内分泌的分子生物学final

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1、内分泌及代谢疾病内分泌及代谢疾病 内分泌系统内分泌系统内分泌腺内分泌腺脏器内分泌组织脏器内分泌组织激素激素体液调节系统（包括旁分泌、自分泌）体液调节系统（包括旁分泌、自分泌）代谢过程代谢过程脏器功能脏器功能生长发育生长发育生殖衰老生殖衰老Endocrine System内分泌学发展三阶段内分泌学发展三阶段n腺体内分泌学腺体内分泌学 Organic Endocrinologyn组织内分泌学组织内分泌学 Histological Endocrinologyn分子内分泌学分子内分泌学 Moleculer Endocrinology细胞信息传递方式细胞信息传递方式 通过相邻细胞的直接接触通过相邻细胞的

2、直接接触 通过细胞分泌各种通过细胞分泌各种化学物质化学物质来调节其来调节其他细胞的代谢和功能他细胞的代谢和功能信息物质信息物质(signal molecules)(signal molecules)跨膜信号转导的一般步骤跨膜信号转导的一般步骤特定的细胞释放信息物质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靶细胞产生生物学效应（一）神经递质（一）神经递质 又称突触分泌信号又称突触分泌信号(synaptic si

3、gnal)根据细胞分泌信息物质的方式，将细胞间信息物质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：分为四类：（二）（二）内分泌激素内分泌激素 又称内分泌信号又称内分泌信号(endocrine signal)（三）局部化学介质（三）局部化学介质 又称又称旁分泌信号旁分泌信号(paracrine signal （四）气体信号（四）气体信号(Gas signal)激素的种类激素的种类Hormones 肽类肽类/蛋白类激素蛋白类激素（Protein or peptide):ACTH,LH,FSH,PHT,TSH,Insulin,Glucagon,IGFs氨基酸衍生物（氨基酸衍生物（Amino

4、 Acid derivatives)：儿茶酚胺类（肾上腺素、去甲肾上腺素）儿茶酚胺类（肾上腺素、去甲肾上腺素）脂肪酸衍生物脂肪酸衍生物(Fatty acid derivatives):前列腺素类、视黄酸前列腺素类、视黄酸 胆固醇衍生物（胆固醇衍生物（Cholesterol derivatives)：考的松，考的松，醛固酮、醛固酮、1,25(OH)2 D3性激素性激素激素的作用机制激素的作用机制n 与膜受体结合与膜受体结合 G蛋白偶联蛋白偶联 发挥生物效应发挥生物效应 （肽类激素、生物胺、前列腺素）n 与膜受体结合与膜受体结合 受体自身磷酸化受体自身磷酸化 发挥生物学效应发挥生物学效应 （酪氨酸

5、激酶）（生长因子家族、Insulin,IGFs)n与核受体结合与核受体结合 与与DNA特异序列结合特异序列结合 功能蛋白转录功能蛋白转录 （甾体类激素）激素是第一信使激素的作用机制激素的作用机制激素信息在细胞内的信号传导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发现了磷酸化酶的可逆磷酸化 （无活性的磷酸化酶（无活性的磷酸化酶b/有活性的磷酸化酶有活性的磷酸化酶a之间的互变）之间的互变）获得获得1951年诺贝尔奖。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）合成与分解的

6、两个关键酶）提出了激素作用的第二信使学说提出了激素作用的第二信使学说 获得获得1971年诺贝尔生理医学奖。年诺贝尔生理医学奖。Krebs&Fisher:于于60年代末发现蛋白激酶年代末发现蛋白激酶A(PKA)（依赖（依赖cAMP,刺激多种底物蛋白磷酸化刺激多种底物蛋白磷酸化)阐明了阐明了PKA启动的磷酸化和去磷酸化途径。启动的磷酸化和去磷酸化途径。获得获得1992年诺贝尔生理医学奖。年诺贝尔生理医学奖。cAMPcAMP-蛋白激酶途径蛋白激酶途径ATPATPcAMPcAMP蛋白激酶蛋白激酶A A蛋白质或蛋白质或酶磷酸化酶磷酸化酶活性改变酶活性改变 基因转录加快基因转录加快 蛋白质合成加速蛋白质合

7、成加速生物效应生物效应AMPAMP磷酸二酯酶磷酸二酯酶R RG GACAC 使有关蛋白或酶使有关蛋白或酶类的类的丝丝氨酸氨酸、苏氨、苏氨酸酸残基磷酸化残基磷酸化NOCOGCPKGGCG蛋白蛋白GTPcGMP：激素（心钠素）：激素（心钠素）R胞胞 膜膜 cGMP-蛋白激酶蛋白激酶G（PKG）途径）途径主要生理效应：主要生理效应：血管平滑肌松弛血管平滑肌松弛增加尿钠，促进钠的排出增加尿钠，促进钠的排出降低血压降低血压受体型受体型TPK：非受体型非受体型TPK类固醇激素与甲状腺素通过胞内类固醇激素与甲状腺素通过胞内受体调节生理过程受体调节生理过程HormoneHalf-lifeAmines2-3 m

8、inThyroid hormones:T4 T36.7 days0.75 daysPolypeptides4-40 minProteins15-170 minSteroids4-120 minType I DiabetesCongenital Adrenal Hyperplasia先天性肾上腺增生(症)Congenital Adrenal Hyperplasia先天性肾上腺增生先天性肾上腺增生(症症)21-羟化酶缺乏羟化酶缺乏 21-羟化酶缺乏对胆固醇的代谢发生哪些变化？羟化酶缺乏对胆固醇的代谢发生哪些变化？雄激素不敏感综合征（睾丸女性化综合征）雄激素不敏感综合征（睾丸女性化综合征）（Test

9、icular Feminization Syndrome）库兴(氏)综合征（Cushings Syndrome）合成代谢类激素Type II diabetes糖尿病的分子机制糖尿病的分子机制Molecular mechanism of Diabetes mellitus(DM)Definition:DM is a group of metabolic diseases characterized by abnormally high levels of sugar(glucose)in the blood resulting from defects in insulin secretion,

10、insulin action or both.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。1.History of Diabetes（糖尿病的历史）（糖尿病的历史）医生发现糖尿病的症状已有几千年的历史医生发现糖尿病的症状已有几千年的历史 Physicians have observed the effects of diabetes for thousands of years.For much of this time,little was known about this fatal disease that caused wasting

11、away of the body（消瘦）,extreme thirst（口渴）,and frequent urination（尿频）.n糖尿病的一种明显的表现是葡萄糖尿，是糖尿病的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一个诊断指标 One of the effects of diabetes is the presence of glucose in the urine(glucosuria).Ancient Hindu writings,many thousands of years old,document how black ants and flies were at

12、tracted to the urine of diabetics.The Indian physician Sushruta in 400 B.C.described the sweet taste of urine from affected individuals,and for many centuries to come,the sweet taste of urine was key to diagnosis.公元250年左右，第一次使用“diabetes”描述糖尿病 Around 250 B.C.,the name“diabetes”was first used.It is a

13、Greek word that means“to syphon（虹吸）”,reflecting how diabetes seemed to rapidly drain fluid from the affected individual.完整的“diabetes mellitus”在1674年确定。The complete term“diabetes mellitus”was coined in 1674 by Thomas Willis。Mellitus is Latin for honey,which is how Willis described the urine of diabet

14、ics(“as if imbued with honey and sugar”).糖尿病之谜的一个突破是出现在1889年。德国医生Joseph von Mering 和Oskar Minkowski手术切除狗的胰腺后，狗立即出现糖尿病。A breakthrough in the puzzle of diabetes came in 1889.German physicians Joseph von Mering and Oskar Minkowski surgically removed the pancreas from dogs.The dogs immediately developed

15、 diabetes.Now that a link was established between the pancreas gland and diabetes,research focused on isolating the pancreatic extract that could treat diabetes.Many great physiologists had tried and failed to isolate an internal secretion from the pancreas.Dr.Frederick Banting took up the challenge

16、 of isolating a pancreatic extract,he was met with much skepticism.Banting,a surgeon,persisted and in May 1921,he began work in the laboratory of Professor John Macloed in Toronto,Canada.Charles Best,a medical student at the time,worked as his assistant.1921年，用胰腺提取物成功降低切除胰腺的狗的血糖。In July 1921,a dog t

17、hat had had its pancreassurgically removed was injected with an extract collected from a duct-tied dog.In the two hoursthat followed the injection,the blood sugar level of the dog fell,and its condition improved.Dr.J.Collip，生物化学学家，生物化学学家，继续改善胰腺提取物的纯度，继续改善胰腺提取物的纯度，随后，随后，Best进行提取工作。进行提取工作。Dr.J.Collip,

18、a biochemist,was drafted to continue improving the purity of the pancreas extract,and later,Best carried on this work.n到1922年，成功应用胰岛素治疗第一例糖尿病病人。It wasnt until 1922 that the first patient was successfully treated with insulin.Four scientists contributed to the discovery of insulinJ.CollipJohn Macloed

19、Charles BestFrederick BantingIn 1923,Banting and Macloed were awarded the Nobel Prize for the discovery of insulin.BantingMacloedwww.nobel.se/medicine/laureates/1923/index.htmCinema:“Glory enough for all”（共同的荣誉）（共同的荣誉）光荣岁月光荣岁月 葡萄糖的代谢概况葡萄糖的代谢概况（Overview of Glucose Metabolism）Glucose is an essential f

20、uel for the body.The amount of glucose in the bloodstream is regulated by many hormones,the most important being insulin.血糖受很多激素调节，其中最重要的是胰岛素。其中最重要的是胰岛素。Insulin is released when glucose is abundant and stimulates the following（胰岛素的作用）促进:muscle and fat cells to remove glucose from the blood（肌肉细胞核脂肪细胞

21、从血液中摄取葡萄糖 cells to breakdown glucose,releasing its energy in the form of ATP(via glycolysis and the citric acid cycle)（分解葡萄糖和提供能量）the liver and muscle to store glucose as glycogen(short-term energy reserve)（肝和肌肉细胞合成糖原）adipose tissue to store glucose as fat(long-term energy reserve)（葡萄糖转变为脂肪）cells to

22、 use glucose in protein synthesis（在蛋白质的合成过程中利用葡萄糖）胰岛素的作用胰岛素的作用 When the amount of glucose in the blood increases,e.g.,after a meal,it triggers the release of the hormone insulin from the pancreas.Insulin stimulates muscle and fat cells to remove glucose from the blood and stimulates the liver to met

23、abolize glucose,causing the blood sugar level to decrease to normal levels Glucagon（胰高血糖素）（胰高血糖素）is the main hormone opposing the action of insulin and is released when food is scarce Changes in blood levels of glucose,insulin,and glucagon after a carbohyrate-rich meal(ingested at time 0 minutes).Th

24、e Story of InsulinInsulin Synthesis（胰岛素的合成）（胰岛素的合成）Insulin Structure（胰岛素的结构）（胰岛素的结构）Insulin secretion（胰岛素的分泌）（胰岛素的分泌）Insulin Receptor（胰岛素受体）（胰岛素受体）Insulin Action（胰岛素的作用）（胰岛素的作用）Insulin SynthesisInsulin StructureIn 1958,Frederick Sanger was awarded his first Nobel Prize in Chemistry for determining t

25、he sequence of the amino acids that make up insulin.This marked the first time that a protein had had the order of its amino acids(the primary sequence)determined.http:/ is composed of two chains of amino acids named chain A(21 amino acids)and chain B(30 amino acids)that are linked together by two d

26、isulfide bridges.There is a 3rd disulfide bridge within the A chain that links the 6th and 11th residues of the A chain togetherInsulin secretionRising levels of glucose inside the pancreatic cells trigger the release of insulin胰腺胰腺 细胞内葡萄糖水平的升高触发胰岛素释放细胞内葡萄糖水平的升高触发胰岛素释放1.Glucose is transported into t

27、he beta cell by type 2 glucose transporters(GLUT2).Once inside,the first step in glucose metabolism is the phosphorylation of glucose to produce glucose-6-phosphate.This step is catalyzed by glucokinase-it is the rate-limiting step in glycolysis.葡萄糖葡萄糖6-磷酸葡萄糖磷酸葡萄糖葡萄糖激酶葡萄糖激酶2.As glucose metabolism pr

28、oceeds,ATP is produced in the mitochondria.葡萄糖代谢过程中葡萄糖代谢过程中,线粒体产生线粒体产生ATPATP3.The increase in the ATP:ADP ratio closes ATP-gated potassium channels in the beta cell membrane.Positively charged potassium ions(K+)are now prevented from leaving the beta cell.细胞内细胞内ATP:ADP比例增加，关闭比例增加，关闭 细胞细胞ATP-钾通道，防止带钾

29、通道，防止带正电的钾离子离开正电的钾离子离开 细胞细胞4.The rise in positive charge inside the beta cell causes depolarization.细胞内正电荷的增加引起细胞去极化细胞内正电荷的增加引起细胞去极化5.Voltage-gated calcium channels open,allowing calcium ions(Ca2+)to flood into the cell.钙离子通道开放，使细胞外的钙离子进入细胞内钙离子通道开放，使细胞外的钙离子进入细胞内6.The increase in intracellular calciu

30、m concentration triggers the secretion of insulin via exocytosis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There are two phases of insulin release in response to a rise in glucose.lThe first is an immediate release of insulin.This is attributable to the release of preformed insulin,which is

31、 stored in secretory granules.l After a short delay,there is a second,more prolonged release of newly synthesized insulin.胰岛素对葡萄糖反应的的释放有两个阶段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，持续时间较长第二阶段：释放新合成的胰岛素，持续时间较长Glucose 1GLUT2ATPMETABOLISM2Ca2+IMMEDIATE SECRETIONCalmodu

32、lin INSULIN BIOSYNTHESIS AND PROCESSING5 Protein kinase CCa2+3 CaM-kinase4 DAGSecreted insulin+C-peptideControl of insulin synthesis and secretion by glucose.CaM kinase:calmodulin-dependent protein kinase;DAG:diacylglycerol6Insulinase found in the liver and kidneys breaks down insulin circulating in

33、 the plasmaInsulin has a half-life of only about 6 minutes.胰岛素在肝脏和肾脏降解。肝脏和肾脏的胰岛素酶分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解血浆中的胰岛素胰岛素的半衰期约胰岛素的半衰期约6分钟分钟 Insulin Receptor（胰岛素受体）（胰岛素受体）the receptor for insulin is embedded in the plasma membrane and is composed of a pair of alpha subunits and a pair of beta subu

34、nits。胰岛素受体是跨膜受体，由两个亚基和两个亚基组成。lTwo and two subunits lReceptor tyrosine kinaselHormone binding site on subunit，subunit-tyrosine kinase activityl Localized to 19th chromosome inHumansThe insulin receptor.Insulin binding to the -chains transmits a signal through the transmembrane domain of the -chains t

35、o activate the tyrosine kinase activity CYTOPLASMEXTRACELLULARNH3+SSSSInsulin-OOC-S-S-+3HNCOO-subunits-subunitsTransmembranedomainTyrosinekinasedomain+3HNNH3+-OOCCOO-PlasmamembraneSSSSExtracellularCytoplasm1insulinbindsLR2IRTK(L)activatedOPOP3IRTK(R)phosphorylated/activatedActivation of the tyrosine

36、 kinase domains of the insulin receptor by insulin binding,followed by interchain autophosphorylation PPPPATPsADPsPhosphorylationcatalyzed by IRTK(L)PExtracellularCytoplasm1insulinbindsLR2IRTK(L)activatedOPOP3IRTK(R)phosphorylated/activatedPOPO4IRTK(L)phosphorylatedOPOPPPPPATPsADPsPhosphorylationcat

37、alyzed by IRTK(L)ATPsADPsPPPhosphorylationcatalyzed by IRTK(R)Activation of the tyrosine kinase domains of the insulin receptor by insulin binding,followed by interchain autophosphorylation Insulin Signal Transductionq several targets are phosphorylated by IRTKq IRS activation is tied to metabolic r

38、esponsesv glucose transport(muscle and fat cells)v activation of protein phosphataseq protein phosphatase removes phosphates from proteins phosphorylated by protein kinase A counter-regulation of glucagonInsulin Action（胰岛素的作用）（胰岛素的作用）Insulin promotes the uptake of glucose into many tissues that expr

39、ess GLUT4 glucose transporters,such as skeletal muscle and fat.Insulin increases the activity of these transporters and increases their numbers by stimulating their recruitment from an intracellular pool to the cell surface.Extracellular spaceCytoplasm tyr-OHIRS4 signals Golgi to traffic GLUT-4 tome

40、mbranePKBGOLGI=GLUT-4Active IRTKPOPOOPOP1 IRTKcatalyzed tyr-OPIRSATP ADPactiveIRS tyr-OPIRSPI-3Kp852 activated by dockingactive IRSHypothetical mechanism for insulin to mobilize GLUT-4 transporter to the plasma membrane in muscle and adipose tissue.IRS,insulin-receptor substrate;IRTK,insulin recepto

41、r tyrosine kinase;PI-3K,phosphatidyl-inositol kinase;PDK;phospholipid-dependent kinasePKB,protein kinase B tyr-OPIRS tyr-OPIRS tyr-OPIRSPIP2PIP3PDK+Insulin stimulated glucose transport(GLUT-4)in adipose or muscle cells Golgi glucose transporter Step1-insulin binding and signal transduction(signal)-P

42、 P-Step 2 translocationFrom Golgi Step 3Binding and fusion Step 4Glucosetransport Step 5Receptor inactivationStep 6translocation back to Golgi GlucoseDiagnostic criteria World Health Organization(1980)1.Symptoms of diabetes plus a plasma glucose concentration 11.1 mmol/l obtained at any time of day

43、and without regard to meals,OR2.Fasting plasma glucose 7.8 mmol/l,OR3.A plasma glucose concentration 11.1 mmol/l 2 h after 75 g of oral glucose糖尿病的诊断糖尿病的诊断Classification Diabetes is classified by underlying cause.The categories are:Type 1 diabetesan autoimmune disease in which the bodys own immune s

44、ystem attacks the pancreas,rendering it unable to produce insulin;Type 2 diabetesin which a resistance to the effects of insulin or a defect in insulin secretion may be seen;Gestational diabetes InsulinresistanceGenetic susceptibility,obesity,Western lifestyleType 2 diabetesIR-celldysfunction Abnorm

45、alglucose toleranceHyperinsulinemia,then -cell failureNormal IGT*Type 2 diabetes Post-prandial glucoseInsulin resistanceIncreased insulinresistanceFasting glucoseHyperglycemiaInsulinsecretion*IGT=impaired glucose toleranceInsulin resistant;low insulin secretion(54%)Insulin resistant;good insulin sec

46、retion(29%)Insulin sensitive;good insulin secretion(1%)Insulin sensitive;low insulin secretion(16%)83%Haffner SM,et al.Circulation 2000;101:975980.Insulinresistance Glucose output Glucose uptake Glucose uptakeHyperglycemiaLiverMuscleAdiposetissueIRIn USA:16 million people suffer from DM.Type 1 diabe

47、tes accounts for 5-10%of cases,affecting 1 of 400 children and adolescents.Type 2 diabetes is extremely common,accounting for 90-95%of all cases of diabetes.This form of diabetes can go undiagnosed for many years,but the number of cases that are being diagnosed is rising rapidly,leading to reports o

48、f a diabetes epidemic.Epidemiology 2003年全球糖尿病病人已超过年全球糖尿病病人已超过1.94亿，预计到本世纪亿，预计到本世纪2025年这个数字将增加近一倍（年这个数字将增加近一倍（3.33亿）亿）我国糖尿病病人数约我国糖尿病病人数约4000万，占全球糖尿病病人的万，占全球糖尿病病人的1/5.型糖尿病占型糖尿病占5.6，型糖尿病占，型糖尿病占93.7，其它类型糖尿病，其它类型糖尿病仅占仅占0.7。Genetic associations（遗传关联）（遗传关联）The clearest association is with class II human le

49、ucocyte antigens(HLA)coded on the short arm of chromosome 6.This locus has been termed IDDM1.The region around the gene coding for insulin is termed IDDM2 and there are associations with loci on chromosomes 15q(IDDM3),11q(IDDM4)and 6q(IDDM5).The number of mutations at other putative sites continues

50、to increase but the exact nature of these associations is not known.Studies in twins indicate that approximately 40%of the risk of type 1 DM is genetic.etiology of type 1 DMEnvironmental factors（环境因素）（环境因素）Viruses.Evidence for a viral etiology of DM in humans is circumstantial though in animal studi

51、es the evidence is good.Viruses implicated include rubella(congenital),mumps,cytomegalovirus and Coxsackie B.Dietary agents.Controversially,those implicated include cows milk(containing bovine serum albumin),preserved meats(containing nitrosamines)and coffee.etiology of type 1 DMImmune markers（免疫标记）

52、（免疫标记）Type 1 DM is characterized by the presence of T lymphocytes within the pancreatic islets that may play a key role in islet destruction.Patients with type 1 DM have circulating antibodies against the islets.Antibodies against the insulin molecule,the enzyme gamma-amino butyric acid decarboxylas

53、e(GAD)or the tyrosine kinase IA-2 have been well characterized.etiology of type 1 DMGenetic associations（遗传关联）（遗传关联）Studies in twins indicate that approximately 30-90%of the risk of type 2 diabetes is genetic.Prevalence of type 2 DM is very high in certain ethnic groups including Pima Indians in Ari

54、zona,Naruans in Polynesia,and Indian sub-continent Asians in the UK.The etiology of type 2 diabetes mellitusEnvironmental factors（环境因素）（环境因素）Obesity(especially central),aging,physical inactivity.These increase insulin resistance.Poor fetal development（胎儿发育不良）.This(the thrifty phenotype hypothesis)is

55、 thought to lead to metabolic sequelae predisposing to type 2 diabetesHypertension,lipoprotein abnormalities and coronary disease in later life.The etiology of type 2 diabetes mellitusDiabeticretinopathyLeading causeof blindnessin working-ageadultsDiabeticnephropathyLeading cause of end-stage renal

56、diseaseCardiovasculardiseaseStroke1.2-to 1.8-fold increase in strokeDiabeticneuropathyLeading cause of non-traumatic lower extremity amputations75%diabetic patients die from CV events(并发症）并发症）.Complications of DM动脉粥样硬化动脉粥样硬化0.60.81.01.21.41.61.8Odds ratio for incident CVDAgeSmokingTotal cholesterol:HDL cholesterolInsulinresistanceComplications of DMMacrosomic baby Complications of DM