2017
Pathogenesis of hypothyroidism-induced NAFLD is driven by intra- and extrahepatic mechanisms
Ferrandino G, Kaspari RR, Spadaro O, Reyna-Neyra A, Perry RJ, Cardone R, Kibbey RG, Shulman GI, Dixit VD, Carrasco N. Pathogenesis of hypothyroidism-induced NAFLD is driven by intra- and extrahepatic mechanisms. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: e9172-e9180. PMID: 29073114, PMCID: PMC5664516, DOI: 10.1073/pnas.1707797114.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseDe novo lipogenesisAdipose tissue lipolysisHepatic insulin resistanceThyroid hormonesHypothyroid miceImpaired suppressionInsulin resistanceTissue lipolysisInsulin secretionHigh thyroid-stimulating hormone levelsRegulation of THThyroid-stimulating hormone levelsLipid utilizationFatty liver diseaseSerum glucose levelsEndogenous glucose productionLow thyroid hormoneFatty acidsHepatic lipid utilizationLiver diseaseSevere hypothyroidismHormone levelsProfound suppressionGlucose levels
2001
Uncoupling Protein-2 Negatively Regulates Insulin Secretion and Is a Major Link between Obesity, β Cell Dysfunction, and Type 2 Diabetes
Zhang C, Baffy G, Perret P, Krauss S, Peroni O, Grujic D, Hagen T, Vidal-Puig A, Boss O, Kim Y, Zheng X, Wheeler M, Shulman G, Chan C, Lowell B. Uncoupling Protein-2 Negatively Regulates Insulin Secretion and Is a Major Link between Obesity, β Cell Dysfunction, and Type 2 Diabetes. Cell 2001, 105: 745-755. PMID: 11440717, DOI: 10.1016/s0092-8674(01)00378-6.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAnimalsBlood GlucoseBody WeightDiabetes MellitusDiabetes Mellitus, Type 2Disease Models, AnimalGene TargetingHomeostasisHumansHyperglycemiaInsulinInsulin SecretionIon ChannelsIslets of LangerhansMaleMembrane Transport ProteinsMiceMice, KnockoutMice, ObeseMitochondrial ProteinsModels, BiologicalObesityProteinsRNA, MessengerThermogenesisUncoupling AgentsUncoupling Protein 2ConceptsOb/ob miceInsulin secretionOb miceCell dysfunctionFirst-phase insulin secretionIslet ATP levelsGlucose-stimulated insulin secretionLevel of glycemiaSerum insulin levelsBeta-cell dysfunctionType 2 diabetesObesity-induced diabetesΒ-cell dysfunctionBeta-cell glucose sensingProtein 2UCP2-deficient miceInsulin levelsPathophysiologic significanceBeta cellsType 2SecretionMiceObesityATP levelsDiabetes
2000
Loss of Insulin Signaling in Hepatocytes Leads to Severe Insulin Resistance and Progressive Hepatic Dysfunction
Michael M, Kulkarni R, Postic C, Previs S, Shulman G, Magnuson M, Kahn C. Loss of Insulin Signaling in Hepatocytes Leads to Severe Insulin Resistance and Progressive Hepatic Dysfunction. Molecular Cell 2000, 6: 87-97. PMID: 10949030, DOI: 10.1016/s1097-2765(05)00015-8.Peer-Reviewed Original ResearchConceptsInsulin resistanceGlucose homeostasisInsulin receptor knockout miceLiver-specific insulin receptor knockout miceDirect insulin actionNormal hepatic functionProgressive hepatic dysfunctionReceptor knockout miceSevere glucose intoleranceSevere insulin resistanceHepatic glucose productionFailure of insulinLoss of insulinHepatic gene expressionHepatic dysfunctionGlucose intoleranceMarked hyperinsulinemiaCre-loxP systemInsulin clearanceHepatic functionInsulin secretionInsulin receptor geneKnockout miceInsulin actionGlucose production
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 ResearchConceptsType 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
Disruption of IRS-2 causes type 2 diabetes in mice
Withers D, Gutierrez J, Towery H, Burks D, Ren J, Previs S, Zhang Y, Bernal D, Pons S, Shulman G, Bonner-Weir S, White M. Disruption of IRS-2 causes type 2 diabetes in mice. Nature 1998, 391: 900-904. PMID: 9495343, DOI: 10.1038/36116.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlood GlucoseCloning, MolecularDiabetes Mellitus, Type 2FemaleGene TargetingHumansInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceIntracellular Signaling Peptides and ProteinsIslets of LangerhansLiverMaleMiceMice, Inbred C57BLMuscle, SkeletalPhosphatidylinositol 3-KinasesPhosphoproteinsPhosphorylationReceptor, InsulinRecombination, GeneticSignal TransductionConceptsType 2 diabetesInsulin resistanceHuman type 2 diabetesPancreatic β-cell functionInsulin secretion increasesSingle molecular abnormalityΒ-cell compensationIRS-2-deficient miceΒ-cell functionHuman type 2Insulin secretionInsulin receptor substrateGlucose homeostasisSecretion increasesInsulin actionType 2DiabetesMolecular abnormalitiesProgressive deteriorationSkeletal muscleIRS-2Insulin signalingIRS-1Mild resistanceMice
1997
Metabolic Defects in Lean Nondiabetic Offspring of NIDDM Parents: A Cross-Sectional Study
Perseghin G, Ghosh S, Gerow K, Shulman G. Metabolic Defects in Lean Nondiabetic Offspring of NIDDM Parents: A Cross-Sectional Study. Diabetes 1997, 46: 1001-1009. PMID: 9166672, DOI: 10.2337/diab.46.6.1001.Peer-Reviewed Original ResearchConceptsInsulin resistanceInsulin sensitivityControl subjectsInsulin secretionNIDDM parentsNIDDM patientsFFA metabolismFFA concentrationsAbove confounding factorsInsulin-resistant offspringFree fatty acid levelsInverse correlationLDL cholesterol levelsHealthy control subjectsNormal insulin sensitivityIntravenous glucose bolusLower insulin sensitivityPlasma FFA concentrationEuglycemic hyperinsulinemic clampCross-sectional studyFirst-degree relativesPathogenesis of NIDDMDefective insulin secretionFatty acid levelsHigh free fatty acid levels
1993
Comparative Effects of Monomethylsuccinate and Glucose on Insulin Secretion from Perifused Rat Islets
Zawalich W, Zawalich K, Cline G, Shulman G, Rasmussen H. Comparative Effects of Monomethylsuccinate and Glucose on Insulin Secretion from Perifused Rat Islets. Diabetes 1993, 42: 843-850. PMID: 8388341, DOI: 10.2337/diab.42.6.843.Peer-Reviewed Original ResearchConceptsPhosphoinositide hydrolysisInsulin secretionCalcium channel antagonist nitrendipineChannel antagonist nitrendipinePerifused rat isletsCalcium channel antagonistsSecond phase releaseGut hormone cholecystokininFirst-phase releaseInsulinotropic effectAntagonist nitrendipineSulfonylurea tolbutamideChannel antagonistsInsulin releaseHormone cholecystokininSubsequent stimulationGlucose-induced responseRat isletsSustained increaseStimulatory effectBiphasic patternMM glucoseMMSuccSecretionMonomethylsuccinateComparative effects of monomethylsuccinate and glucose on insulin secretion from perifused rat islets
Zawalich W, Zawalich K, Cline G, Shulman G, Rasmussen H. Comparative effects of monomethylsuccinate and glucose on insulin secretion from perifused rat islets. Diabetes 1993, 42: 843-850. DOI: 10.2337/diabetes.42.6.843.Peer-Reviewed Original Research
1987
Physiological role of cholecystokinin in meal-induced insulin secretion in conscious rats. Studies with L 364718, a specific inhibitor of CCK-receptor binding
Rossetti L, Shulman G, Zawalich W. Physiological role of cholecystokinin in meal-induced insulin secretion in conscious rats. Studies with L 364718, a specific inhibitor of CCK-receptor binding. Diabetes 1987, 36: 1212-1215. DOI: 10.2337/diabetes.36.10.1212.Peer-Reviewed Original ResearchPhysiological Role of Cholecystokinin in Meal-Induced Insulin Secretion in Conscious Rats: Studies With L 364718, A Specific Inhibitor of CCK-Receptor Binding
Rossetti L, Shulman G, Zawalich W. Physiological Role of Cholecystokinin in Meal-Induced Insulin Secretion in Conscious Rats: Studies With L 364718, A Specific Inhibitor of CCK-Receptor Binding. Diabetes 1987, 36: 1212-1215. PMID: 3308589, DOI: 10.2337/diab.36.10.1212.Peer-Reviewed Original ResearchConceptsPlasma insulinPostprandial plasma insulinGut hormone cholecystokininImportant physiologic roleCCK receptor bindingIntraduodenal catheterInsulin outputPrior administrationConscious ratsEnteroinsular axisGlucagon concentrationsVehicle injectionCCK antagonistsCCK secretionProtein ingestionInsulin secretionSpecific antagonistHormone cholecystokininCholecystokininPhysiologic roleInsulinAntagonistGlucagonRatsVivo regulation