內(nèi)分泌及代謝疾病的學(xué)習(xí)

1、內(nèi)分泌及代謝疾病的學(xué)習(xí) 內(nèi)分泌系統(tǒng)內(nèi)分泌腺臟器內(nèi)分泌組織激素體液調(diào)節(jié)系統(tǒng)（包括旁分泌、自分泌）代謝過程臟器功能Endocrine System內(nèi)分泌學(xué)發(fā)展三階段腺體內(nèi)分泌學(xué) Organic Endocrinology組織內(nèi)分泌學(xué) Histological Endocrinology分子內(nèi)分泌學(xué) Moleculer Endocrinology腺體內(nèi)分泌學(xué)觀察切除內(nèi)分泌腺前、后生理生化變化將內(nèi)分泌腺中提取的有效成分補(bǔ)充給切除了內(nèi)分泌腺的動物，觀察其恢復(fù)情況從內(nèi)分泌腺提取激素，了解其化學(xué)結(jié)構(gòu)，制備同類物與拮抗物組織內(nèi)分泌學(xué)放免的創(chuàng)建，可測量微量激素（1960年 Yalow 首次用放免法測量血漿胰島素

2、）獲1977年諾貝爾獎免疫熒光顯微技術(shù)，了解激素分布、分泌發(fā)現(xiàn)某些組織器官分泌激素:心臟分子內(nèi)分泌學(xué)激素及其受體的基因基因的表達(dá)、轉(zhuǎn)錄、翻譯及其調(diào)控基因缺失、插入基因重組技術(shù)人工合成激素激素作用機(jī)制激素與細(xì)胞代謝、增生、分化、凋亡等細(xì)胞信息傳遞方式 通過相鄰細(xì)胞的直接接觸 通過細(xì)胞分泌各種化學(xué)物質(zhì)來調(diào)節(jié)其他細(xì)胞的代謝和功能信息物質(zhì)(signal molecules)跨膜信號轉(zhuǎn)導(dǎo)的一般步驟特定的細(xì)胞釋放信息物質(zhì)信息物質(zhì)經(jīng)擴(kuò)散或血循環(huán)到達(dá)靶細(xì)胞與靶細(xì)胞的受體特異性結(jié)合受體對信號進(jìn)行轉(zhuǎn)換并啟動細(xì)胞內(nèi)信使系統(tǒng)靶細(xì)胞產(chǎn)生生物學(xué)效應(yīng)（一）神經(jīng)遞質(zhì) 又稱突觸分泌信號(synaptic signal) 根據(jù)細(xì)

3、胞分泌信息物質(zhì)的方式，將細(xì)胞間信息物質(zhì)分為四類：（二） 內(nèi)分泌激素 又稱內(nèi)分泌信號(endocrine signal)（三）局部化學(xué)介質(zhì) 又稱旁分泌信號(paracrine signal （四）氣體信號 (Gas signal)激素的分泌方式內(nèi)分泌旁分泌自分泌激素的種類Hormones 肽類/蛋白類激素 （Protein or peptide) : ACTH,LH, FSH, PHT, TSH, Insulin ,Glucagon, IGFs氨基酸衍生物（Amino Acid derivatives)： 兒茶酚胺類（腎上腺素、去甲腎上腺素）脂肪酸衍生物(Fatty acid derivativ

4、es ): 前列腺素類、視黃酸 膽固醇衍生物（Cholesterol derivatives )： 考的松， 醛固酮、1,25(OH)2 D3性激素激素的作用機(jī)制 與膜受體結(jié)合 G蛋白偶聯(lián) 發(fā)揮生物效應(yīng) （肽類激素、生物胺、前列腺素） 與膜受體結(jié)合 受體自身磷酸化 發(fā)揮生物學(xué)效應(yīng) （酪氨酸激酶） （生長因子家族、Insulin , IGFs)與核受體結(jié)合 與DNA特異序列結(jié)合 功能蛋白轉(zhuǎn)錄 （甾體類激素）激素是第一信使激素的作用機(jī)制激素信息在細(xì)胞內(nèi)的信號傳導(dǎo)Coris: 發(fā)現(xiàn)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。Sutherlan

5、d: 成功分離和確定的腺苷酸環(huán)化酶和磷酸二酯酶 （cAMP合成與分解的兩個關(guān)鍵酶） 提出了激素作用的第二信使學(xué)說 獲得1971年諾貝爾生理醫(yī)學(xué)獎。Krebs & Fisher: 于60年代末發(fā)現(xiàn)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(yī)學(xué)獎。 cAMP-蛋白激酶途徑ATPcAMP蛋白激酶A蛋白質(zhì)或酶磷酸化酶活性改變 基因轉(zhuǎn)錄加快 蛋白質(zhì)合成加速生物效應(yīng)AMP磷酸二酯酶RGAC 使有關(guān)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

6、酶G（PKG）途徑主要生理效應(yīng)：血管平滑肌松弛增加尿鈉，促進(jìn)鈉的排出降低血壓受體型TPK：非受體型TPK類固醇激素與甲狀腺素通過胞內(nèi)受體調(diào)節(jié)生理過程MCR（代謝清除率） of some hormones HormoneHalf-lifeAmines2-3 minThyroid hormones: T4 T36.7 days0.75 daysPolypeptides4-40 minProteins15-170 minSteroids4-120 min內(nèi)分泌疾病的機(jī)制 Mechanisms of endocrine disease由激素缺乏、過量或抵抗引起的內(nèi)分泌疾病Endocrine disor

7、ders result from hormone deficiency, hormone excess or hormone resistance 由于感染、壞死、腫瘤的物理性壓縮以及自身免疫性疾病導(dǎo)致的分泌腺破壞引起的激素缺乏 Deficiency usually is due to destructive process occurring at gland in which hormone is producedinfection, infarction, physical compression by tumor growth, autoimmune attackType I Diab

8、etes內(nèi)分泌疾病的機(jī)制 Mechanisms of endocrine disease由于遺傳缺陷（激素基因缺失或突變），導(dǎo)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 Deficiency can also arise from genetic defects in hormone productiongene deletion or mutation, failure to cleave precursor, specific enzymatic defect (steroid or thyroid hormones) Congenital Adrenal H

9、yperplasia先天性腎上腺增生(癥) 內(nèi)分泌疾病的機(jī)制 Mechanisms of endocrine diseaseCongenital Adrenal Hyperplasia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(fā)生哪些變化？受體的滅活性突變導(dǎo)致激素缺乏 Inactivating mutations of receptors can cause hormone deficiency雄激素不敏感綜合征（睪丸女性化綜合征）（Testicular Feminization Syndrome）內(nèi)分泌疾病的機(jī)制 Mechanisms of endocrine

10、disease由于疾病引起的激素分泌過多 Hormone excess usually results in disease 腺體分泌過量或非內(nèi)分泌組織的分泌導(dǎo)致激素生成 過量 Hormone may be overproduced by gland that normally secretes it, or by a tissue that is not an endocrine organ. 內(nèi)分泌腺腫瘤引起激素分泌過量 Endocrine gland tumors produce hormone in an unregulated manner. 庫興(氏)綜合征（Cushings Sy

11、ndrome）內(nèi)分泌疾病的機(jī)制 Mechanisms of endocrine disease使用外源性激素導(dǎo)致體內(nèi)激素過量。如糖皮質(zhì)激素或合成代謝類激素 Exogenous ingestion of hormone is the cause of hormone excessfor exle, glucocorticoid excess or anabolic steroid abuse 內(nèi)分泌疾病的機(jī)制 Mechanisms of endocrine disease受體數(shù)量和功能的異常引起內(nèi)分泌異常 Alterations in receptor number and function r

12、esult in endocrine disorders比較常見的是激素水平的異常增高引起可利用受體的數(shù)量減少 Most commonly, an aberrant increase in the level of a specific hormone will cause a decrease in available receptors Type II diabetes內(nèi)分泌疾病的機(jī)制 Mechanisms of endocrine disease糖尿病的分子機(jī)制Molecular mechanism of Diabetes mellitus(DM) Definition: DM is a

13、 group of metabolic diseases characterized by abnormally high levels of sugar (glucose) in the blood resulting from defects in insulin secretion, insulin action or both.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(dǎo)致以血糖增高為特征的代謝性疾病。1.History of Diabetes（糖尿病的歷史） 醫(yī)生發(fā)現(xiàn)糖尿病的癥狀已有幾千年的歷史 Physicians have observed the effect

14、s of diabetes for thousands of years. For much of this time, little was known about this fatal disease that caused wasting away of the body（消瘦）, extreme thirst（口渴）, and frequent urination（尿頻）. 糖尿病的一種明顯的表現(xiàn)是葡萄糖尿，是糖尿病的一個診斷指標(biāo) One of the effects of diabetes is the presence of glucose in the urine (glucos

15、uria). Ancient Hindu writings, many thousands of years old, document how black ants and flies were attracted 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

16、 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 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年確定。 The complete term “diabetes melli

17、tus” was coined in 1674 by Thomas Willis。Mellitus is Latin for honey, which is how Willis described the urine of diabetics (“as if imbued with honey and sugar”). 糖尿病之謎的一個突破是出現(xiàn)在1889年。德國醫(yī)生Joseph von Mering 和Oskar Minkowski手術(shù)切除狗的胰腺后，狗立即出現(xiàn)糖尿病。 A breakthrough in the puzzle of diabetes came in 1889. Germa

18、n physicians Joseph von Mering and Oskar Minkowski surgically removed the pancreas from dogs. The dogs immediately developed 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 p

19、hysiologists had tried and failed to isolate an internal secretion from the pancreas. Dr. Frederick Banting took up the challenge 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 Maclo

20、ed 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 that 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

21、sugar level of the dog fell, and its condition improved.Dr. J. Collip，生物化學(xué)學(xué)家，繼續(xù)改善胰腺提取物的純度，隨后，Best進(jìn)行提取工作。Dr. J. Collip, a biochemist, was drafted to continue improving the purity of the pancreas extract, and later, Best carried on this work.到1922年，成功應(yīng)用胰島素治療第一例糖尿病病人。 It wasnt until 1922 that the first

22、 patient was successfully treated with insulin.Four scientists contributed to the discovery of insulinJ. CollipJohn MacloedCharles BestFrederick BantingIn 1923, Banting and Macloed were awarded the Nobel Prize for the discovery of insulin.BantingMacloedCinema: “Glory enough for all”（共同的榮譽(yù)）光榮歲月 葡萄糖的代

23、謝概況（Overview of Glucose Metabolism） Glucose is an essential fuel for the body. The amount of glucose in the bloodstream is regulated by many hormones, the most important being insulin.血糖受很多激素調(diào)節(jié)，其中最重要的是胰島素。 Insulin is released when glucose is abundant and stimulates the following（胰島素的作用）促進(jìn): muscle an

24、d fat cells to remove glucose from the blood（肌肉細(xì)胞核脂肪細(xì)胞從血液中攝取葡萄糖 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)（肝和肌肉細(xì)胞合成糖原） adipose tissue to store

25、 glucose as fat (long-term energy reserve)（葡萄糖轉(zhuǎn)變?yōu)橹荆?cells to use glucose in protein synthesis（在蛋白質(zhì)的合成過程中利用葡萄糖）胰島素的作用 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 re

26、move glucose from the blood and stimulates the liver to metabolize glucose, causing the blood sugar level to decrease to normal levels Glucagon（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 afte

27、r a carbohyrate-rich meal (ingested at time 0 minutes).The Story of InsulinInsulin Synthesis（胰島素的合成）Insulin Structure（胰島素的結(jié)構(gòu)）Insulin secretion（胰島素的分泌）Insulin Receptor（胰島素受體）Insulin Action（胰島素的作用）Insulin SynthesisInsulin StructureIn 1958, Frederick Sanger was awarded his first Nobel Prize in Chemistr

28、y for determining the 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.Insulin is composed of two chains of amino acids named chain A (21 amino acids) and chain B (30 amino acids) that a

29、re linked together by two disulfide 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胰腺細(xì)胞內(nèi)葡萄糖水平的升高觸發(fā)胰島素釋放1. Glucose is transporte

30、d into the 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6-磷酸葡萄糖葡萄糖激酶2. As glucose metabolism pr

31、oceeds, ATP is produced in the mitochondria.葡萄糖代謝過程中,線粒體產(chǎn)生ATP3.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.細(xì)胞內(nèi)ATP:ADP比例增加，關(guān)閉細(xì)胞ATP-鉀通道，防止帶正電的鉀離子離開細(xì)胞4.The rise in po

32、sitive charge inside the beta cell causes depolarization.細(xì)胞內(nèi)正電荷的增加引起細(xì)胞去極化5.Voltage-gated calcium channels open, allowing calcium ions (Ca2+ ) to flood into the cell.鈣離子通道開放，使細(xì)胞外的鈣離子進(jìn)入細(xì)胞內(nèi)6.The increase in intracellular calcium concentration triggers the secretion of insulin via exocytosis細(xì)胞內(nèi)鈣離子的增加觸發(fā)胰

33、島素通過胞吐作用分泌到細(xì)胞外There are two phases of insulin release in response to a rise in glucose. The first is an immediate release of insulin. This is attributable to the release of preformed insulin, which is stored in secretory granules. After a short delay, there is a second, more prolonged release of new

34、ly synthesized insulin.胰島素對葡萄糖反應(yīng)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(xù)時間較長Glucose 1GLUT2ATPMETABOLISM2Ca2+ IMMEDIATE SECRETIONCalmodulin INSULIN BIOSYNTHESIS AND PROCESSING5 Protein kinase CCa2+3CaM-kinase4DAGSecreted insulin + C-peptideControl of insulin synthesis and secretion by glucose.

35、 CaM kinase: calmodulin-dependent protein kinase; DAG: diacylglycerol6Insulinase found in the liver and kidneys breaks down insulin circulating in the plasmaInsulin has a half-life of only about 6 minutes.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 Insulin Receptor（胰島素受體）the receptor for insulin is e

36、mbedded in the plasma membrane and is composed of a pair of alpha subunits and a pair of beta subunits。胰島素受體是跨膜受體，由兩個亞基和兩個亞基組成。Two and two subunits Receptor tyrosine kinaseHormone binding site on subunit， subunit - tyrosine kinase activity Localized to 19th chromosome inHumansThe insulin receptor. I

37、nsulin binding to the -chains transmits a signal through the transmembrane domain of the -chains to activate the tyrosine kinase activity CYTOPLASMEXTRACELLULARNH3+SSSSInsulin-OOC-S-S-+3HNCOO-subunits-subunitsTransmembranedomainTyrosinekinasedomain+3HNNH3+-OOCCOO- PlasmamembraneSSSSExtracellularCyto

38、plasm1insulinbindsLR2IRTK (L)activatedOPOP3IRTK (R)phosphorylated/activatedActivation of the tyrosine kinase domains of the insulin receptor by insulin binding, followed by interchain autophosphorylation PPPPATPsADPsPhosphorylationcatalyzed by IRTK (L)PExtracellularCytoplasm1insulinbindsLR2IRTK (L)a

39、ctivatedOPOP3IRTK (R)phosphorylated/activatedPOPO4IRTK (L)phosphorylatedOPOPPPPPATPsADPsPhosphorylationcatalyzed by IRTK (L)ATPsADPsPPPhosphorylationcatalyzed by IRTK (R)Activation of the tyrosine kinase domains of the insulin receptor by insulin binding, followed by interchain autophosphorylation I

40、nsulin Signal Transductionseveral targets are phosphorylated by IRTKIRS activation is tied to metabolic responses glucose transport (muscle and fat cells) activation of protein phosphataseprotein phosphatase removes phosphates from proteins phosphorylated by protein kinase A counter-regulation of gl

41、ucagonInsulin Action（胰島素的作用） Insulin promotes the uptake of glucose into many tissues that express 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

42、 to the cell surface.Extracellular spaceCytoplasm tyr-OHIRS4 signals Golgi to traffic GLUT-4 tomembranePKBGOLGI= GLUT-4Active IRTKPOPOOPOP1 IRTKcatalyzed tyr-OPIRSATP ADPactiveIRS tyr-OPIRSPI-3Kp852 activated by dockingactive IRSHypothetical mechanism for insulin to mobilize GLUT-4 transporter to th

43、e plasma membrane in muscle and adipose tissue. IRS, insulin-receptor substrate; IRTK, insulin receptor 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)

44、 in adipose or muscle cells Golgi glucose transporter Step1 - insulin binding and signal transduction (signal) -P P- Step 2 translocationFrom Golgi Step 3Binding and fusion Step 4Glucosetransport Step 5Receptor inactivationStep 6translocation back to Golgi GlucoseDiagnostic criteria World Health Org

45、anization (1980)1. Symptoms of diabetes plus a plasma glucose concentration 11.1 mmol/l obtained at any time of day 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糖尿病的診斷Classification Diabetes is clas

46、sified by underlying cause. The categories are: Type 1 diabetesan autoimmune disease in which the bodys own immune system 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; Gestati

47、onal diabetesMajor defect in individuals with type 2 diabetesReduced biological response to insulinStrong predictor of type 2 diabetesClosely associated with obesityWhat is insulin resistance?What is -cell dysfunction?Major defect in individuals with type 2 diabetesReduced ability of -cells to secre

48、te insulin in response to hyperglycemiaInsulin resistance and -cell dysfunction are core defects of type 2 diabetesInsulinresistanceGenetic susceptibility,obesity, Western lifestyleType 2 diabetesIRb-celldysfunctionHow do insulin resistance and -cell dysfunction combine to cause type 2 diabetes?Abno

49、rmalglucose toleranceHyperinsulinemia,then -cell failureNormal IGT*Type 2 diabetes Post-prandial glucoseInsulin resistanceIncreased insulinresistanceFasting glucoseHyperglycemiaInsulinsecretion*IGT = impaired glucose toleranceMore than 80% of patients progressing to type 2 diabetes are insulin resis

50、tantInsulin resistant;low insulin secretion (54%)Insulin resistant; good insulin secretion (29%)Insulin sensitive;good insulin secretion (1%)Insulin sensitive;low insulin secretion (16%)83%Haffner SM, et al. Circulation 2000; 101:975980.Insulin resistance reduced response to circulating insulinInsul

51、inresistance Glucose output Glucose uptake Glucose uptakeHyperglycemiaLiverMuscleAdiposetissueIRIn USA:16 million people suffer from DM. Type 1 diabetes 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 o

52、f 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 of a diabetes epidemic.Epidemiology 2003年全球糖尿病病人已超過1.94億，預(yù)計(jì)到本世紀(jì)2025年這個數(shù)字將增加近一倍（3.33億）我國糖尿病病人數(shù)約4000萬，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，其它類型糖尿病僅占0.7

53、。Genetic associations（遺傳關(guān)聯(lián)）The clearest association is with class II human leucocyte 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),

54、 11q (IDDM4) and 6q (IDDM5). The number of mutations at other putative sites continues 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（環(huán)境因素）Viruses. E

55、vidence for a viral etiology of DM in humans is circumstantial though in animal studies 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 (containi