内分泌及代谢疾病课件

内分泌的分子生物学final内分泌及代谢疾病内分泌的分子生物学final

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内分泌的分子生物学final内分泌的分子生物学final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内分泌的分子生物学final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内分泌的分子生物学final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:心脏内分泌的分子生物学final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、凋亡等内分泌的分子生物学final内分泌的分子生物学final细胞信息传递方式①通过相邻细胞的直接接触②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)内分泌的分子生物学final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内分泌的分子生物学final（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)内分泌的分子生物学final激素的分泌方式内分泌旁分泌自分泌内分泌的分子生物学final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性激素内分泌的分子生物学final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）激素是第一信使内分泌的分子生物学final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。Krebs&Fisher:于60年代末发现蛋白激酶A(PKA)

（依赖cAMP,刺激多种底物蛋白磷酸化)

阐明了PKA启动的磷酸化和去磷酸化途径。

获得1992年诺贝尔生理医学奖。

cAMP-蛋白激酶途径ATPcAMP蛋白激酶A蛋白质或酶磷酸化酶活性改变基因转录加快蛋白质合成加速生物效应AMP磷酸二酯酶RGAC内分泌的分子生物学final

使有关蛋白或酶类的丝氨酸、苏氨酸残基磷酸化NOCOGCPKGGCG蛋白GTPcGMP：激素（心钠素）R胞膜cGMP-蛋白激酶G（PKG）途径主要生理效应：血管平滑肌松弛增加尿钠，促进钠的排出降低血压内分泌的分子生物学final受体型TPK：非受体型TPK内分泌的分子生物学final类固醇激素与甲状腺素通过胞内受体调节生理过程内分泌的分子生物学finalMCR（代谢清除率）ofsomehormonesHormoneHalf-lifeAmines2-3minThyroidhormones:T4T36.7days0.75daysPolypeptides4-40minProteins15-170minSteroids4-120min内分泌的分子生物学final内分泌疾病的机制

Mechanismsofendocrinedisease由激素缺乏、过量或抵抗引起的内分泌疾病Endocrinedisordersresultfromhormonedeficiency,hormoneexcessorhormoneresistance

内分泌的分子生物学final由于感染、坏死、肿瘤的物理性压缩以及自身免疫性疾病导致的分泌腺破坏引起的激素缺乏

Deficiency

usuallyisduetodestructiveprocessoccurringatglandinwhichhormoneisproduced—infection,infarction,physicalcompressionbytumorgrowth,autoimmuneattackTypeIDiabetes内分泌疾病的机制

Mechanismsofendocrinedisease内分泌的分子生物学final由于遗传缺陷（激素基因缺失或突变），导致激素前体的断裂、特异性酶缺乏（甾体类激素或甲状腺素），引起激素合成减少

Deficiencycanalsoarisefromgeneticdefectsinhormoneproduction—genedeletionormutation,failuretocleaveprecursor,specificenzymaticdefect(steroidorthyroidhormones)CongenitalAdrenalHyperplasia先天性肾上腺增生(症)内分泌疾病的机制

Mechanismsofendocrinedisease内分泌的分子生物学finalCongenitalAdrenalHyperplasia先天性肾上腺增生(症)

21-羟化酶缺乏21-羟化酶缺乏对胆固醇的代谢发生哪些变化？内分泌的分子生物学final受体的灭活性突变导致激素缺乏

Inactivatingmutationsofreceptorscancausehormonedeficiency雄激素不敏感综合征（睾丸女性化综合征）（TesticularFeminizationSyndrome）内分泌疾病的机制

Mechanismsofendocrinedisease内分泌的分子生物学final由于疾病引起的激素分泌过多

Hormoneexcessusuallyresultsindisease腺体分泌过量或非内分泌组织的分泌导致激素生成过量

Hormonemaybeoverproducedbyglandthatnormallysecretesit,orbyatissuethatisnotanendocrineorgan.内分泌腺肿瘤引起激素分泌过量

Endocrineglandtumorsproducehormoneinanunregulatedmanner.库兴(氏)综合征（Cushing’sSyndrome）内分泌疾病的机制

Mechanismsofendocrinedisease内分泌的分子生物学final使用外源性激素导致体内激素过量。如糖皮质激素或合成代谢类激素

Exogenousingestionofhormoneisthecauseofhormoneexcess—forexample,glucocorticoidexcessoranabolicsteroidabuse

内分泌疾病的机制

Mechanismsofendocrinedisease内分泌的分子生物学final受体数量和功能的异常引起内分泌异常

Alterationsinreceptornumberandfunctionresultinendocrinedisorders比较常见的是激素水平的异常增高引起可利用受体的数量减少

Mostcommonly,anaberrantincreaseinthelevelofaspecifichormonewillcauseadecreaseinavailablereceptorsTypeIIdiabetes内分泌疾病的机制

Mechanismsofendocrinedisease内分泌的分子生物学final糖尿病的分子机制MolecularmechanismofDiabetesmellitus(DM)内分泌的分子生物学finalDefinition:DMisagroupofmetabolicdiseasescharacterizedbyabnormallyhighlevelsofsugar(glucose)inthebloodresultingfromdefectsininsulinsecretion,insulinactionorboth.定义：糖尿病是一组由于胰岛素不足或／和胰岛素作用缺陷（抵抗）而导致以血糖增高为特征的代谢性疾病。内分泌的分子生物学final1.HistoryofDiabetes（糖尿病的历史）

医生发现糖尿病的症状已有几千年的历史

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

内分泌的分子生物学final糖尿病的一种明显的表现是葡萄糖尿，是糖尿病的一个诊断指标

Oneoftheeffectsofdiabetesisthepresenceofglucoseintheurine(glucosuria).AncientHinduwritings,manythousandsofyearsold,documenthowblackantsandflies

wereattractedtotheurineofdiabetics.TheIndianphysicianSushrutain400B.C.describedthesweettasteofurinefromaffectedindividuals,andformanycenturiestocome,thesweettasteofurinewaskeytodiagnosis.内分泌的分子生物学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年确定。

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

糖尿病之谜的一个突破是出现在1889年。德国医生JosephvonMering和OskarMinkowski手术切除狗的胰腺后，狗立即出现糖尿病。

Abreakthroughinthepuzzleofdiabetescamein1889.GermanphysiciansJosephvonMeringandOskarMinkowskisurgicallyremovedthepancreasfromdogs.Thedogsimmediatelydevelopeddiabetes.Nowthatalinkwasestablishedbetweenthepancreasglandanddiabetes,

researchfocusedonisolatingthepancreaticextractthatcouldtreatdiabetes.内分泌的分子生物学finalManygreatphysiologistshadtriedandfailedtoisolateaninternalsecretionfromthepancreas.Dr.FrederickBantingtookupthechallengeofisolatingapancreaticextract,hewasmetwithmuchskepticism.

内分泌的分子生物学finalBanting,asurgeon,persistedandinMay1921,hebeganworkinthelaboratoryofProfessorJohnMacloedinToronto,Canada.CharlesBest,amedicalstudentatthetime,workedashisassistant.内分泌的分子生物学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.内分泌的分子生物学finalDr.J.Collip，生物化学学家，继续改善胰腺提取物的纯度，随后，Best进行提取工作。Dr.J.Collip,abiochemist,wasdraftedtocontinueimprovingthepurityofthepancreasextract,andlater,Bestcarriedonthiswork.内分泌的分子生物学final到1922年，成功应用胰岛素治疗第一例糖尿病病人。

Itwasn'tuntil1922thatthefirstpatientwassuccessfullytreatedwithinsulin.内分泌的分子生物学finalFourscientistscontributedtothediscoveryofinsulinJ.CollipJohnMacloedCharlesBestFrederickBanting内分泌的分子生物学finalIn1923,BantingandMacloedwereawardedtheNobelPrizeforthediscoveryofinsulin.BantingMacloed内分泌的分子生物学finalCinema:“Gloryenoughforall”（共同的荣誉）光荣岁月

内分泌的分子生物学final葡萄糖的代谢概况（OverviewofGlucoseMetabolism）

Glucoseisanessentialfuelforthebody.Theamountofglucoseinthebloodstreamisregulatedbymanyhormones,themostimportantbeinginsulin.血糖受很多激素调节，其中最重要的是胰岛素。

内分泌的分子生物学final内分泌的分子生物学finalInsulinisreleasedwhenglucoseisabundantandstimulatesthefollowing（胰岛素的作用）促进:•muscleandfatcellstoremoveglucosefromtheblood（肌肉细胞核脂肪细胞从血液中摄取葡萄糖•cellstobreakdownglucose,releasingitsenergyintheformofATP(viaglycolysisandthecitricacidcycle)（分解葡萄糖和提供能量）内分泌的分子生物学final•

theliverandmuscletostoreglucoseasglycogen(short-termenergyreserve)（肝和肌肉细胞合成糖原）•

adiposetissuetostoreglucoseasfat(long-termenergyreserve)（葡萄糖转变为脂肪）•

cellstouseglucoseinproteinsynthesis（在蛋白质的合成过程中利用葡萄糖）胰岛素的作用内分泌的分子生物学finalWhentheamountofglucoseinthebloodincreases,e.g.,afterameal,ittriggersthereleaseofthehormoneinsulinfromthepancreas.Insulinstimulatesmuscleandfatcellstoremoveglucosefromthebloodandstimulatesthelivertometabolizeglucose,causingthebloodsugarleveltodecreasetonormallevels内分泌的分子生物学final

Glucagon（胰高血糖素）

isthemainhormoneopposingtheactionofinsulinandisreleasedwhenfoodisscarce内分泌的分子生物学finalChangesinbloodlevelsofglucose,insulin,andglucagonafteracarbohyrate-richmeal(ingestedattime0minutes).内分泌的分子生物学finalTheStoryofInsulinInsulinSynthesis（胰岛素的合成）InsulinStructure（胰岛素的结构）Insulinsecretion（胰岛素的分泌）InsulinReceptor（胰岛素受体）InsulinAction（胰岛素的作用）内分泌的分子生物学finalInsulinSynthesis内分泌的分子生物学finalInsulinStructureIn1958,FrederickSangerwasawardedhisfirstNobelPrizeinChemistryfordeterminingthesequenceoftheaminoacidsthatmakeupinsulin.Thismarkedthefirsttimethataproteinhadhadtheorderofitsaminoacids(theprimarysequence)determined.InsuliniscomposedoftwochainsofaminoacidsnamedchainA(21aminoacids)andchainB(30aminoacids)thatarelinkedtogetherbytwodisulfidebridges.Thereisa3rddisulfidebridgewithintheAchainthatlinksthe6thand11thresiduesoftheAchaintogether内分泌的分子生物学finalInsulinsecretionRisinglevelsofglucoseinsidethepancreaticcellstriggerthereleaseofinsulin胰腺细胞内葡萄糖水平的升高触发胰岛素释放内分泌的分子生物学final1.Glucoseistransportedintothebetacellbytype2glucosetransporters(GLUT2).Onceinside,thefirststepinglucosemetabolismisthephosphorylationofglucosetoproduceglucose-6-phosphate.Thisstepiscatalyzedbyglucokinase--itistherate-limitingstepinglycolysis.葡萄糖6-磷酸葡萄糖葡萄糖激酶内分泌的分子生物学final2.Asglucosemetabolismproceeds,ATPisproducedinthemitochondria.葡萄糖代谢过程中,线粒体产生ATP内分泌的分子生物学final3.TheincreaseintheATP:ADPratioclosesATP-gatedpotassiumchannelsinthebetacellmembrane.Positivelychargedpotassiumions(K+)arenowpreventedfromleavingthebetacell.细胞内ATP:ADP比例增加，关闭细胞ATP-钾通道，防止带正电的钾离子离开细胞内分泌的分子生物学final4.Theriseinpositivechargeinsidethebetacellcausesdepolarization.

细胞内正电荷的增加引起细胞去极化内分泌的分子生物学final5.Voltage-gatedcalciumchannelsopen,allowingcalciumions(Ca2+)tofloodintothecell.钙离子通道开放，使细胞外的钙离子进入细胞内内分泌的分子生物学final6.Theincreaseinintracellularcalciumconcentrationtriggersthesecretionofinsulinviaexocytosis细胞内钙离子的增加触发胰岛素通过胞吐作用分泌到细胞外内分泌的分子生物学finalTherearetwophasesofinsulinreleaseinresponsetoariseinglucose.Thefirstisanimmediatereleaseofinsulin.Thisisattributabletothereleaseofpreformedinsulin,whichisstoredinsecretorygranules.Afterashortdelay,thereisasecond,moreprolongedreleaseofnewlysynthesizedinsulin.胰岛素对葡萄糖反应的的释放有两个阶段第一阶段：立即释放储存在分泌颗粒中的胰岛素第二阶段：释放新合成的胰岛素，持续时间较长Glucose1GLUT2ATPMETABOLISM2Ca2+

IMMEDIATESECRETIONCalmodulin

INSULINBIOSYNTHESISANDPROCESSING5

ProteinkinaseCCa2+3

CaM-kinase4

DAGSecretedinsulin+C-peptideControlofinsulinsynthesisandsecretionbyglucose.CaMkinase:calmodulin-dependentproteinkinase;DAG:diacylglycerol6内分泌的分子生物学finalInsulinasefoundintheliverandkidneysbreaksdowninsulincirculatingintheplasmaInsulinhasahalf-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分钟内分泌的分子生物学finalInsulinReceptor（胰岛素受体）内分泌的分子生物学finalthereceptorforinsulinisembeddedintheplasmamembraneandiscomposedofapairofalphasubunitsandapairofbetasubunits。胰岛素受体是跨膜受体，由两个亚基和两个亚基组成。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内分泌的分子生物学finalInsulinSignalTransductionseveraltargetsarephosphorylatedbyIRTKIRSactivationistiedtometabolicresponsesglucosetransport(muscleandfatcells)activationofproteinphosphataseproteinphosphataseremovesphosphatesfromproteinsphosphorylatedbyproteinkinaseA–counter-regulationofglucagon内分泌的分子生物学finalInsulinAction（胰岛素的作用）InsulinpromotestheuptakeofglucoseintomanytissuesthatexpressGLUT4glucosetransporters,suchasskeletalmuscleandfat.Insulinincreasestheactivityofthesetransportersandincreasestheirnumbersbystimulatingtheirrecruitmentfromanintracellularpooltothecellsurface.内分泌的分子生物学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内分泌的分子生物学finalDiagnosticcriteria

WorldHealthOrganization(1980)

1.Symptomsofdiabetesplusaplasmaglucoseconcentration>11.1mmol/lobtainedatanytimeofdayandwithoutregardtomeals,OR

2.Fastingplasmaglucose>7.8mmol/l,OR

3.Aplasmaglucoseconcentration>11.1mmol/l2hafter75goforalglucose糖尿病的诊断内分泌的分子生物学finalClassificationDiabetesisclassifiedbyunderlyingcause.Thecategoriesare:Type1diabetes—anautoimmunediseaseinwhichthebody'sownimmunesystemattacksthepancreas,renderingitunabletoproduceinsulin;Type2diabetes—inwhicharesistancetotheeffectsofinsulinoradefectininsulinsecretionmaybeseen;Gestationaldiabetes内分泌的分子生物学final内分泌的分子生物学finalMajordefectinindividualswithtype2diabetesReducedbiologicalresponsetoinsulinStrongpredictoroftype2diabetesCloselyassociatedwithobesityWhatisinsulinresistance?内分泌的分子生物学finalWhatis-celldysfunction?Majordefectinindividualswithtype2diabetesReducedabilityof

-cellstosecreteinsulininresponsetohyperglycemia

内分泌的分子生物学finalInsulinresistanceand

-celldysfunctionarecoredefectsoftype2diabetesInsulinresistanceGeneticsusceptibility,obesity,WesternlifestyleType2diabetesIRb-celldysfunction

内分泌的分子生物学finalHowdoinsulinresistanceand

-celldysfunctioncombinetocausetype2diabetes?AbnormalglucosetoleranceHyperinsulinemia,then

-cellfailureNormal IGT* Type2diabetesPost-prandialglucoseInsulinresistanceIncreasedinsulin

resistanceFastingglucoseHyperglycemiaInsulinsecretion*IGT=impairedglucosetolerance内分泌的分子生物学finalMorethan80%ofpatientsprogressingtotype2diabetesareinsulinresistantInsulinresistant;

lowinsulinsecretion(54%)Insulinresistant;

goodinsulinsecretion(29%)Insulinsensitive;

goodinsulinsecretion(1%)Insulinsensitive;

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

Glucose

output

Glucoseuptake

Glucose

uptakeHyperglycemiaLiverMuscleAdipose

tissueIR内分泌的分子生物学finalInUSA:16millionpeoplesufferfromDM.Type1diabetesaccountsfor5-10%ofcases,affecting1of400childrenandadolescents.Type2diabetesisextremelycommon,accountingfor90-95%ofallcasesofdiabetes.Thisformofdiabetescangoundiagnosedformanyyears,butthenumberofcasesthatarebeingdiagnosedisrisingrapidly,leadingtoreportsofadiabetesepidemic.Epidemiology2003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1/5.１型糖尿病占5.6％，２型糖尿病占93.7％，其它类型糖尿病仅占0.7％。内分泌的分子生物学finalGeneticassociations（遗传关联）

TheclearestassociationiswithclassIIhumanleucocyteantigens(HLA)codedontheshortarmofchromosome6.ThislocushasbeentermedIDDM1.TheregionaroundthegenecodingforinsulinistermedIDDM2

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