內分泌的分子生物學final內分泌及代謝疾病內分泌的分子生物學final

內分泌系統內分泌腺臟器內分泌組織激素體液調節系統（包括旁分泌、自分泌）代謝過程臟器功能生長發育生殖衰老EndocrineSystem內分泌的分子生物學final內分泌的分子生物學final內分泌學發展三階段腺體內分泌學

OrganicEndocrinology組織內分泌學

HistologicalEndocrinology分子內分泌學

MoleculerEndocrinology內分泌的分子生物學final腺體內分泌學觀察切除內分泌腺前、后生理生化變化將內分泌腺中提取的有效成分補充給切除了內分泌腺的動物，觀察其恢復情況從內分泌腺提取激素，了解其化學結構，制備同類物與拮抗物內分泌的分子生物學final組織內分泌學放免的創建，可測量微量激素 （1960年Yalow首次用放免法測量血漿胰島素）獲1977年諾貝爾獎免疫熒光顯微技術，了解激素分布、分泌發現某些組織器官分泌激素:心臟內分泌的分子生物學final分子內分泌學激素及其受體的基因基因的表達、轉錄、翻譯及其調控基因缺失、插入基因重組技術人工合成激素激素作用機制激素與細胞代謝、增生、分化、凋亡等內分泌的分子生物學final內分泌的分子生物學final細胞信息傳遞方式①通過相鄰細胞的直接接觸②通過細胞分泌各種化學物質來調節其他細胞的代謝和功能信息物質(signalmolecules)內分泌的分子生物學final跨膜信號轉導的一般步驟特定的細胞釋放信息物質信息物質經擴散或血循環到達靶細胞與靶細胞的受體特異性結合受體對信號進行轉換并啟動細胞內信使系統靶細胞產生生物學效應內分泌的分子生物學final（一）神經遞質

又稱突觸分泌信號(synapticsignal)

根據細胞分泌信息物質的方式，將細胞間信息物質分為四類：（二）內分泌激素

又稱內分泌信號(endocrinesignal)（三）局部化學介質又稱旁分泌信號(paracrinesignal

（四）氣體信號

(Gassignal)內分泌的分子生物學final激素的分泌方式內分泌旁分泌自分泌內分泌的分子生物學final激素的種類Hormones肽類/蛋白類激素（Proteinorpeptide):ACTH,LH,FSH,PHT,TSH,Insulin,Glucagon,IGFs氨基酸衍生物（AminoAcidderivatives)：

兒茶酚胺類（腎上腺素、去甲腎上腺素）脂肪酸衍生物(Fattyacidderivatives):

前列腺素類、視黃酸膽固醇衍生物（Cholesterolderivatives)：考的松，醛固酮、1,25(OH)2D3性激素內分泌的分子生物學final激素的作用機制

與膜受體結合G蛋白偶聯發揮生物效應（肽類激素、生物胺、前列腺素）

與膜受體結合受體自身磷酸化發揮生物學效應（酪氨酸激酶）

（生長因子家族、Insulin,IGFs)與核受體結合與DNA特異序列結合功能蛋白轉錄

（甾體類激素）激素是第一信使內分泌的分子生物學final激素的作用機制激素信息在細胞內的信號傳導Coris:

發現了磷酸化酶的可逆磷酸化（無活性的磷酸化酶b/有活性的磷酸化酶a之間的互變）

獲得1951年諾貝爾獎。Sutherland:成功分離和確定的腺苷酸環化酶和磷酸二酯酶（cAMP合成與分解的兩個關鍵酶）

提出了激素作用的第二信使學說

獲得1971年諾貝爾生理醫學獎。Krebs&Fisher:于60年代末發現蛋白激酶A(PKA)

（依賴cAMP,刺激多種底物蛋白磷酸化)

闡明了PKA啟動的磷酸化和去磷酸化途徑。

獲得1992年諾貝爾生理醫學獎。

cAMP-蛋白激酶途徑ATPcAMP蛋白激酶A蛋白質或酶磷酸化酶活性改變基因轉錄加快蛋白質合成加速生物效應AMP磷酸二酯酶RGAC內分泌的分子生物學final

使有關蛋白或酶類的絲氨酸、蘇氨酸殘基磷酸化NOCOGCPKGGCG蛋白GTPcGMP：激素（心鈉素）R胞膜cGMP-蛋白激酶G（PKG）途徑主要生理效應：血管平滑肌松弛增加尿鈉，促進鈉的排出降低血壓內分泌的分子生物學final受體型TPK：非受體型TPK內分泌的分子生物學final類固醇激素與甲狀腺素通過胞內受體調節生理過程內分泌的分子生物學finalMCR（代謝清除率）ofsomehormonesHormoneHalf-lifeAmines2-3minThyroidhormones:T4T36.7days0.75daysPolypeptides4-40minProteins15-170minSteroids4-120min內分泌的分子生物學final內分泌疾病的機制

Mechanismsofendocrinedisease由激素缺乏、過量或抵抗引起的內分泌疾病Endocrinedisordersresultfromhormonedeficiency,hormoneexcessorhormoneresistance

內分泌的分子生物學final由于感染、壞死、腫瘤的物理性壓縮以及自身免疫性疾病導致的分泌腺破壞引起的激素缺乏

Deficiency

usuallyisduetodestructiveprocessoccurringatglandinwhichhormoneisproduced—infection,infarction,physicalcompressionbytumorgrowth,autoimmuneattackTypeIDiabetes內分泌疾病的機制

Mechanismsofendocrinedisease內分泌的分子生物學final由于遺傳缺陷（激素基因缺失或突變），導致激素前體的斷裂、特異性酶缺乏（甾體類激素或甲狀腺素），引起激素合成減少

Deficiencycanalsoarisefromgeneticdefectsinhormoneproduction—genedeletionormutation,failuretocleaveprecursor,specificenzymaticdefect(steroidorthyroidhormones)CongenitalAdrenalHyperplasia先天性腎上腺增生(癥)內分泌疾病的機制

Mechanismsofendocrinedisease內分泌的分子生物學finalCongenitalAdrenalHyperplasia先天性腎上腺增生(癥)

21-羥化酶缺乏21-羥化酶缺乏對膽固醇的代謝發生哪些變化？內分泌的分子生物學final受體的滅活性突變導致激素缺乏

Inactivatingmutationsofreceptorscancausehormonedeficiency雄激素不敏感綜合征（睪丸女性化綜合征）（TesticularFeminizationSyndrome）內分泌疾病的機制

Mechanismsofendocrinedisease內分泌的分子生物學final由于疾病引起的激素分泌過多

Hormoneexcessusuallyresultsindisease腺體分泌過量或非內分泌組織的分泌導致激素生成過量

Hormonemaybeoverproducedbyglandthatnormallysecretesit,orbyatissuethatisnotanendocrineorgan.內分泌腺腫瘤引起激素分泌過量

Endocrineglandtumorsproducehormoneinanunregulatedmanner.庫興(氏)綜合征（Cushing’sSyndrome）內分泌疾病的機制

Mechanismsofendocrinedisease內分泌的分子生物學final使用外源性激素導致體內激素過量。如糖皮質激素或合成代謝類激素

Exogenousingestionofhormoneisthecauseofhormoneexcess—forexample,glucocorticoidexcessoranabolicsteroidabuse

內分泌疾病的機制

Mechanismsofendocrinedisease內分泌的分子生物學final受體數量和功能的異常引起內分泌異常

Alterationsinreceptornumberandfunctionresultinendocrinedisorders比較常見的是激素水平的異常增高引起可利用受體的數量減少

Mostcommonly,anaberrantincreaseinthelevelofaspecifichormonewillcauseadecreaseinavailablereceptorsTypeIIdiabetes內分泌疾病的機制

Mechanismsofendocrinedisease內分泌的分子生物學final糖尿病的分子機制MolecularmechanismofDiabetesmellitus(DM)內分泌的分子生物學finalDefinition:DMisagroupofmetabolicdiseasescharacterizedbyabnormallyhighlevelsofsugar(glucose)inthebloodresultingfromdefectsininsulinsecretion,insulinactionorboth.定義：糖尿病是一組由于胰島素不足或／和胰島素作用缺陷（抵抗）而導致以血糖增高為特征的代謝性疾病。內分泌的分子生物學final1.HistoryofDiabetes（糖尿病的歷史）

醫生發現糖尿病的癥狀已有幾千年的歷史

Physicianshaveobservedtheeffectsofdiabetesforthousandsofyears.Formuchofthistime,littlewasknownaboutthisfataldiseasethatcausedwastingawayofthebody（消瘦）,extremethirst（口渴）,andfrequenturination（尿頻）.

內分泌的分子生物學final糖尿病的一種明顯的表現是葡萄糖尿，是糖尿病的一個診斷指標

Oneoftheeffectsofdiabetesisthepresenceofglucoseintheurine(glucosuria).AncientHinduwritings,manythousandsofyearsold,documenthowblackantsandflies

wereattractedtotheurineofdiabetics.TheIndianphysicianSushrutain400B.C.describedthesweettasteofurinefromaffectedindividuals,andformanycenturiestocome,thesweettasteofurinewaskeytodiagnosis.內分泌的分子生物學final

公元250年左右，第一次使用“diabetes”描述糖尿病

Around250B.C.,thename“diabetes”wasfirstused.ItisaGreekwordthatmeans“tosyphon（虹吸）”,reflectinghowdiabetesseemedtorapidlydrainfluidfromtheaffectedindividual.

完整的“diabetesmellitus”

在1674年確定。

Thecompleteterm“diabetesmellitus”wascoinedin1674byThomasWillis。MellitusisLatinforhoney,whichishowWillisdescribedtheurineofdiabetics(“asifimbuedwithhoneyandsugar”).內分泌的分子生物學final

糖尿病之謎的一個突破是出現在1889年。德國醫生JosephvonMering和OskarMinkowski手術切除狗的胰腺后，狗立即出現糖尿病。

Abreakthroughinthepuzzleofdiabetescamein1889.GermanphysiciansJosephvonMeringandOskarMinkowskisurgicallyremovedthepancreasfromdogs.Thedogsimmediatelydevelopeddiabetes.Nowthatalinkwasestablishedbetweenthepancreasglandanddiabetes,

researchfocusedonisolatingthepancreaticextractthatcouldtreatdiabetes.內分泌的分子生物學finalManygreatphysiologistshadtriedandfailedtoisolateaninternalsecretionfromthepancreas.Dr.FrederickBantingtookupthechallengeofisolatingapancreaticextract,hewasmetwithmuchskepticism.

內分泌的分子生物學finalBanting,asurgeon,persistedandinMay1921,hebeganworkinthelaboratoryofProfessorJohnMacloedinToronto,Canada.CharlesBest,amedicalstudentatthetime,workedashisassistant.內分泌的分子生物學final1921年，用胰腺提取物成功降低切除胰腺的狗的血糖。

InJuly1921,adogthathadhaditspancreassurgicallyremovedwasinjectedwithanextractcollectedfromaduct-tieddog.Inthetwohoursthatfollowedtheinjection,thebloodsugarlevelofthedogfell,anditsconditionimproved.內分泌的分子生物學finalDr.J.Collip，生物化學學家，繼續改善胰腺提取物的純度，隨后，Best進行提取工作。Dr.J.Collip,abiochemist,wasdraftedtocontinueimprovingthepurityofthepancreasextract,andlater,Bestcarriedonthiswork.內分泌的分子生物學final到1922年，成功應用胰島素治療第一例糖尿病病人。

Itwasn'tuntil1922thatthefirstpatientwassuccessfullytreatedwithinsulin.內分泌的分子生物學finalFourscientistscontributedtothediscoveryofinsulinJ.CollipJohnMacloedCharlesBestFrederickBanting內分泌的分子生物學finalIn1923,BantingandMacloedwereawardedtheNobelPrizeforthediscoveryofinsulin.BantingMacloed內分泌的分子生物學finalCinema:“Gloryenoughforall”（共同的榮譽）光榮歲月

內分泌的分子生物學final葡萄糖的代謝概況（OverviewofGlucoseMetabolism）

Glucoseisanessentialfuelforthebody.Theamountofglucoseinthebloodstreamisregulatedbymanyhormones,themostimportantbeinginsulin.血糖受很多激素調節，其中最重要的是胰島素。

內分泌的分子生物學final內分泌的分子生物學finalInsulinisreleasedwhenglucoseisabundantandstimulatesthefollowing（胰島素的作用）促進:?muscleandfatcellstoremoveglucosefromtheblood（肌肉細胞核脂肪細胞從血液中攝取葡萄糖?cellstobreakdownglucose,releasingitsenergyintheformofATP(viaglycolysisandthecitricacidcycle)（分解葡萄糖和提供能量）內分泌的分子生物學final?

theliverandmuscletostoreglucoseasglycogen(short-termenergyreserve)（肝和肌肉細胞合成糖原）?

adiposetissuetostoreglucoseasfat(long-termenergyreserve)（葡萄糖轉變為脂肪）?

cellstouseglucoseinproteinsynthesis（在蛋白質的合成過程中利用葡萄糖）胰島素的作用內分泌的分子生物學finalWhentheamountofglucoseinthebloodincreases,e.g.,afterameal,ittriggersthereleaseofthehormoneinsulinfromthepancreas.Insulinstimulatesmuscleandfatcellstoremoveglucosefromthebloodandstimulatesthelivertometabolizeglucose,causingthebloodsugarleveltodecreasetonormallevels內分泌的分子生物學final

Glucagon（胰高血糖素）

isthemainhormoneopposingtheactionofinsulinandisreleasedwhenfoodisscarce內分泌的分子生物學finalChangesinbloodlevelsofglucose,insulin,andglucagonafteracarbohyrate-richmeal(ingestedattime0minutes).內分泌的分子生物學finalTheStoryofInsulinInsulinSynthesis（胰島素的合成）InsulinStructure（胰島素的結構）Insulinsecretion（胰島素的分泌）InsulinReceptor（胰島素受體）InsulinAction（胰島素的作用）內分泌的分子生物學finalInsulinSynthesis內分泌的分子生物學finalInsulinStructureIn1958,FrederickSangerwasawardedhisfirstNobelPrizeinChemistryfordeterminingthesequenceoftheaminoacidsthatmakeupinsulin.Thismarkedthefirsttimethataproteinhadhadtheorderofitsaminoacids(theprimarysequence)determined.InsuliniscomposedoftwochainsofaminoacidsnamedchainA(21aminoacids)andchainB(30aminoacids)thatarelinkedtogetherbytwodisulfidebridges.Thereisa3rddisulfidebridgewithintheAchainthatlinksthe6thand11thresiduesoftheAchaintogether內分泌的分子生物學finalInsulinsecretionRisinglevelsofglucoseinsidethepancreaticcellstriggerthereleaseofinsulin胰腺細胞內葡萄糖水平的升高觸發胰島素釋放內分泌的分子生物學final1.Glucoseistransportedintothebetacellbytype2glucosetransporters(GLUT2).Onceinside,thefirststepinglucosemetabolismisthephosphorylationofglucosetoproduceglucose-6-phosphate.Thisstepiscatalyzedbyglucokinase--itistherate-limitingstepinglycolysis.葡萄糖6-磷酸葡萄糖葡萄糖激酶內分泌的分子生物學final2.Asglucosemetabolismproceeds,ATPisproducedinthemitochondria.葡萄糖代謝過程中,線粒體產生ATP內分泌的分子生物學final3.TheincreaseintheATP:ADPratioclosesATP-gatedpotassiumchannelsinthebetacellmembrane.Positivelychargedpotassiumions(K+)arenowpreventedfromleavingthebetacell.細胞內ATP:ADP比例增加，關閉細胞ATP-鉀通道，防止帶正電的鉀離子離開細胞內分泌的分子生物學final4.Theriseinpositivechargeinsidethebetacellcausesdepolarization.

細胞內正電荷的增加引起細胞去極化內分泌的分子生物學final5.Voltage-gatedcalciumchannelsopen,allowingcalciumions(Ca2+)tofloodintothecell.鈣離子通道開放，使細胞外的鈣離子進入細胞內內分泌的分子生物學final6.Theincreaseinintracellularcalciumconcentrationtriggersthesecretionofinsulinviaexocytosis細胞內鈣離子的增加觸發胰島素通過胞吐作用分泌到細胞外內分泌的分子生物學finalTherearetwophasesofinsulinreleaseinresponsetoariseinglucose.Thefirstisanimmediatereleaseofinsulin.Thisisattributabletothereleaseofpreformedinsulin,whichisstoredinsecretorygranules.Afterashortdelay,thereisasecond,moreprolongedreleaseofnewlysynthesizedinsulin.胰島素對葡萄糖反應的的釋放有兩個階段第一階段：立即釋放儲存在分泌顆粒中的胰島素第二階段：釋放新合成的胰島素，持續時間較長Glucose1GLUT2ATPMETABOLISM2Ca2+

IMMEDIATESECRETIONCalmodulin

INSULINBIOSYNTHESISANDPROCESSING5

ProteinkinaseCCa2+3

CaM-kinase4

DAGSecretedinsulin+C-peptideControlofinsulinsynthesisandsecretionbyglucose.CaMkinase:calmodulin-dependentproteinkinase;DAG:diacylglycerol6內分泌的分子生物學finalInsulinasefoundintheliverandkidneysbreaksdowninsulincirculatingintheplasmaInsulinhasahalf-lifeofonlyabout6minutes.胰島素在肝臟和腎臟降解。肝臟和腎臟的胰島素酶分解血漿中的胰島素胰島素的半衰期約6分鐘內分泌的分子生物學finalInsulinReceptor（胰島素受體）內分泌的分子生物學finalthereceptorforinsulinisembeddedintheplasmamembraneandiscomposedofapairofalphasubunitsandapairofbetasubunits。胰島素受體是跨膜受體，由兩個亞基和兩個亞基組成。TwoαandtwoβsubunitsReceptortyrosinekinaseHormonebindingsiteonαsubunit，βsubunit-tyrosinekinaseactivityLocalizedto19thchromosomeinHumansTheinsulinreceptor.Insulinbindingtothe

-chainstransmitsasignalthroughthetransmembranedomainofthe

-chainstoactivatethetyrosinekinaseactivityCYTOPLASMEXTRACELLULARNH3+SSSSInsulin-OOC-S-S-+3HNCOO-

-subunits

-subunitsTransmembranedomainTyrosinekinasedomain+3HNNH3+-OOCCOO-

PlasmamembraneSSSSExtracellularCytoplasm1insulinbindsLR2IRTK(L)activatedOPOP3IRTK(R)phosphorylated/activatedActivationofthetyrosinekinasedomainsoftheinsulinreceptorbyinsulinbinding,followedbyinterchainautophosphorylationPPPPATPsADPsPhosphorylationcatalyzedbyIRTK(L)PExtracellularCytoplasm1insulinbindsLR2IRTK(L)activatedOPOP3IRTK(R)phosphorylated/activatedPOPO4IRTK(L)phosphorylatedOPOPPPPPATPsADPsPhosphorylationcatalyzedbyIRTK(L)ATPsADPsPPPhosphorylationcatalyzedbyIRTK(R)Activationofthetyrosinekinasedomainsoftheinsulinreceptorbyinsulinbinding,followedbyinterchainautophosphorylation內分泌的分子生物學finalInsulinSignalTransductionseveraltargetsarephosphorylatedbyIRTKIRSactivationistiedtometabolicresponsesglucosetransport(muscleandfatcells)activationofproteinphosphataseproteinphosphataseremovesphosphatesfromproteinsphosphorylatedbyproteinkinaseA–counter-regulationofglucagon內分泌的分子生物學finalInsulinAction（胰島素的作用）InsulinpromotestheuptakeofglucoseintomanytissuesthatexpressGLUT4glucosetransporters,suchasskeletalmuscleandfat.Insulinincreasestheactivityofthesetransportersandincreasestheirnumbersbystimulatingtheirrecruitmentfromanintracellularpooltothecellsurface.內分泌的分子生物學finalExtracellularspaceCytoplasm

tyr-OHIRS[4]signalsGolgitotrafficGLUT-4tomembranePKBGOLGI=GLUT-4ActiveIRTKPOPOOPOP[1]IRTKcatalyzed

tyr-OPIRSATP

ADP

activeIRS

tyr-OPIRSPI-3Kp85[2]activatedbydockingactiveIRSHypotheticalmechanismforinsulintomobilizeGLUT-4transportertotheplasmamembraneinmuscleandadiposetissue.IRS,insulin-receptorsubstrate;IRTK,insulinreceptortyrosinekinase;PI-3K,phosphatidyl-inositolkinase;PDK;phospholipid-dependentkinasePKB,proteinkinaseB

tyr-OPIRS

tyr-OPIRS

tyr-OPIRSPIP2PIP3PDK+Insulinstimulatedglucosetransport(GLUT-4)inadiposeormusclecellsGolgi

glucose

transporter

Step1

-insulinbinding

andsignaltransduction

(signal)

-P

P-

Step2

translocationFromGolgi

Step3Bindingandfusion

Step4Glucosetransport

Step5ReceptorinactivationStep6translocationbacktoGolgi

Glucose內分泌的分子生物學finalDiagnosticcriteria

WorldHealthOrganization(1980)

1.Symptomsofdiabetesplusaplasmaglucoseconcentration>11.1mmol/lobtainedatanytimeofdayandwithoutregardtomeals,OR

2.Fastingplasmaglucose>7.8mmol/l,OR

3.Aplasmaglucoseconcentration>11.1mmol/l2hafter75goforalglucose糖尿病的診斷內分泌的分子生物學finalClassificationDiabetesisclassifiedbyunderlyingcause.Thecategoriesare:Type1diabetes—anautoimmunediseaseinwhichthebody'sownimmunesystemattacksthepancreas,renderingitunabletoproduceinsulin;Type2diabetes—inwhicharesistancetotheeffectsofinsulinoradefectininsulinsecretionmaybeseen;Gestationaldiabetes內分泌的分子生物學final內分泌的分子生物學finalMajordefectinindividualswithtype2diabetesReducedbiologicalresponsetoinsulinStrongpredictoroftype2diabetesCloselyassociatedwithobesityWhatisinsulinresistance?內分泌的分子生物學finalWhatis-celldysfunction?Majordefectinindividualswithtype2diabetesReducedabilityof

-cellstosecreteinsulininresponsetohyperglycemia

內分泌的分子生物學finalInsulinresistanceand

-celldysfunctionarecoredefectsoftype2diabetesInsulinresistanceGeneticsusceptibility,obesity,WesternlifestyleType2diabetesIRb-celldysfunction

內分泌的分子生物學finalHowdoinsulinresistanceand

-celldysfunctioncombinetocausetype2diabetes?AbnormalglucosetoleranceHyperinsulinemia,then

-cellfailureNormal IGT* Type2diabetesPost-prandialglucoseInsulinresistanceIncreasedinsulin

resistanceFastingglucoseHyperglycemiaInsulinsecretion*IGT=impairedglucosetolerance內分泌的分子生物學finalMorethan80%ofpatientsprogressingtotype2diabetesareinsulinresistantInsulinresistant;

lowinsulinsecretion(54%)Insulinresistant;

goodinsulinsecretion(29%)Insulinsensitive;

goodinsulinsecretion(1%)Insulinsensitive;

lowinsulinsecretion(16%)83%HaffnerSM,etal.Circulation2000;101:975–980.內分泌的分子生物學finalInsulinresistance–reducedresponsetocirculatinginsulinInsulinresistance

Glucose

output

Glucoseuptake

Glucose

uptakeHyperglycemiaLiverMuscleAdipose

tissueIR內分泌的分子生物學finalInUSA:16millionpeoplesufferfromDM.Type1diabetesaccountsfor5-10%ofcases,affecting1of400childrenandadolescents.Type2diabetesisextremelycommon,accountingfor90-95%ofallcasesofdiabetes.Thisformofdiabetescangoundiagnosedformanyyears,butthenumberofcasesthatarebeingdiagnosedisrisingrapidly,leadingtoreportsofadiabetesepidemic.Epidemiology2003年全球糖尿病病人已超過1.94億，預計到本世紀2025年這個數字將增加近一倍（3.33億）我國糖尿病病人數約4000萬，占全球糖尿病病人的1/5.１型糖尿病占5.6％，２型糖尿病占93.7％，其它類型糖尿病僅占0.7％。內分泌的分子生物學finalGeneticassociations（遺傳關聯）

TheclearestassociationiswithclassIIhumanleucocyteantigens(HLA)codedontheshortarmofchromosome6.ThislocushasbeentermedIDDM1.TheregionaroundthegenecodingforinsulinistermedIDDM2

andthereareassociationswithlocionchromosomes15q(IDDM3),11q(IDDM4)and6q(IDDM5).Thenumberofmutationsatotherputativesitescontinuestoincreasebuttheexactnatureoftheseassociationsisnotknown.Studiesintwinsindicatethatapproximately40%oftheriskoftype1DMisgenetic.etiologyoftype1DM內分泌的分子生物學finalEnvironmentalfactors（環境因素）Viruses.EvidenceforaviraletiologyofDMinhumansiscircumstantialthoughinanimalstudiestheevidenceisgood.Virusesimplicatedincluderubella(congenital),mumps,cytomegalovirusandCoxsackieB.Dietaryagents.Controversially,thoseimplicatedincludecow'smilk(containingbovineserumalbumin),preservedmeats(containingnit