Historic Perspectives of Drug Development for Diabetes 糖尿病研究進展課件

HistoricPerspectivesofDrugDevelopmentforDiabetesYuguangShi,Ph.D.ProfessorofPhysiologyDeptofCellularandMolecularPhysiologyPennsylvaniaStateUniversityCollegeofMedicineHershey,PA17033Email:yus11@HistoricPerspectivesofDrug23.0M36.2M↑57.0%14.2M26.2M↑85%48.4M58.6M↑21%

43.0M

75.8M

↑79%

7.1M15.0M↑111%

39.3M

81.6M

↑108%M=million,AFR=Africa,NA=NorthAmerica,EUR=Europe,SACA=SouthandCentralAmerica,EMME=EasternMediterraneanandMiddleEast,SEA=South-EastAsia,WP=WesternPacificDiabetesAtlasCommittee.DiabetesAtlas2ndEdition:IDF2003.GlobalProjectionsfortheDiabetesEpidemic:2003-2025World2003=194M2025=333M↑72%AFRNASACAEURSEAWP19.2M39.4M↑105%EMME20032025?2005.AmericanCollegeofPhysicians.AllRightsReserved.23.0M14.2M48.4M 43.0M7.1MHistoricPerspectivesofDrugDevelopmentforDiabetes糖尿病研究進展課件TodiabetesMetabolicSyndrome?DiabetesR.HeineMD?2005.AmericanCollegeofPhysicians.AllRightsReserved.TodiabetesMetabolicDiabetesR.Hepatic

glucoseoutputInsulin

resistanceGlucoseuptakeGlucagon(acell)Insulin(betacell)PancreasLiverHyperglycemiaIslet-celldysfunctionMajorPathophysiologicDefects

inType2DiabetesMuscleAdipose

tissueHepatic

glucoseoutputInsulinHistoricPerspectivesofDrugDevelopmentforDiabetes糖尿病研究進展課件InsulinSynthesizedinthebcellsoftheisletsofLangerhans80%oftheisletcellmassmustbesurgicallyremovedbeforediabetesbecomesclinicallyapparentProinsulin,istransportedfromtheendoplasmicreticulumtotheGolgicomplexwhereitispackagedintogranulesandcleavedintoinsulinandaresidualconnectingpeptide,orCpeptideInsulinSynthesizedinthebceOskarMinkowski(1858–1931)PancreasandDiabetesTheirlandmarkstudyin1889indogsinduceddiabetesbyremovingtheirpancreas.ItwasMinkowskiwhoperformedtheoperationandmadethecruciallinktorecognizethatthesymptomsofthetreateddogswereduetodiabetes.JosefvonMering(1849-1908)OskarMinkowski(1858–1931)PanHistoricPerspectivesofDrugDevelopmentforDiabetes糖尿病研究進展課件HistoricPerspectivesofDrugDevelopmentforDiabetes糖尿病研究進展課件InsulinandAnaloguesInsulinandAnaloguesInsulinRapidactingLispro,Aspart,Glulisine,Inhaled*ShortactingRegularIntermediateactingNPH(NeutralProtamineHagedorn)LongactingGlargineDetemirInsulinRapidactingHistoricPerspectivesofDrugDevelopmentforDiabetes糖尿病研究進展課件InsulinAdvantagesMimicsnormalpancreaticresponsetoglucoseCanachievenormalbloodglucoselevelsNewerdeliveryoptionsDisadvantagesHypoglycemiaWeightgainPatientresistancetoinjectionsFrequentbloodglucosemonitoringExpensivecostofinhaledinsulinSpirometryneededforinhaledinsulinInsulinAdvantagesDisadvantagesMetforminDecreaseshepaticglucoseproductionImprovesinsulinsensitivityinperipheryDecreasesintestinalabsorptionofglucoseMetforminDecreaseshepaticgluMetforminAdvantagesConsiderableA1creductionUsedincombinationwithoralsandinsulinAvailableasextendedreleasetabletandliquidformulationInexpensiveDisadvantagesGastrointestinaladverseeffectsAvoidinheartfailure,renalandhepaticinsufficiencyRiskforlacticacidosisMetforminAdvantagesDisadvantagThiazolidinediones(TZDs)Insulinsensitizer(improvestargetcellresponsetoinsulin)DoesnotincreasepancreaticinsulinsecretionAvailableproducts:Avandia(rosiglitazone),Actos(pioglitazone)Thiazolidinediones(TZDs)InsulThiazolidinediones(TZDs)AdvantagesUseasmonotherapyorincombinationwithothermedicationsNohypoglycemia(monotherapyorwithmetformin)OnceortwicedailydosingIncreaseinHDLDecreaseinTriglyceridesDisadvantagesSeveralweeksoftherapybeforeoptimalglucosereductionPeripheraledemaWeightgainMacularedema,heartproblemsMonitoringofliverfunctionIncreaseinLDL(Avandia)ExpensiveThiazolidinediones(TZDs)AdvanAlpha-GlucosidaseInhibitorsStarchblockers(delayglucoseabsorptionanddecreasepostprandialglucose)Glyset(Miglitol)andPrecose(Acarbose)Alpha-GlucosidaseInhibitorsStAlpha-GlucosidaseInhibitorsAdvantagesReducespostprandialglucoseDisadvantagesGastrointestinaladverseeffectsDosedwithfirstbiteofeachmealPureglucosemustbeusedtotreathypoglycemiaDrugInteractionsExpensiveAlpha-GlucosidaseInhibitorsAdGLP-1TheStimulus-SecretionPathwaysinPancreaticb-CellsGLP-1TheStimulus-SecretionPaSulfonylureasStimulatesinsulinreleasefrompancreaticbetacellsReducesglucoseoutputfromliverImprovesinsulinsensitivityinperipheryAvailableproducts:Glyburide,Glipizide,Glimepiride(Amaryl)SulfonylureasStimulatesinsuliSulfonylureasAdvantages:Rapid,pronounceddecreaseinglucoseOnceortwicedailydosingInexpensiveAvailableincombinationwithotheroralagentsDisadvantages:HypoglycemiaDrugInteractionsConcernforeffectivenessafterseveralyearsoftreatmentSulfonylureasAdvantages:DisadvMeglitinidesStimulatesinsulinreleaseofpancreaticbetacellsDifferentchemicalstructurethansulfonylureasAvailableproducts:Prandin(repaglinide),Starlix(nateglinide)MeglitinidesStimulatesinsulinMeglitinidesAdvantages Shorthalflife/durationofactionMealtimeglucosecoverageLesshypoglycemiacomparedtosulfonylureas DisadvantagesShortdurationofactionDosedwitheachmealDrugInteractionsExpensiveMeglitinidesAdvantages DisadvaPramlintideAmylinanalog(co-secretedwithinsulinfrombetacells)ProlongsgastricemptyingtimeReducespostprandialglucagonsecretionReducesfoodintake(centrally-mediatedappetitesuppressionAvailableproduct:SymlinPramlintideAmylinanalog(co-sPramlintideAdvantages:UseinType1andType2diabetesImprovespostprandialglucoseDisadvantages:MultipleinjectionsSmalldosingininsulinsyringeGastrointestinaladverseeffectsHypoglycemiaDrugInteractionsExpensiveCannotbemixedwithinsulininsamesyringePramlintideAdvantages:DisadvanIncretinsPeptidehormonessecretedbyenteroendocrinecellsintheGItractModulatepancreaticisletsecretionsaspartofthe“enteroinsularaxis”O(jiān)thereffectsonnutrienthomeostasisTwomajorincretinsthataffectglucosemetabolism-GLP-1:glucagon-likepeptide-1;GIP:glucose-dependentinsulinotropicpeptide(gastricinhibitorypolypeptide)

?2005.AmericanCollegeofPhysicians.AllRightsReserved.IncretinsPeptidehormonessecrGLP-1isDerivedFrom

ProglucagonGRPPGlucagonIP-1GLP-1IP-2GLP-2130646978107/8162158158123111726133GlicentinMPGFPancreasIntestineGlucagonMPGFGlicentinOxyntomodulinGLP-1GLP-2IP-2OxyntomodulinDruckerDJ.MolEndocrinol2003;17:161-171?2005.AmericanCollegeofPhysicians.AllRightsReserved.GLP-1isDerivedFrom

ProglucaGLP-1ModesofActioninHumansGLP-1issecretedfromtheL-cellsintheintestineThisinturn…Stimulatesglucose-dependent

insulinsecretionSuppressesglucagonsecretionSlowsgastricemptyingLongtermeffects

demonstratedinanimals…Increasesbeta-cellmassand

maintainsbeta-cellefficiencyImprovesinsulinsensitivityReducesfoodintakeUponingestionoffood…DruckerDJ.CurrPharmDes2001;7:1399-1412

DruckerDJ.MolEndocrinol2003;17:161-171?2005.AmericanCollegeofPhysicians.AllRightsReserved.GLP-1ModesofActioninHumaIncretinEffectNormalWeight:Non-DiabeticSubjectsNormalWeight:DiabeticSubjectsPlasmaInsulinResponsestoOralandIntravenousGlucoseNon-DiabeticSubjects(glucoserange3.9-6.7mmol/L)

DiabeticSubjects(glucoserange4.7-12.2mmol/L)OralGlucoseIntravenousGlucoseOralGlucoseIntravenousGlucose60PlasmaInsulin(U/mL)3000601201803090150060120180309015090PlasmaInsulin(U/mL)6030090Time(min)Time(min)IncretinEffectNormalWeight:PostprandialGLP-1LevelsareDecreasedinSubjectsWithIGTandType2DiabetesDatafrom:

Toft-NielsenM,etal.JClinEndocrinolMetab2001;86:3717-3723*

P<0.05betweenT2DMandNGTgroup.20151050060120180240Time(min)Mean(SE)

GLP-1(pmol/L)********MealNGTsubjectsIGTsubjectsT2DMpatients?2005.AmericanCollegeofPhysicians.AllRightsReserved.PostprandialGLP-1LevelsareGlucoseDependentActionsofGLP-1

inPatientsWithType2DiabetesDatafrom:

NauckMA,etal.Diabetologia1993;36:741-744Dataaremean±SE.*P<0.052520151050Glucagon(pmol/L)Time(min)-30060120180240****17.515.012.510.07.55.02.50.0*Glucose(mmol/L)GLP-1/PBOinfusion******-30060120180240350300250200150100500Insulin(pmol/L)GLP-1/PBOinfusionTime(min)********GLP-1/PBOinfusionTime(min)-30060120180240PlaceboGLP-1?2005.AmericanCollegeofPhysicians.AllRightsReserved.GlucoseDependentActionsofGEffectofGLP-1InfusiononGlucoseConcentrationinPatientsWithType2Diabetes

(PreviouslyonOralAgents)Glucose

(mmol/L)0246810121416Datafrom:RachmanJ,etal.Diabetologia1997;40:205-211SalineGLP-1Non-diabeticControlsGLP-1IVinfusion(1.2pmol/min/kg)ClockTime(h)BreakfastLunchSnack24.0002.0004.0006.0008.0010.0012.0014.0022.0016.00?2005.AmericanCollegeofPhysicians.AllRightsReserved.EffectofGLP-1InfusiononGlStrategiestoEnhanceIncretinActioninDiabetes GLP-1analogues Exendin4[Exenatide] DPP-IVinhibitors?2005.AmericanCollegeofPhysicians.AllRightsReserved.StrategiestoEnhanceIncretinExenatide(Byetta)ApeptidefromGilamonstersalivathatshares50%homologywithhumanGLP-1FunctionsasanincretinmimeticIncreasesinsulinsecretionIncreasesbetacellgrowth/replicationSlowsgastricemptyingDecreasesfoodintakeCausessustainedweightlossintype2patientsExenatide(Byetta)ApeptidefrDiabetesCare.2005May;28(5):1092-100

Exenatide(Byetta)andWeightLossDiabetesCare.2005May;28(5):Exenatide(Byetta)OngoingeffortsforslowreleaseformPotentialusageasanantiobesitydrugPotentialusageforbetacellregenerationSideeffectsinclude:

nausea(common)andpancreatitis(veryrare)Exenatide(Byetta)OngoingeffoAserineproteasewidelyexpressedoncellmembranes,knownasCD26DPP-IValsoexistsasasolubleforminplasmaPrefersprolineoralanineatposition2oftheN-terminusforcleavage,butcanalsocleaveatnonpreferredaminoacidsOverlappingsubstratespecificitywithseveralrelatedenzymesDPP-IV?2005.AmericanCollegeofPhysicians.AllRightsReserved.AserineproteasewidelyexpreDipeptidylpeptidase4(DPP4)Inactivates

GlucagonLikePeptide-1(GLP-1)GLP-1InactiveGLP-1ActionsMixedmealGLP-1ActivePlasmaIntestinalGLP-1releaseDPP-IVRapidinactivation(>80%ofpool)ExcretedbykidneysDeaconetal.Diabetes.1995;44:1126.?2005.AmericanCollegeofPhysicians.AllRightsReserved.Dipeptidylpeptidase4(DPP4)IDPP-IVAndGLP-1InactivationDPP-IVAndGLP-1InactivationAugmentingGLP-1LevelsbyInhibitingDPP-IVActivity

GLP-1InactiveGLP-1ActionsMixedmealPlasmaIntestinalGLP-1releaseDPP-IVRapidinactivation(>80%ofpool)ExcretedbykidneysGLP-1ActiveDeaconetal.Diabetes.1995;44:1126.?2005.AmericanCollegeofPhysicians.AllRightsReserved.AugmentingGLP-1LevelsbyInhAdvantagesofDPP-IVInhibitionLowriskofhypoglycemiaOraltherapy,providingdosingconveniencetothepatientEndogenousGLP-1levelsareincreased