2025
Hepatic PKA Mediates Liver and Pancreatic α-Cell Cross Talk
Bao K, Berger J, Na E, Su Q, Halasz G, Sleeman M, Okamoto H. Hepatic PKA Mediates Liver and Pancreatic α-Cell Cross Talk. Diabetes 2025, 74: 885-897. PMID: 40095004, PMCID: PMC12097458, DOI: 10.2337/db24-0958.Peer-Reviewed Original ResearchConceptsAmino acid catabolismGlucagon receptorControlling amino acid metabolismDownstream effectorsGlucagon receptor blockadeA cellsElevated plasma amino acidsAmino acidsAlpha cell massPlasma amino acidsCatabolism of amino acidsPKA knockdownAmino acid metabolismGlucagon-stimulated hepatic glucose productionCatabolic genesGcgr signalingPancreatic A cellsEPAC2 knockdownGNASHyperplasiaHepatic glucose productionDownstream factorsAcid metabolismCell massEpac2Suppression of endothelial ceramide de novo biosynthesis by Nogo-B contributes to cardiometabolic diseases
Rubinelli L, Manzo O, Sungho J, Del Gaudio I, Bareja R, Marino A, Palikhe S, Di Mauro V, Bucci M, Falcone D, Elemento O, Ersoy B, Diano S, Sasset L, Di Lorenzo A. Suppression of endothelial ceramide de novo biosynthesis by Nogo-B contributes to cardiometabolic diseases. Nature Communications 2025, 16: 1968. PMID: 40000621, PMCID: PMC11862206, DOI: 10.1038/s41467-025-56869-9.Peer-Reviewed Original ResearchConceptsNogo-BEndothelial dysfunctionHFD miceCardiometabolic diseasesSphingolipid signalingDevelopment of therapeutic strategiesBioactive sphingolipidsCeramide degradationSphingosine-1-phosphateHepatic glucose productionIn vivo evidenceEndothelial cellsEndothelial specific deletionCeramideBiosynthesisHigh-fat dietPathological implicationsSphingolipidsGlucose productionHFDIn vivoMale miceMetabolic dysfunctionTherapeutic strategiesMetabolic disorders
2024
Small molecules targeting selective PCK1 and PGC-1α lysine acetylation cause anti-diabetic action through increased lactate oxidation
Mutlu B, Sharabi K, Sohn J, Yuan B, Latorre-Muro P, Qin X, Yook J, Lin H, Yu D, Camporez J, Kajimura S, Shulman G, Hui S, Kamenecka T, Griffin P, Puigserver P. Small molecules targeting selective PCK1 and PGC-1α lysine acetylation cause anti-diabetic action through increased lactate oxidation. Cell Chemical Biology 2024, 31: 1772-1786.e5. PMID: 39341205, PMCID: PMC11500315, DOI: 10.1016/j.chembiol.2024.09.001.Peer-Reviewed Original ResearchPhosphoenolpyruvate carboxykinase 1Lysine acetylationTricarboxylic acidAnti-diabetic effectsAnaplerotic reactionsGluconeogenic reactionsLiver-specific expressionGluconeogenic metabolitesLactate oxidationSmall moleculesAnti-diabetic actionSuppressed gluconeogenesisHepatic glucose productionPGC-1aAcetylationOxaloacetateGluconeogenesisObese miceGlucose productionIncreased glucoseGlucose oxidationSubstrate oxidationOxidationGlucoseMutantsFood perception promotes phosphorylation of MFFS131 and mitochondrial fragmentation in liver
Henschke S, Nolte H, Magoley J, Kleele T, Brandt C, Hausen A, Wunderlich C, Bauder C, Aschauer P, Manley S, Langer T, Wunderlich F, Brüning J. Food perception promotes phosphorylation of MFFS131 and mitochondrial fragmentation in liver. Science 2024, 384: 438-446. PMID: 38662831, DOI: 10.1126/science.adk1005.Peer-Reviewed Original ResearchConceptsMitochondrial fragmentationInsulin-stimulated suppression of hepatic glucose productionInduced mitochondrial fragmentationMitochondrial fission factorPro-opiomelanocortin (POMC)-expressing neuronsControl of hepatic glucose metabolismKnock-in mutationHepatic glucose metabolismFission factorMitochondrial dynamicsSerine 131Fragments in vitroNutrient availabilityKnock-in miceMitochondrial functionDynamic regulationHepatic glucose productionLiver mitochondriaSuppression of hepatic glucose productionMetabolic adaptationPhosphorylationNutritional stateGlucose productionIn vivoGlucose metabolism
2023
191-OR: Deletion of the Type 2 Diabetes Candidate Gene SLC16A11 Reduces Peripheral Insulin Sensitivity in Mice
EL-AGROUDY N, SCHUMANN T, KURZBACH A, SANCAR G, SANDFORTH L, HERRMANN C, SHULMAN G, BIRKENFELD A. 191-OR: Deletion of the Type 2 Diabetes Candidate Gene SLC16A11 Reduces Peripheral Insulin Sensitivity in Mice. Diabetes 2023, 72 DOI: 10.2337/db23-191-or.Peer-Reviewed Original ResearchDb/db miceOb/obInsulin sensitivityDb miceMRNA expressionWhole-body insulin sensitivitySkeletal muscle insulin sensitivitySkeletal muscle insulin resistanceSkeletal musclePeripheral insulin sensitivityTreatment of T2D.Hyperinsulinemic-euglycemic clampLiver fat contentGlucose infusion rateMuscle insulin sensitivityMuscle insulin resistanceHepatic glucose productionHepatic mitochondrial functionWT littermate miceGastric bypass alters diurnal feeding behavior and reprograms hepatic clock to regulate endogenous glucose flux
Ye Y, Abu El Haija M, Obeid R, Herz H, Tian L, Linden B, Chu Y, Guo D, Levine D, Cedernaes J, Rahmouni K, Bass J, Mokadem M. Gastric bypass alters diurnal feeding behavior and reprograms hepatic clock to regulate endogenous glucose flux. JCI Insight 2023, 8: e166618. PMID: 36787197, PMCID: PMC10070113, DOI: 10.1172/jci.insight.166618.Peer-Reviewed Original ResearchConceptsRoux-en-Y gastric bypassGastric bypassGlucose fluxDiurnal feeding behaviorEffects of Roux-en-Y gastric bypassEating behaviorsMolecular clockWeight-independent effectsRoux-en-YGlucose metabolismWeight loss effectsDiurnal eating patternReporter mouse modelHepatic glucose productionHepatic clockClock activityHepatic glucose fluxesPair-feeding experimentsPeripheral clocksBariatric proceduresClock oscillatorGlucose homeostasisFeeding behaviorMutant miceFood intake
2022
Let-7 underlies metformin-induced inhibition of hepatic glucose production
Xie D, Chen F, Zhang Y, Shi B, Song J, Chaudhari K, Yang SH, Zhang GJ, Sun X, Taylor HS, Li D, Huang Y. Let-7 underlies metformin-induced inhibition of hepatic glucose production. Proceedings Of The National Academy Of Sciences Of The United States Of America 2022, 119: e2122217119. PMID: 35344434, PMCID: PMC9169108, DOI: 10.1073/pnas.2122217119.Peer-Reviewed Original ResearchConceptsHepatic glucose productionAntidiabetic effectsMouse modelGlucose productionPotent antidiabetic actionsHepatocyte nuclear factor 4 alphaNuclear factor 4 alphaFunction mouse modelsHuman primary hepatocytesMetformin-induced inhibitionAntidiabetic actionTherapeutic effectGlucose homeostasisSuprapharmacological concentrationsRelevant dosesHepatic deliveryMetforminFetal isoformsPotential therapeuticsPrimary hepatocytesMost studiesLet-7Regulatory pathwaysHyperglycemiaDiabetes
2021
281-OR: Endothelial Cell Cd36 Regulates Systemic Glucose and Lipid Metabolism
GOEDEKE L, SON N, LAMOIA T, NASIRI A, KAHN M, ZHANG X, CLINE G, GOLDBERG I, SHULMAN G. 281-OR: Endothelial Cell Cd36 Regulates Systemic Glucose and Lipid Metabolism. Diabetes 2021, 70 DOI: 10.2337/db21-281-or.Peer-Reviewed Original ResearchFatty acid uptakeLong-chain fatty acid uptakeAcid uptakeEndothelial cell CD36EC-specific deletionDifferent cell typesInsulin-stimulated glucose uptakeLipid metabolismWhole-body glucose toleranceTransmembrane proteinTissue fatty acid uptakeWhole-body insulin sensitivityEndothelial cellsHepatic glucose productionCell typesInsulin sensitivityGlucose transportSystemic glucoseSkeletal muscleCD36Glucose uptakeWhole-body fat utilizationGlucose productionSynthase fluxNon-esterified fatty acid levels
2020
Aging is associated with increased TRB3, ER stress, and hepatic glucose production in the liver of rats
Gaspar R, Muñoz V, Nakandakari S, Vieira R, da Conceição L, de Oliveira F, Crisol B, da Silva A, Cintra D, de Moura L, Ropelle E, Zaghloul I, Mekary R, Pauli J. Aging is associated with increased TRB3, ER stress, and hepatic glucose production in the liver of rats. Experimental Gerontology 2020, 139: 111021. PMID: 32659331, DOI: 10.1016/j.exger.2020.111021.Peer-Reviewed Original ResearchConceptsER stressEukaryotic translation initiation factorProtein kinase RNA-like endoplasmic reticulum kinaseRNA-like endoplasmic reticulum kinaseTranslation initiation factorPhosphorylation of inositolStress response regulationEndoplasmic reticulum kinaseEndoplasmic reticulum stress pathwayMammalian homologDrosophila tribblesEndoplasmic reticulum stressInitiation factorsProtein contentTRB3Multiple tissuesStress pathwaysImmunoglobulin proteinEnzymes of gluconeogenesisReticulum stressHepatic glucose productionEnzyme 1Response regulationMolecular changesPyruvate challengeGlucagon 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 miceHepatic TET3 contributes to type-2 diabetes by inducing the HNF4α fetal isoform
Da Li, Cao T, Sun X, Jin S, Di Xie, Huang X, Yang X, Carmichael GG, Taylor HS, Diano S, Huang Y. Hepatic TET3 contributes to type-2 diabetes by inducing the HNF4α fetal isoform. Nature Communications 2020, 11: 342. PMID: 31953394, PMCID: PMC6969024, DOI: 10.1038/s41467-019-14185-z.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDiabetes Mellitus, Type 2DioxygenasesDisease Models, AnimalDNA DemethylationDNA MethylationDNA-Binding ProteinsFastingGene Expression RegulationGlucagonGlucoseHepatocyte Nuclear Factor 3-betaHepatocyte Nuclear Factor 4LiverMaleMiceMice, Inbred C57BLMice, KnockoutPromoter Regions, GeneticProtein IsoformsTranscriptional ActivationTranscriptomeUp-RegulationConceptsHepatic glucose productionType 2 diabetesGlucose homeostasisAdult liverSystemic glucose homeostasisPotential therapeutic targetGenetic mouse modelsFetal versionKey gluconeogenic genesMouse modelTherapeutic targetHNF4α functionGlucose productionFetal isoformsLiverT2D.DiabetesPromoter demethylationGluconeogenic genesTET3 overexpressionHNF4αHomeostasisTET3Regulatory mechanismsIsoforms
2019
Distinct Hepatic PKA and CDK Signaling Pathways Control Activity-Independent Pyruvate Kinase Phosphorylation and Hepatic Glucose Production
Gassaway BM, Cardone RL, Padyana AK, Petersen MC, Judd ET, Hayes S, Tong S, Barber KW, Apostolidi M, Abulizi A, Sheetz JB, Kshitiz, Aerni HR, Gross S, Kung C, Samuel VT, Shulman GI, Kibbey RG, Rinehart J. Distinct Hepatic PKA and CDK Signaling Pathways Control Activity-Independent Pyruvate Kinase Phosphorylation and Hepatic Glucose Production. Cell Reports 2019, 29: 3394-3404.e9. PMID: 31825824, PMCID: PMC6951436, DOI: 10.1016/j.celrep.2019.11.009.Peer-Reviewed Original ResearchConceptsCyclin-dependent kinasesMetabolic control pointPhosphorylation sitesNuclear retentionCDK activityPKL activityDays high-fat dietKinase phosphorylationImportant enzymePyruvate kinaseHigh-fat dietS113KinaseEnzyme kineticsPhosphorylationAdditional control pointsRegulationGlucose productionHepatic glucose productionInsulin resistanceGlycolysisEnzymePKAPathwayActivity282-LB: Dysregulated FGF21 Links Hepatic Insulin Resistance to Dysfunctional BAT
STOEHR O, TAO R, COPPS K, WHITE M. 282-LB: Dysregulated FGF21 Links Hepatic Insulin Resistance to Dysfunctional BAT. Diabetes 2019, 68 DOI: 10.2337/db19-282-lb.Peer-Reviewed Original ResearchHepatic insulin resistanceFGF-21Insulin resistanceHFD feedingControl miceDiabetic phenotypeGlucose metabolismFGF-21 serum levelsWhole-body glucose metabolismGlucose uptakeInsulin-resistant liverImproved glucose toleranceWild-type miceHepatic glucose productionSevere diabetic phenotypeNormal glucose uptakeHealthy batsBAT dysfunctionSerum levelsGlucose toleranceBAT functionType miceNormal rangeInsulin actionAdenoviral infection266-OR: Plasma Membrane sn-1,2 Diacylglycerol Mediates Lipid-Induced Hepatic Insulin Resistance
LYU K, ZHANG Y, ZHANG D, KAHN M, NOZAKI Y, BHANOT S, BOGAN J, CLINE G, SAMUEL V, SHULMAN G. 266-OR: Plasma Membrane sn-1,2 Diacylglycerol Mediates Lipid-Induced Hepatic Insulin Resistance. Diabetes 2019, 68 DOI: 10.2337/db19-266-or.Peer-Reviewed Original ResearchHepatic insulin resistanceInsulin resistanceExogenous fatty acidsInsulin actionLipid dropletsHepatic ceramide contentHyperinsulinemic-euglycemic clampHepatic insulin actionBioactive lipid speciesHepatic glucose productionChow-fed ratsHepatic diacylglycerol contentAdvisory PanelFatty acidsHepatic steatosisImpaired suppressionSingle doseSpouse/partnerGlucose productionPKCε activationJanssen ResearchAcute knockdownCeramide contentNational InstituteReceptor kinase activationPhosphorylation of Forkhead Protein FoxO1 at S253 Regulates Glucose Homeostasis in Mice
Zhang K, Guo X, Yan H, Wu Y, Pan Q, Shen J, Li X, Chen Y, Li L, Qi Y, Xu Z, Xie W, Zhang W, Threadgill D, He L, Villarreal D, Sun Y, White M, Zheng H, Guo S. Phosphorylation of Forkhead Protein FoxO1 at S253 Regulates Glucose Homeostasis in Mice. Endocrinology 2019, 160: 1333-1347. PMID: 30951171, PMCID: PMC6482038, DOI: 10.1210/en.2018-00853.Peer-Reviewed Original ResearchConceptsKey phosphorylation sitesForkhead protein FoxO1Protein kinase BTranscription factor forkhead box O1Factor forkhead box O1FOXO1 nuclear localizationMultiple physiological functionsMouse Foxo1Forkhead box O1Pancreatic plasticityPhosphorylation sitesHuman FOXO1Nuclear localizationTarget genesMolecular basisS253Kinase BFoxO1 activityPhysiological functionsGlucose homeostasisBox O1Pancreatic β-cell functionFOXO1PhosphorylationHepatic glucose production
2018
PEPCK1 Antisense Oligonucleotide Prevents Adiposity and Impairs Hepatic Glycogen Synthesis in High-Fat Male Fed Rats
Beddow SA, Gattu AK, Vatner DF, Paolella L, Alqarzaee A, Tashkandi N, Popov V, Church C, Rodeheffer M, Cline G, Geisler J, Bhanot S, Samuel VT. PEPCK1 Antisense Oligonucleotide Prevents Adiposity and Impairs Hepatic Glycogen Synthesis in High-Fat Male Fed Rats. Endocrinology 2018, 160: 205-219. PMID: 30445425, PMCID: PMC6307100, DOI: 10.1210/en.2018-00630.Peer-Reviewed Original ResearchMeSH KeywordsAdipose Tissue, WhiteAdiposityAnimalsDiabetes Mellitus, Type 2Diet, High-FatGlucokinaseHumansInsulinIntracellular Signaling Peptides and ProteinsLipogenesisLiverLiver GlycogenMaleMiceMice, Inbred C57BLOligonucleotides, AntisensePhosphoenolpyruvate Carboxykinase (GTP)RatsRats, Sprague-DawleyConceptsHepatic glycogen synthesisAdipose tissueAntisense oligonucleotideType 2 diabetes mellitusWhite adipose tissue massIncreased hepatic gluconeogenesisChow fed ratsHepatic insulin sensitivityMale Sprague-DawleyAdipose tissue massHepatic insulin resistanceWhite adipose tissueHepatic glucose productionDe novo lipogenesisHepatic glucokinase expressionControl antisense oligonucleotideGlycogen synthesisTranscription factor 3HFF ratsDiabetes mellitusHepatic steatosisInsulin resistanceHyperglycemic clampPlasma glucoseInsulin sensitivityInsulin regulates POMC neuronal plasticity to control glucose metabolism
Dodd GT, Michael NJ, Lee-Young RS, Mangiafico SP, Pryor JT, Munder AC, Simonds SE, Brüning JC, Zhang ZY, Cowley MA, Andrikopoulos S, Horvath TL, Spanswick D, Tiganis T. Insulin regulates POMC neuronal plasticity to control glucose metabolism. ELife 2018, 7: e38704. PMID: 30230471, PMCID: PMC6170188, DOI: 10.7554/elife.38704.Peer-Reviewed Original ResearchConceptsHepatic glucose productionPOMC neuronsSuch adaptive processesNutritional cuesGene expressionMolecular mechanismsGlucose metabolismInsulin receptorDiet-induced obesityTCPTPNeuronal plasticityAdaptive processHypothalamic neuronsNeuronal excitabilityGlucose productionMetabolismInsulinNeuronsRepressionNeural responsesObesityRegulationMechanismPlasticityExpressionMechanism by Which Dapagliflozin Induces Euglycemic Ketoacidosis in Rats
PERRY R, SONG J, WANG Y, SHULMAN G. Mechanism by Which Dapagliflozin Induces Euglycemic Ketoacidosis in Rats. Diabetes 2018, 67 DOI: 10.2337/db18-254-or.Peer-Reviewed Original ResearchSodium-glucose transport protein 2 inhibitorsHepatic glucose productionEffect of dapagliflozinEuglycemic ketoacidosisHepatic ketogenesisVolume depletionGlucose productionPlasma catecholaminesWhite adipose tissue lipolysisPlasma glucagon concentrationsExtracellular volume depletionPlasma insulin levelsAdipose tissue lipolysisPlasma insulin concentrationHepatic acetyl-CoA contentNormal Sprague-DawleyICV injectionWAT lipolysisInsulin levelsFurosemide treatmentGlucagon concentrationsAcetyl-CoA contentSaline infusionTissue lipolysisInsulin concentrationsMembrane sn-1,2 Diacylglycerol Mediates Lipid-Induced Hepatic Insulin Resistance In Vivo
LYU K, ZHANG D, NOZAKI Y, ZHANG Y, BHANOT S, CLINE G, SAMUEL V, SHULMAN G. Membrane sn-1,2 Diacylglycerol Mediates Lipid-Induced Hepatic Insulin Resistance In Vivo. Diabetes 2018, 67 DOI: 10.2337/db18-243-lb.Peer-Reviewed Original ResearchHepatic insulin resistanceLipid-induced hepatic insulin resistanceDiglyceride acyltransferase 2Hepatic DAG contentInsulin resistanceHepatic insulin sensitivityInsulin sensitivityImpaired insulin-mediated suppressionActivation/translocationDGAT2 inhibitionAntisense oligonucleotideRegular chow dietInsulin-mediated suppressionHepatic insulin actionHepatic glucose productionInsulin receptor kinaseDAG contentChow dietASO treatmentIonis PharmaceuticalsInsulin actionGlucose productionPKCε activationSREBP-1cGilead SciencesInactivating hepatic follistatin alleviates hyperglycemia
Tao R, Wang C, Stöhr O, Qiu W, Hu Y, Miao J, Dong X, Leng S, Stefater M, Stylopoulos N, Lin L, Copps K, White M. Inactivating hepatic follistatin alleviates hyperglycemia. Nature Medicine 2018, 24: 1058-1069. PMID: 29867232, PMCID: PMC6039237, DOI: 10.1038/s41591-018-0048-0.Peer-Reviewed Original ResearchConceptsHepatic glucose productionAdipose tissue insulinGlucose toleranceTissue insulinSuppression of HGPGastric bypass surgeryFed obese miceHepatic insulin resistanceWhite adipose tissuePotential clinical significanceInsulin receptor substrate-1Bypass surgeryGlucose intoleranceHepatic inactivationObese miceInsulin resistanceObese individualsGlycated hemoglobinTranscription factor FOXO1Insulin sensitivityNormal suppressionClinical significanceReceptor substrate-1Adipose tissueExpression of Fst
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