Chap32InsulinandOralHypoglycemicAgentsInsulinOralhypoglycemicagentsSulfonylureasBiguanidesαglucosidaseinhibitoreuglycemicagentsDiabetesMellitusisagroupofsyndromescharacterizedby

HyperglycemiaAlteredmetabolismoflipids,carbohydratesandproteinAnincreasedriskofcomplicationsfromvasculardiseaseWhatisDiabetesMellitus?Theclassicsymptomsofdiabetesare:excessiveurination,includingfrequenttripstothebathroominthemiddleofthenightintensethirstandhungerseverefatigue.Othersymptomsofdiabetesmayinclude:dryskinblurredvisionunexplainedweightlossthin,malnourishedappearance.DifferentformsofDiabetesMellitusIDDM(InsulindependentDiabetesMellitus)NIDDM(non-insulindependentDiabetesMellitus)GestationaldiabetesMellitusOthersSection1Insulin

Pancreaticisland

Acell

25%，secreteglucagon

Bcell

60%，secreteinsulin

Dcell

less，secretesomatostatinItisamicromoleculeprotein，twopolypeptidechainsjoinedtogetherbydisulfidelinkages.InsulinAbstractedfrompancreasofdomesticanimal.Semisynthesis

DNArecombination

Itrepresentsalandmarkinmedicalhistory.BantingandMacleodwasawardedNobelPrizeinMedicine1923becauseofthediscoveryofinsulinThediscoveryofInsulinThediscoveryofinsulinin1921allowedthepreviouslyfataldisordersofinsulin–dependentdiabetesmellitustobetreated.Insulinissynthesizedbythebeta-cellofthepancreasThebeta-cellsynthesizeinsulinfromasinglepolypeptidechainpreproinsulin,whichiscleavedtoyieldtheinsulinprecursor,proinsulin.IntheGolgicomplex,proinsulinenzymaticallycleavedtoinsulin.BiosythesisofInsulinPhysiologicalActions

—glycometabolism

fatmetabolism

proteinmetabolismlowerserumK+long-termeffect1.GlycometabolismDecreasebloodglucoseIncreaseuptakeandutilizationDecreasesourceCardiacmuscle,skeletalmuscleanddipocyte:transportationofglucose↑Liver:oxydationandzymolysis（酵解

）↑Liverandmuscle:glycogensynthesis↑Transformation:fatandaminoacids↑Inhibitglyconeogenesis（糖異生

）,glycogenolysis：Antagonizeglycagon,ADandglucocorticosteroidInsulindeficiencyresultsinplasmaglucoserisebloodglucose80~120mg%hepaticglycogenglucogensynthesisglyconeogenesisfat,aminoacidoxygenolysisfoodRenalGlucoseThresholdWhenthebloodglucoselevelisnormal(about80mg/dl(4.4mmol/l))the"renaldam"holdsthesugarback.Sugarcannotbedetectedintheurine.Onlywhenthebloodglucoselevelrisesabove160mg/dl(8.9mmol/l)-forinstancewhenitreaches180mg/dl(10mmol/l)-issugarexcretedintheurine.Inhibitlipodieretic（脂肪分解）effectoflypase,AD,growthhormone；PromoteFFAentercell

2．FatMetabolismInhibitdecompose,promotesynthesisDeficiencyofinsulin：fatmetabolicdisorder3．ProteinMetabolism

PromoteaminoacidstoentercellsIncreaseproteinsynthesisInhibitproteindecompose（分解）Positivenitrogenbalance5.Long-termeffectPromoteK+enterthecell4．LowertheconcentrationofplasmaK+enzymeexpression

MechanismofAction

MechanismReceptorgatherandinternalize(聚集和內化

)Long-termeffect：Raspassway,partiallyTheappropriatesignalingthroughtheinsulinpathwayiscriticalfortheregulationofglucoselevelsandtheavoidanceofdiabetes.InsulinformsacomplexwiththeInsulinReceptor(IR)andbchainstoformtheactivesignalingcomplex.ThroughrecruitmentofadaptormoleculesandtheactivationofRAS,theactivatedIRcancausetranscriptionalactivation.Itcannotbetakenorallybutmustbeadministeredparenterally(Sc,iv)Intravenouslyinjectedinsulinhasat1/2of5-6minutes.Themajorsiteofcatabolismistheliver,where50%isdestroyedinasinglepassage.Disulfidebondisdeoxidizedtohydrosulfidegroupbytransportase.

PharmacokineticsClinicalUsesIDDMNIDDMDiabeteswithacuteorseriouscomplicationsDiabeteswithseriousinfection,wastingdisease,pregnancy,surgery,hyperpyrexia,delivery,wound1．Allkindsofdiabetes2.Otherclinicaluses（1）Hyperpotassaemia（2）CorrectpotassiumdeficiencyofcellGIK:glucose,insulinandKCI,ivdrip,topreventarrhythmiacausedbymyocardialinfarction,decreasemortalityAdversereactionsStarvationWeaknessSweatingCardiopalmus(心悸)PallorHeadacheTremorEmotionalinstability

1．hypoglycemiaoverdosehypoglycemicshockEclampsiaComaDeathdrinksacchar-waterortakefoodiv50%glucosesolutionH1receptorblockageGlucocorticosteroid2．hypersensitivereactionnettlerash(風疹

)acutecircumscribededema(血管神經性水腫

)allergicshock-seldomForeignprotein:antigenicityProinsulinorfragment:immunogenicityTherapeutics3．TolerationAcutetoleration:stringentstate（應激狀態）Chronictoleration:insulinresistance4．Flare(潮紅)

、induration(硬結)

andlipoatrophy(脂肪萎縮

)

Preparationregularinsulinglobinzineinsulin珠蛋白鋅胰島素isophaneinsulinsuspension中性精蛋白胰島素懸液protaminezincinsulin魚精蛋白鋅胰島素(長效)purepreparationsingle-peakinsulin單峰胰島素Single-componentinsulin單成分胰島素Section2OralHypoglycemicAgentsSulfonylureasBiguanidesαglucosidaseinhibitoreuglycemicagent胰島素增敏劑

SulfonylureasPowerful，rapid，remain8-10hStrongerthanfirst-generation,remian>24h。hypoglycemiaActonthesulfonylureareceptorofβ-cell,increasereleaseofinsulin

tolbutamide,(D860甲苯磺丁脲)

chlorpropamide(氯磺丙脲)

gluburide（格列苯脲,優降糖）

glipizide（格列吡嗪,美必達）

gliclazide

（格列齊特,達美康）

glimepiride(格列美脲)

gliquidone(格列奎酮)MechanismofAction

1.StimulateB-celltoreleaseinsulinItiseffectivetohealthadultsanddiabetes30%functionisnecessaryK+channelblockerItbindstosulfonylureasreceptorofBcell(ATP-sensitivepotassiumchannel)andinhibitstheeffluxofpotassiumionsthroughthechannel,andresultsindepolarization.Openavoltage-gatedcalciumchannelandresultsincalciuminflux,insulinrelease.

2.Enhancethesensitivityoftargetcelltoinsulin3.Decreasebindingofinsulintoplasmaprotein4.Increasesomatostatinreleaseandinhibitglucagonrelease刺激胰島素分泌降低肝糖生成增加葡萄糖攝取胰腺刺激胰島

細胞分泌胰島素肌肉肝臟血糖控制磺脲類藥物的作用機制(一)磺脲類藥物的作用機制(二)葡萄糖ATP敏感的K+通道關閉GLUT-2胰島素Ca2+通道開放胰島素葡萄糖6-磷酸葡萄糖葡萄糖激酶去極化細胞排顆粒作用顆粒轉位K+通道關閉糖酵解K+ATP去極化K+磺脲類藥物磺脲類藥物的受體ClinicalUsesNIDDM；Diabetesinsipidus:chlorpropamideAdverseReactionsRash,photosensitivedermatitisGranulocytopenia

Cholestasisjaundice,hepaticlesion3.HypoglycemiaPeriodicinspection：HepaticfunctionHemogram1.Gastrointestinaltract2.Hypersensitivereaction（1-2m）DrugInteraction1.Plasmaproteinbinding：salylicacid,sulfanilamide,butalidon,dicoumarinandmethotrexate2.Inhibitorsofdrug-metabolizingenzymes：chloromycin,INH3.Thiadiazides,corticosteroids:decreasetheeffectsofsulfonylureasItisasthesameassulfonylurea,blockK+channelandstimulateβcelltoreleaseinsulin.Repaglinide（瑞格列奈）Biguanidecompoundsphenformin(苯乙雙胍，苯乙福明，降糖靈)metformin(二甲雙胍，甲福明，降糖片)Itisnoeffectstohealthadult.Pharmacological

Actions1.Inhibittheabsorptionofglucosefromsmallinstestinal2.Enhanceintakeandutilazation,promoteanaerobicglycolysis（無氧糖酵解）ofmuscle3.Inhibitthereleaseofglucagon4.Inhibitglyconeogenesis5.Enhancethesensitivityoftargetcelltoinsulin，inhibitinsulinantagonist；6.LowerthelevelofLDLandVLDL（metformin）ClinicalUsesNIDDM：mildcase，corpulentsufferer（肥胖患者）；ArtherosclerosisAdverseReaction1.Digestivetract2.Ketonuria,lacticemia：promoteanaerobicglycolysis,producelacticacidα-GlucosidaseinhibitorsAcarbose（阿卡波糖）DecreasepostprandialglucoseItreducesintestinalabsorptionofstarch,dextrin（糊精）anddisaccharides（雙糖）byinhibitingtheactionofintestinalbrushborderα-glucosidase.

Inhibitionofthisenzymeslowstheabsorptionofcarbohydrates;thepostprandialriseinplasmaglucoseisbluntedinbothnormalanddiabeticsubjects.ClinicalUses

Allsortsofdiabetes，corpulentsuffererEuglycemicAgentsthiazalidinedione

(噻唑烷二酮)Include：troglitazone（曲格列酮）rosiglitazone（羅格列酮）pioglitazone（吡格列酮）

Pharmacologi