2025
358-OR: Acute Fatty Acid Elevation Does Not Alter Brain Glucose Uptake in Humans
MATSON B, CHANG W, PALMIOTTO J, ROTHMAN D, BELFORT DE AGUIAR R, MASON G, HWANG J. 358-OR: Acute Fatty Acid Elevation Does Not Alter Brain Glucose Uptake in Humans. Diabetes 2025, 74 DOI: 10.2337/db25-358-or.Peer-Reviewed Original ResearchElevation of non-esterified fatty acidsNon-esterified fatty acid levelsHyperglycemic clampBrain glucose uptakeCirculating non-esterified fatty acidsBrain glucoseAcute elevationIntralipid infusionInsulin resistanceIntravenous infusion of salineAbsence of insulin resistanceNon-esterified fatty acidsInduce peripheral insulin resistanceHealthy adultsInfusion of salinePresence of hyperglycemiaGlucose uptakeMeasures of insulin sensitivityPeripheral insulin resistanceHigh-fat dietGlucose infusion rateIntravenous infusionPlasma glucoseLean individualsMRS scans
2024
Depletion of TBC1D4 Improves the Metabolic Exercise Response by Overcoming Genetically Induced Peripheral Insulin Resistance.
Springer C, Binsch C, Weide D, Toska L, Cremer A, Backes H, Scheel A, Espelage L, Kotzka J, Sill S, Kurowski A, Kim D, Karpinski S, Schnurr T, Hansen T, Hartwig S, Lehr S, Cames S, Brüning J, Lienhard M, Herwig R, Börno S, Timmermann B, Al-Hasani H, Chadt A. Depletion of TBC1D4 Improves the Metabolic Exercise Response by Overcoming Genetically Induced Peripheral Insulin Resistance. Diabetes 2024, 73: 1058-1071. PMID: 38608276, DOI: 10.2337/db23-0463.Peer-Reviewed Original ResearchWhite adipose tissueLoss-of-function variantsAnalysis of glucose uptakeRegulation of glucose transportInterscapular brown adipose tissueHigh-fat dietEnhanced expression levelsDevelopment of insulin resistanceBrown adipose tissueMitochondrial activityTBC1D4Gene variantsInsulin resistanceAdipose tissueGlucose uptakePeripheral insulin resistanceGlucose transportExpression levelsGenesPrecision medicineInsulin toleranceGeneticsIncreased glucose clearanceExercise responseIn vivo
2019
1835-P: Deletion of Insulin Receptor Substrate 2 in AGRP Neurons Causes Beta-Cell Dysfunction
TAO R, COPPS K, WHITE M, STOEHR O. 1835-P: Deletion of Insulin Receptor Substrate 2 in AGRP Neurons Causes Beta-Cell Dysfunction. Diabetes 2019, 68 DOI: 10.2337/db19-1835-p.Peer-Reviewed Original ResearchAgRP neuronsArcuate nucleusInsulin resistanceInsulin secretionInsulin receptor substrateType 2 diabetes progressesCompensatory insulin secretionL-arginine treatmentBeta-cell compensationBeta-cell dysfunctionPeripheral insulin resistanceBeta-cell failureBeta-cell functionHigh-fat dietInsulin secretory functionType 2 diabetesSteady-state hyperglycemiaGlucose infusion rateΒ-cell dysfunctionInsulin receptor substrate 2Pancreatic β-cellsGrowth-promoting actionDiabetes progressesFat dietHyperglycemic clamp
2017
Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases
Samuel VT, Shulman GI. Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases. Cell Metabolism 2017, 27: 22-41. PMID: 28867301, PMCID: PMC5762395, DOI: 10.1016/j.cmet.2017.08.002.Peer-Reviewed Original ResearchConceptsInsulin resistanceNonalcoholic fatty liver diseaseFatty liver diseasePeripheral insulin resistanceHepatic insulin resistanceNew pharmacological strategiesHepatic complicationsBariatric surgeryLiver diseaseInsulin-stimulated glycogen synthesisHepatic diseasePharmacological strategiesNAFLDReceptor activationHepatic glucoseLipid metabolismInsulin receptor activationWeight lossEnergy expenditureHepatic diacylglycerolsGlycogen synthesisDiseaseLipid synthesisFlux of substratesComplicationsHepatic Diacylglycerol-Associated Protein Kinase Cε Translocation Links Hepatic Steatosis to Hepatic Insulin Resistance in Humans
Horst K, Gilijamse PW, Versteeg RI, Ackermans MT, Nederveen AJ, la Fleur SE, Romijn JA, Nieuwdorp M, Zhang D, Samuel VT, Vatner DF, Petersen KF, Shulman GI, Serlie MJ. Hepatic Diacylglycerol-Associated Protein Kinase Cε Translocation Links Hepatic Steatosis to Hepatic Insulin Resistance in Humans. Cell Reports 2017, 19: 1997-2004. PMID: 28591572, PMCID: PMC5469939, DOI: 10.1016/j.celrep.2017.05.035.Peer-Reviewed Original ResearchConceptsHepatic insulin resistanceInsulin resistanceHepatic steatosisObese subjectsPKCε activationTissue-specific insulin sensitivityHepatic ceramide contentPeripheral insulin resistanceHepatic lipid accumulationPathogenesis of NAFLDLiver biopsyIntrahepatic triglyceridesLiver fatInsulin sensitivityAdipose tissueTranslational evidenceSteatosisLipid accumulationCeramide contentPKCε translocationSubjectsMolecular mechanismsDiacylglycerol contentHumansActivation
2015
Second‐generation antisense oligonucleotides against β‐catenin protect mice against diet‐induced hepatic steatosis and hepatic and peripheral insulin resistance
Popov VB, Jornayvaz FR, Akgul EO, Kanda S, Jurczak MJ, Zhang D, Abudukadier A, Majumdar SK, Guigni B, Petersen KF, Manchem VP, Bhanot S, Shulman GI, Samuel VT. Second‐generation antisense oligonucleotides against β‐catenin protect mice against diet‐induced hepatic steatosis and hepatic and peripheral insulin resistance. The FASEB Journal 2015, 30: 1207-1217. PMID: 26644352, PMCID: PMC4750414, DOI: 10.1096/fj.15-271999.Peer-Reviewed Original ResearchConceptsHepatic steatosisInsulin resistanceAntisense oligonucleotideDiet-induced hepatic steatosisWhole-body glucose metabolismLipid-induced insulin resistanceMale C57BL/6 micePeripheral insulin resistanceHyperinsulinemic-euglycemic clampType 2 diabetesHepatic insulin sensitivityΒ-cateninHepatic lipid compositionWhite adipose tissueWnt/β-cateninΒ-catenin expressionMetabolic syndromeProtect miceC57BL/6 miceΒ-catenin mRNAFed miceHepatic triglyceridesInsulin sensitivityAwake miceGlucose metabolism
2010
A common variant in the patatin‐like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents
Santoro N, Kursawe R, D'Adamo E, Dykas DJ, Zhang CK, Bale AE, Calí AM, Narayan D, Shaw MM, Pierpont B, Savoye M, Lartaud D, Eldrich S, Cushman SW, Zhao H, Shulman GI, Caprio S. A common variant in the patatin‐like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents. Hepatology 2010, 52: 1281-1290. PMID: 20803499, PMCID: PMC3221304, DOI: 10.1002/hep.23832.Peer-Reviewed Original ResearchConceptsPatatin-like phospholipase 3 geneNonalcoholic fatty liver diseaseFatty liver diseaseG alleleHepatic steatosisLiver diseaseLow leptinObese youthPeripheral glucose disposal rateAdipogenesis/lipogenesisHepatic glucose production ratePNPLA3 G alleleGlucose disposal ratePeripheral insulin resistanceSingle nucleotide polymorphismsSirtuin 1 expressionSubcutaneous fat biopsiesHepatic fat contentAdipocyte cell sizeSubset of subjectsAdipose cell sizeMagnetic resonance imagingAfrican AmericansCommon variantsExpression of PNPLA3
2009
Insulin Resistance
Samuel V, Petersen K, Shulman G. Insulin Resistance. 2009, 469-483. DOI: 10.1002/9780470747919.ch31.Peer-Reviewed Original ResearchInsulin-sensitizing agentsPeripheral insulin resistanceInsulin resistanceHepatic insulin resistanceSensitizing agentNAFLDHyperglycemiaFat
2008
Abdominal Obesity in Older Women: Potential Role for Disrupted Fatty Acid Reesterification in Insulin Resistance
Yeckel CW, Dziura J, DiPietro L. Abdominal Obesity in Older Women: Potential Role for Disrupted Fatty Acid Reesterification in Insulin Resistance. The Journal Of Clinical Endocrinology & Metabolism 2008, 93: 1285-1291. PMID: 18198225, PMCID: PMC2291490, DOI: 10.1210/jc.2007-1875.Peer-Reviewed Original ResearchConceptsFatty acid reesterificationPeripheral insulin resistanceAbdominal obesityInsulin resistanceHepatic glucose productionAbdominal adiposityOlder womenGlucose utilizationGeneral Clinical Research CenterBasal hepatic glucose productionGlucose productionFree fatty acid metabolismExcess abdominal adiposityPerturbed glucose metabolismGlucose-lowering medicationsHormone replacement therapyClinical Research CenterPeripheral glucose utilizationGlycerol appearance rateInactive older womenTotal body fatCross-sectional studyAbdominal circumference valuesInsulin-stimulated suppressionFree fatty acid ratio
2006
Regulating insulin signaling and -cell function through IRS proteinsThis paper is one of a selection of papers published in this Special Issue, entitled Second Messengers and Phosphoproteins12th International Conference.
White M. Regulating insulin signaling and -cell function through IRS proteinsThis paper is one of a selection of papers published in this Special Issue, entitled Second Messengers and Phosphoproteins12th International Conference. Canadian Journal Of Physiology And Pharmacology 2006, 84: 725-737. PMID: 16998536, DOI: 10.1139/y06-008.Peer-Reviewed Original ResearchConceptsType 2 diabetesInsulin resistanceBeta-cell destructionPeripheral insulin resistanceDiabetes mellitusChronic hyperglycemiaSystemic disordersFemale infertilityInsulin secretionCardiovascular diseaseCell functionInevitable progressionComplex disorderDisordersDiabetesGreater frequencyPrevalent formInsulinPhosphoproteins12th International ConferenceAgeSecond messengerDyslipidemiaHypertensionMellitusAutoimmune
2005
Symptoms of Obstructive Sleep Apnea in Patients with Nonalcoholic Fatty Liver Disease
Singh H, Pollock R, Uhanova J, Kryger M, Hawkins K, Minuk GY. Symptoms of Obstructive Sleep Apnea in Patients with Nonalcoholic Fatty Liver Disease. Digestive Diseases And Sciences 2005, 50: 2338-2343. PMID: 16416185, DOI: 10.1007/s10620-005-3058-y.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseSymptoms of OSANonalcoholic fatty liverObstructive sleep apneaFatty liver diseaseNAFLD patientsNASH patientsNonalcoholic steatohepatitisRisk factorsLiver diseaseSleep apneaInsulin resistancePrevalence of OSASleep apnea questionnaireIndependent risk factorPrevalence of diabetesBody mass indexPeripheral insulin resistanceLiver biopsyFatty liverMass indexTriglyceride levelsQuestionnaire criteriaPrevalence ratesPatients
2004
Insulin receptor substrate proteins and diabetes
Lee Y, White M. Insulin receptor substrate proteins and diabetes. Archives Of Pharmacal Research 2004, 27: 361-370. PMID: 15180298, DOI: 10.1007/bf02980074.Peer-Reviewed Original ResearchConceptsInsulin receptor substrate (IRS) proteinsSubstrate proteinsPancreatic β-cell growthInsulin/IGFIntracellular signaling cascadesReceptor tyrosine kinasesΒ-cell growthCell surface receptorsIRS proteinsGrowth factor actionProtein signalingSerine phosphorylationSignaling cascadesInsulin resistanceTyrosine kinaseInsulin-like growth factor actionIrs2 branchCell growthSurface receptorsFactor actionPeripheral insulin responsePeripheral insulin resistanceIRS2ProteinImportant mechanism
2003
Prediabetes in obese youth: a syndrome of impaired glucose tolerance, severe insulin resistance, and altered myocellular and abdominal fat partitioning
Weiss R, Dufour S, Taksali SE, Tamborlane WV, Petersen KF, Bonadonna RC, Boselli L, Barbetta G, Allen K, Rife F, Savoye M, Dziura J, Sherwin R, Shulman GI, Caprio S. Prediabetes in obese youth: a syndrome of impaired glucose tolerance, severe insulin resistance, and altered myocellular and abdominal fat partitioning. The Lancet 2003, 362: 951-957. PMID: 14511928, PMCID: PMC2995523, DOI: 10.1016/s0140-6736(03)14364-4.Peer-Reviewed Original ResearchConceptsImpaired glucose toleranceNormal glucose toleranceGlucose toleranceObese childrenInsulin resistanceObese adolescentsGlucose disposalInsulin sensitivitySevere peripheral insulin resistanceNon-oxidative glucose metabolismSubcutaneous fatH plasma glucose concentrationsAbdominal fat partitioningVisceral lipid contentsPeripheral glucose disposalHigher intramyocellular lipid contentAbdominal fat distributionDegree of obesityIntramyocellular lipid contentPeripheral insulin resistanceHigh visceral fatAbdominal subcutaneous fatEuglycaemic hyperinsulinaemic clampSevere insulin resistancePlasma glucose concentration
2001
IRS proteins and beta-cell function.
Burks D, White M. IRS proteins and beta-cell function. Diabetes 2001, 50: s140. PMID: 11272176, DOI: 10.2337/diabetes.50.2007.s140.Peer-Reviewed Original ResearchConceptsInsulin receptor substrateIRS proteinsIRS protein familyBeta-cell functionBeta-cell massClassical insulin target tissuesDownstream effector pathwaysPeripheral insulin resistanceIRS-2 geneInsulin resistanceProtein familyInsulin target tissuesReceptor substrateIRS-1Effector pathwaysPancreatic beta-cell massInsulin secretory reserveGrowth-promoting actionProteinBeta-cell dysfunctionSomatic growthType 2 diabetesCritical roleDiabetic phenotypeRegulation
2000
Dysregulation of IRS-proteins causes insulin resistance and diabetes
Aguirre V, White M. Dysregulation of IRS-proteins causes insulin resistance and diabetes. Current Opinion In Endocrinology Diabetes And Obesity 2000, 7: 1-7. DOI: 10.1097/00060793-200002000-00001.Peer-Reviewed Original ResearchIRS proteinsInsulin receptor substrate (IRS) proteinsInsulin/insulin-like growth factorPeripheral insulin resistanceType 2 diabetesInsulin resistanceSubstrate proteinsGenetic approachesCommon type 2 diabetesΒ-cell failureInsulin-like growth factorCompensatory insulin secretionDevelopment of diabetesNormal carbohydrate metabolismEarly-onset formCarbohydrate metabolismGrowth factorInsulin secretionDiabetesInsulin actionImportant insightsDysregulationSecretionProteinResistanceDysregulation of IRS-proteins causes insulin resistance and diabetes
Aguirre V, White M. Dysregulation of IRS-proteins causes insulin resistance and diabetes. Current Opinion In Endocrinology Diabetes And Obesity 2000, 7: 1. DOI: 10.1097/00075197-200002000-00001.Peer-Reviewed Original ResearchIRS proteinsPeripheral insulin resistanceInsulin receptor substrate (IRS) proteinsInsulin/insulin-like growth factorType 2 diabetesΒ-cell differentiationInsulin-like growth factorInsulin receptor substrateCompensatory insulin secretionChronic insulin resistanceInsulin resistanceInsulin-signaling pathwayCarbohydrate metabolismInsulin secretionSubstrate proteinsGrowth factorSignal transductionTranscription factorsGenetic approachesCommon type 2 diabetesMolecular basisPancreatic β-cellsReceptor substrateInsulin actionInsulin-signaling system
1999
Irs-2 coordinates Igf-1 receptor-mediated β-cell development and peripheral insulin signalling
Withers D, Burks D, Towery H, Altamuro S, Flint C, White M. Irs-2 coordinates Igf-1 receptor-mediated β-cell development and peripheral insulin signalling. Nature Genetics 1999, 23: 32-40. PMID: 10471495, DOI: 10.1038/12631.Peer-Reviewed Original ResearchMeSH KeywordsAge FactorsAnimalsApoptosisBlood GlucoseBody WeightFemaleGene Expression Regulation, DevelopmentalGlucose Tolerance TestInsulinInsulin Receptor Substrate ProteinsIntracellular Signaling Peptides and ProteinsIslets of LangerhansLiverMaleMiceMice, KnockoutMuscle, SkeletalPancreasPhosphoproteinsReceptor, IGF Type 1Signal TransductionTime FactorsConceptsIGF-1 receptorΒ-cell developmentIGF-1Glucose homeostasisΒ-cellsPeripheral insulin resistancePeripheral target tissuesEffect of insulinPancreatic β-cellsPeripheral insulinInsulin resistanceInsulin receptor substratePost-natal growthGlucose metabolismNull allelesTarget tissuesInsulinMiceReceptor substrateIR-1Carbohydrate metabolismReceptorsSurvivalCell growthPleiotropic effects
1998
Mapping of the human insulin receptor substrate-2 gene, identification of a linked polymorphic marker and linkage analysis in families with Type II diabetes: no evidence for a major susceptibility role
Kalidas K, Wasson J, Glaser B, Meyer J, Duprat L, White M, Permutt M. Mapping of the human insulin receptor substrate-2 gene, identification of a linked polymorphic marker and linkage analysis in families with Type II diabetes: no evidence for a major susceptibility role. Diabetologia 1998, 41: 1389-1391. PMID: 9833949, DOI: 10.1007/s001250051081.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBase SequenceChromosome MappingChromosomes, Human, Pair 13Diabetes Mellitus, Type 1Europe, EasternGenetic Carrier ScreeningGenetic LinkageGenetic MarkersGenotypeHumansInsulin Receptor Substrate ProteinsIntracellular Signaling Peptides and ProteinsJewsMiceMicrosatellite RepeatsPhosphoproteinsPolymorphism, GeneticStatistics, NonparametricConceptsIRS-2 geneRadiation hybrid panel mappingPolymorphic markersInsulin receptor substrate 2Nonparametric linkage analysisMap positionChromosome 13q34Evidence of linkageInsulin receptor substrate-2 (IRS-2) geneGene regionLinkage analysisGenesSubstrate 2Excess alleleInsulin receptorNearby markersType II diabetesAshkenazi Jewish familiesMice resultsII diabetesSusceptibility roleMarkersFamilyPeripheral insulin resistance
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