealthy subjectsBiopsy samplesInfusion studiesIdentical protocolInfusionIRS-1-associated PI
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
1995
Contribution of Hepatic Glycogenolysis to Glucose Production in Humans in Response to a Physiological Increase in Plasma Glucagon Concentration
Magnusson I, Rothman D, Gerard D, Katz L, Shulman G. Contribution of Hepatic Glycogenolysis to Glucose Production in Humans in Response to a Physiological Increase in Plasma Glucagon Concentration. Diabetes 1995, 44: 185-189. PMID: 7859939, DOI: 10.2337/diab.44.2.185.Peer-Reviewed Original ResearchConceptsNet hepatic glycogenolysisLiver glycogen concentrationPlasma glucagon concentrationsHepatic glycogenolysisGlucagon concentrationsGlycogen concentrationLiver volumeGlucose productionPlasma glucose concentrationOverall glucose productionTwo-compartment modelHealthy subjectsPhysiological incrementsPhysiological increaseGlucose appearanceSame time periodMagnetic resonance imagesGlucose kineticsBaseline RaInfusionGlycogenolysisGlucose concentrationResonance imagesMumol
1993
Non-Invasive Measurements of the Cerebral Steady-State Glucose Concentration and Transport in Humans by 13C Nuclear Magnetic Resonance
Gruetter R, Novotny E, Boulware S, Rothman D, Mason G, Shulman G, Tamborlane W, Shulman R. Non-Invasive Measurements of the Cerebral Steady-State Glucose Concentration and Transport in Humans by 13C Nuclear Magnetic Resonance. Advances In Experimental Medicine And Biology 1993, 331: 35-40. PMID: 8333347, DOI: 10.1007/978-1-4615-2920-0_7.Peer-Reviewed Original Research
1980
Effect of hyperglycemia independent of changes in insulin or glucagon on lipolysis in the conscious dog
Shulman G, Williams P, Liljenquist J, Lacy W, Keller U, Cherrington A. Effect of hyperglycemia independent of changes in insulin or glucagon on lipolysis in the conscious dog. Metabolism 1980, 29: 317-320. PMID: 6103495, DOI: 10.1016/0026-0495(80)90004-9.Peer-Reviewed Original ResearchConceptsArterial plasma glucose concentrationDirect antilipolytic effectHepatic glycerol uptakeFree fatty acid concentrationsInfusion of somatostatinContinuous glucose infusionPlasma glucose concentrationBlood glycerol levelsHyperglycemia independentConscious dogsBlood glycerolFatty acid concentrationsPancreatic hormonesAntilipolytic effectGlucose infusionBasal levelsSignificant decreaseGlycerol levelsGlucose concentrationHyperglycemiaInfusionGlucagonInsulinFractional extraction