内分泌的分子生物学.ppt

内分泌及代谢疾病,内分泌系统,内分泌腺,脏器内分泌组织,激素体液调节系统（包括旁分泌、自分泌）,代谢过程,脏器功能,生长发育,生殖衰老,EndocrineSystem,内分泌学发展三阶段,腺体内分泌学OrganicEndocrinology组织内分泌学HistologicalEndocrinology分子内分泌学MoleculerEndocrinology,腺体内分泌学,观察切除内分泌腺前、后生理生化变化将内分泌腺中提取的有效成分补充给切除了内分泌腺的动物，观察其恢复情况从内分泌腺提取激素，了解其化学结构，制备同类物与拮抗物,组织内分泌学,放免的创建，可测量微量激素（1960年Yalow首次用放免法测量血浆胰岛素）获1977年诺贝尔奖免疫荧光显微技术，了解激素分布、分泌发现某些组织器官分泌激素:心脏,分子内分泌学,激素及其受体的基因基因的表达、转录、翻译及其调控基因缺失、插入基因重组技术人工合成激素激素作用机制激素与细胞代谢、增生、分化、凋亡等,细胞信息传递方式,通过相邻细胞的直接接触,通过细胞分泌各种化学物质来调节其他细胞的代谢和功能,信息物质(signalmolecules),跨膜信号转导的一般步骤,特定的细胞释放信息物质,信息物质经扩散或血循环到达靶细胞,与靶细胞的受体特异性结合,受体对信号进行转换并启动细胞内信使系统,靶细胞产生生物学效应,（一）神经递质又称突触分泌信号(synapticsignal),根据细胞分泌信息物质的方式，将细胞间信息物质分为四类：,（二）内分泌激素又称内分泌信号(endocrinesignal),（三）局部化学介质又称旁分泌信号(paracrinesignal,（四）气体信号(Gassignal),激素的分泌方式,内分泌旁分泌自分泌,激素的种类Hormones,肽类/蛋白类激素（Proteinorpeptide):ACTH,LH,FSH,PHT,TSH,Insulin,Glucagon,IGFs氨基酸衍生物（AminoAcidderivatives)：儿茶酚胺类（肾上腺素、去甲肾上腺素）脂肪酸衍生物(Fattyacidderivatives):前列腺素类、视黄酸胆固醇衍生物（Cholesterolderivatives)：考的松，醛固酮、1,25(OH)2D3性激素,激素的作用机制,与膜受体结合G蛋白偶联发挥生物效应,（肽类激素、生物胺、前列腺素）,与膜受体结合受体自身磷酸化发挥生物学效应（酪氨酸激酶）（生长因子家族、Insulin,IGFs),与核受体结合与DNA特异序列结合功能蛋白转录（甾体类激素）,激素是第一信使,激素的作用机制,激素信息在细胞内的信号传导,Coris:发现了磷酸化酶的可逆磷酸化（无活性的磷酸化酶b/有活性的磷酸化酶a之间的互变）获得1951年诺贝尔奖。Sutherland:成功分离和确定的腺苷酸环化酶和磷酸二酯酶（cAMP合成与分解的两个关键酶）提出了激素作用的第二信使学说获得1971年诺贝尔生理医学奖。KrebsDAG:diacylglycerol,6,InsulinasefoundintheliverandkidneysbreaksdowninsulincirculatingintheplasmaInsulinhasahalf-lifeofonlyabout6minutes.胰岛素在肝脏和肾脏降解。肝脏和肾脏的胰岛素酶分解血浆中的胰岛素胰岛素的半衰期约6分钟,InsulinReceptor（胰岛素受体）,thereceptorforinsulinisembeddedintheplasmamembraneandiscomposedofapairofalphasubunitsandapairofbetasubunits。胰岛素受体是跨膜受体，由两个亚基和两个亚基组成。,TwoandtwosubunitsReceptortyrosinekinaseHormonebindingsiteonsubunit，subunit-tyrosinekinaseactivityLocalizedto19thchromosomeinHumans,Theinsulinreceptor.Insulinbindingtothe-chainstransmitsasignalthroughthetransmembranedomainofthe-chainstoactivatethetyrosinekinaseactivity,CYTOPLASM,EXTRACELLULAR,NH3+,-OOC,-S-S-,+3HN,-subunits,-subunits,Transmembranedomain,Tyrosinekinasedomain,+3HN,-OOC,COO-,Plasmamembrane,Extracellular,Cytoplasm,Activationofthetyrosinekinasedomainsoftheinsulinreceptorbyinsulinbinding,followedbyinterchainautophosphorylation,P,P,P,P,ATPs,ADPs,P,Extracellular,Cytoplasm,P,P,P,P,P,P,Activationofthetyrosinekinasedomainsoftheinsulinreceptorbyinsulinbinding,followedbyinterchainautophosphorylation,InsulinSignalTransduction,severaltargetsarephosphorylatedbyIRTKIRSactivationistiedtometabolicresponsesglucosetransport(muscleandfatcells)activationofproteinphosphataseproteinphosphataseremovesphosphatesfromproteinsphosphorylatedbyproteinkinaseAcounter-regulationofglucagon,InsulinAction（胰岛素的作用）,InsulinpromotestheuptakeofglucoseintomanytissuesthatexpressGLUT4glucosetransporters,suchasskeletalmuscleandfat.Insulinincreasestheactivityofthesetransportersandincreasestheirnumbersbystimulatingtheirrecruitmentfromanintracellularpooltothecellsurface.,ExtracellularspaceCytoplasm,4signalsGolgitotrafficGLUT-4tomembrane,PKB,GOLGI,=GLUT-4,ActiveIRTK,1IRTKcatalyzed,activeIRS,PI-3K,p85,2activatedbydockingactiveIRS,HypotheticalmechanismforinsulintomobilizeGLUT-4transportertotheplasmamembraneinmuscleandadiposetissue.IRS,insulin-receptorsubstrate;IRTK,insulinreceptortyrosinekinase;PI-3K,phosphatidyl-inositolkinase;PDK;phospholipid-dependentkinasePKB,proteinkinaseB,PDK,+,Insulinstimulatedglucosetransport(GLUT-4)inadiposeormusclecells,Golgi,glucose,transporter,(signal),-,P,P,-,Step2translocationFromGolgi,Step3Bindingandfusion,Step4Glucosetransport,Step5Receptorinactivation,Step6translocationbacktoGolgi,Glucose,DiagnosticcriteriaWorldHealthOrganization(1980)1.Symptomsofdiabetesplusaplasmaglucoseconcentration11.1mmol/lobtainedatanytimeofdayandwithoutregardtomeals,OR2.Fastingplasmaglucose7.8mmol/l,OR3.Aplasmaglucoseconcentration11.1mmol/l2hafter75goforalglucose,糖尿病的诊断,Classification,Diabetesisclassifiedbyunderlyingcause.Thecategoriesare:Type1diabetesanautoimmunediseaseinwhichthebodysownimmunesystemattacksthepancreas,renderingitunabletoproduceinsulin;Type2diabetesinwhicharesistancetotheeffectsofinsulinoradefectininsulinsecretionmaybeseen;Gestationaldiabetes,Majordefectinindividualswithtype2diabetesReducedbiologicalresponsetoinsulinStrongpredictoroftype2diabetesCloselyassociatedwithobesity,Whatisinsulinresistance?,Whatis-celldysfunction?,Majordefectinindividualswithtype2diabetesReducedabilityof-cellstosecreteinsulininresponsetohyperglycemia,Insulinresistanceand-celldysfunctionarecoredefectsoftype2diabetes,Howdoinsulinresistanceand-celldysfunctioncombinetocausetype2diabetes?,Morethan80%ofpatientsprogressingtotype2diabetesareinsulinresistant,Insulinresistant;lowinsulinsecretion(54%),Insulinresistant;goodinsulinsecretion(29%),Insulinsensitive;goodinsulinsecretion(1%),Insulinsensitive;lowinsulinsecretion(16%),83%,HaffnerSM,etal.Circulation2000;101:975980.,Insulinresistancereducedresponsetocirculatinginsulin,Insulinresistance,Glucoseoutput,Glucoseuptake,Glucoseuptake,Hyperglycemia,Liver,Muscle,Adiposetissue,InUSA:16millionpeoplesufferfromDM.Type1diabetesaccountsfor5-10%ofcases,affecting1of400childrenandadolescents.Type2diabetesisextremelycommon,accountingfor90-95%ofallcasesofdiabetes.Thisformofdiabetescangoundiagnosedformanyyears,butthenumberofcasesthatarebeingdiagnosedisrisingrapidly,leadingtoreportsofadiabetesepidemic.,Epidemiology,2019年全球糖尿病病人已超过1.94亿，预计到本世纪2025年这个数字将增加近一倍（3.33亿）,我国糖尿病病人数约4000万，占全球糖尿病病人的1/5.型糖尿病占5.6，型糖尿病占93.7，其它类型糖尿病仅占0.7。,Geneticassociations（遗传关联）TheclearestassociationiswithclassIIhumanleucocyteantigens(HLA)codedontheshortarmofchromosome6.ThislocushasbeentermedIDDM1.TheregionaroundthegenecodingforinsulinistermedIDDM2andthereareassociationswithlocionchromosomes15q(IDDM3),11q(IDDM4)and6q(IDDM5).Thenumberofmutationsatotherputativesitescontinuestoincreasebuttheexactnatureoftheseassociationsisnotknown.Studiesintwinsindicatethatapproximately40%oftheriskoftype1DMisgenetic.,etiologyoftype1DM,Environmentalfactors（环境因素）Viruses.EvidenceforaviraletiologyofDMinhumansiscircumstantialthoughinanimalstudiestheevidenceisgood.Virusesimplicatedincluderubella(congenital),mumps,cytomegalovirusandCoxsackieB.Dietaryagents.Controversially,thoseimplicatedincludecowsmilk(containingbovineserumalbumin),preservedmeats(containingnitrosamines)andcoffee.,etiologyoftype1DM,Immunemarkers（免疫标记）Type1DMischaracterizedbythepresenceofTlymphocyteswithinthepancreaticisletsthatmayplayakeyroleinisletdestruction.Patientswithtype1DMhavecirculatingantibodiesagainsttheislets.Antibodiesagainsttheinsulinmolecule,theenzymegamma-aminobutyricaciddecarboxylase(GAD)orthetyrosinekinaseIA-2havebeenwellcharacterized.,etiologyoftype1DM,Geneticassociations（遗传关联）Studiesintwinsindicatethatapproximately30-90%oftheriskoftype2diabetesisgenetic.Prevalenceoftype2DMisveryhighincertainethnicgroupsincludingPimaIndiansinArizona,NaruansinPolynesia,andIndiansub-continentAsiansintheUK.,Theetiologyoftype2diabetesmellitus,Environmentalfactors（环境因素）Obesity(especiallycentral),aging,physicalinactivity.Theseincreaseinsulinresistance.Poorfetaldevelopment（胎儿发育不良）.This(thethriftyphenotypehypothesis)isthoughttoleadtometabolicsequelaepredisposingtotype2d