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1、 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理系统包括旁分泌、自分泌体液调理系统包括旁分泌、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内分泌学开展三阶段内分泌学开展三阶段n腺体内分泌学腺体内分泌学n Organic Endocrinologyn组织内分泌学组织内分泌学n Histological Endocrinologyn分子内分泌学分子内分泌学n Moleculer Endocrinology腺体内分泌学腺体内分泌学n n察看切除内分泌腺前、后生理生化变化n n将内分泌腺中提取的有效成分补充给切
2、除了内分泌腺的动物，察看其恢复情况n n从内分泌腺提取激素，了解其化学构造，制备同类物与拮抗物组织内分泌学组织内分泌学n n放免的创建，可丈量微量激素n n1960年 Yalow 初次用放免法丈量血浆胰岛素获1977年诺贝尔奖n n免疫荧光显微技术，了解激素分布、分泌n n发现某些组织器官分泌激素:心脏分子内分泌学分子内分泌学n n激素及其受体的基因n n基因的表达、转录、翻译及其调控n n基因缺失、插入n n基因重组技术人工合成激素n n激素作用机制n n激素与细胞代谢、增生、分化、凋亡等细胞信息传送方式细胞信息传送方式 经过相相邻细胞的直接接触胞的直接接触 经过细胞胞分分泌泌各各种种化化学
3、学物物质来来调理理其其他他细胞的代胞的代谢和功能和功能信息物质信息物质(signal molecules)(signal molecules)跨膜信号转导的普通步骤跨膜信号转导的普通步骤特定的特定的细胞胞释放信息物放信息物质信息物信息物质经分散或血循分散或血循环到达靶到达靶细胞胞与靶与靶细胞的受体特异性胞的受体特异性结合合受体受体对信号信号进展展转换并启并启动细胞内信使系胞内信使系统靶靶细胞胞产生生物学效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 signal) 根据细胞分泌信息物质的方式，将细胞间信息物根据细胞分泌信息物质的方式，将细胞间信息物质分为
4、四类：质分为四类：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)(endocrine signal)三部分化学介质三部分化学介质 又称旁分泌信号又称旁分泌信号(paracrine signal 四气体信号四气体信号 (Gas signal)激素的分泌方式激素的分泌方式n n内分泌n n旁分泌n n自分泌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 Aci
5、d derivatives)： 儿茶酚胺类肾上腺素、去甲肾上腺儿茶酚胺类肾上腺素、去甲肾上腺素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性激性激素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 发扬生物效应发扬生物效应 肽类激素、生物胺、前列腺素n 与膜受体结合与膜受体结合 受体本身磷酸化受体本身磷酸化 发扬生物学效应发扬生物学效应n 酪氨酸激酶酪氨酸激
6、酶 n 生长因子家族、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n 甾体类激素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: 胜利分别和确定的腺苷酸环化酶和磷酸二酯酶胜利分别和确定的腺苷酸环化酶和磷酸二酯酶 cAMP合成与分解的两
7、个关键酶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。 cAMP-cAMP-蛋白激酶途径蛋白激酶途径ATPATPcAMPcAMP蛋白激蛋白激酶A A蛋白蛋白质或或酶磷酸化磷酸化酶活性改活性改动 基因基因转录加快加快
8、蛋白蛋白质合成加速合成加速生物效生物效应AMPAMP磷酸二酯酶磷酸二酯酶R RG GACAC 使有关蛋白或使有关蛋白或酶类的的丝氨酸、氨酸、苏氨氨酸残基磷酸化酸残基磷酸化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GPKG途径途径主要生理效主要生理效应：血管平滑肌松弛血管平滑肌松弛添加尿添加尿钠，促，促进钠的排出的排出降低血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经过胞内类固醇激素与甲状腺素经过胞内受体调理生理过程受体调理生理过程MCR代代谢去除率去除率 of some hormones Hormo
9、neHalf-lifeAmines2-3 minThyroid hormones: T4 T36.7 days0.75 daysPolypeptides4-40 minProteins15-170 minSteroids4-120 min内分泌疾病的机制内分泌疾病的机制 Mechanisms of endocrine diseasen n由激素缺乏、由激素缺乏、由激素缺乏、由激素缺乏、过过量或抵抗引起的内分泌疾病量或抵抗引起的内分泌疾病量或抵抗引起的内分泌疾病量或抵抗引起的内分泌疾病Endocrine disorders result from hormone Endocrine disord
10、ers result from hormone deficiency, hormone excess or hormone deficiency, hormone excess or hormone resistance resistance n n由于感染、坏死、由于感染、坏死、肿肿瘤的物理性瘤的物理性紧缩紧缩以及本身免以及本身免疫性疾病疫性疾病导导致的分泌腺破坏引起的激素缺乏致的分泌腺破坏引起的激素缺乏n n Deficiency usually is due to destructive process Deficiency usually is due to destructive p
11、rocess occurring at gland in which hormone is occurring at gland in which hormone is producedinfection, infarction, physical producedinfection, infarction, physical compression by tumor growth, autoimmune compression by tumor growth, autoimmune attackattackType I Diabetes内分泌疾病的机制内分泌疾病的机制 Mechanisms
12、of endocrine diseasen n由于由于遗传遗传缺陷激素基因缺失或突缺陷激素基因缺失或突变变，导导致激素前体的断裂、特异性致激素前体的断裂、特异性酶酶缺乏甾体缺乏甾体类类激素或甲状腺素，引起激素合成减少激素或甲状腺素，引起激素合成减少n n Deficiency can also arise from genetic Deficiency can also arise from genetic defects in hormone productiongene defects in hormone productiongene deletion or mutation, fail
13、ure to cleave deletion or mutation, failure to cleave precursor, specific enzymatic defect (steroid precursor, specific enzymatic defect (steroid or thyroid hormones) or thyroid hormones) Congenital Adrenal Hyperplasia先天性先天性肾上腺增生上腺增生(症症) 内分泌疾病的机制内分泌疾病的机制 Mechanisms of endocrine diseaseCongenital Adr
14、enal 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？n n受体的受体的灭灭活性突活性突变导变导致激素缺乏致激素缺乏n n Inactivating mutations of receptors can Inactivating mutations of receptors can cause hormone deficiencycause hormone deficiency雄激素不敏感雄激素不敏感综合征睾丸女性化合征睾丸女性化综合征合征Testicular Fe
15、minization Syndrome内分泌疾病的机制内分泌疾病的机制 Mechanisms of endocrine diseasen n由于疾病引起的激素分泌由于疾病引起的激素分泌过过多多n n Hormone excess usually results in disease Hormone excess usually results in disease n n腺体分泌腺体分泌过过量或非内分泌量或非内分泌组织组织的分泌的分泌导导致激素生成致激素生成n n 过过量量 n n Hormone may be overproduced by gland that Hormone may be
16、 overproduced by gland that normally secretes it, or by a tissue that is not an normally secretes it, or by a tissue that is not an endocrine organ. endocrine organ. n n内分泌腺内分泌腺肿肿瘤引起激素分泌瘤引起激素分泌过过量量n n Endocrine gland tumors produce hormone in an Endocrine gland tumors produce hormone in an unregulat
17、ed manner. unregulated manner. 库兴(氏)综合征Cushings Syndrome内分泌疾病的机制内分泌疾病的机制 Mechanisms of endocrine diseasen n运用外源性激素运用外源性激素导导致体内激致体内激素素过过量。如糖皮量。如糖皮质质激素或合激素或合成代成代谢类谢类激素激素n n Exogenous ingestion of Exogenous ingestion of hormone is the cause of hormone is the cause of hormone excessfor hormone excessfor
18、 example, glucocorticoid example, glucocorticoid excess or anabolic steroid excess or anabolic steroid abuse abuse 内分泌疾病的机制内分泌疾病的机制 Mechanisms of endocrine diseasen n受体数量和功能的异常引起内分泌异常受体数量和功能的异常引起内分泌异常n n Alterations in receptor number and function result in Alterations in receptor number and functio
19、n result in endocrine disordersendocrine disordersn n比比较较常常见见的是激素程度的异常增高引起可利用受体的数的是激素程度的异常增高引起可利用受体的数量减少量减少n n Most commonly, an aberrant increase in the level of Most commonly, an aberrant increase in the level of a specific hormone will cause a decrease in available a specific hormone will cause a
20、 decrease in available receptors receptors Type II diabetes内分泌疾病的机制内分泌疾病的机制 Mechanisms of endocrine disease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 fr
21、om defects in insulin secretion, insulin action or both.定义：糖尿病是一组由于胰岛素缺乏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 医生发现糖尿病的病症已有几千年的历史医生发现糖尿病的病症已有几千年的历史 Physicians have observed the effects of diabetes for thousands of years. For much of this time, little was known about this fata
22、l disease that caused wasting away of the body消瘦消瘦, extreme thirst口渴口渴, and frequent urination尿频尿频. n n糖尿病的一种明显的表现是葡萄糖尿，是糖尿病的一糖尿病的一种明显的表现是葡萄糖尿，是糖尿病的一糖尿病的一种明显的表现是葡萄糖尿，是糖尿病的一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目的个诊断目的个诊断目的个诊断目的n n One of the effects of diabetes is the One of the effects of diabetes is the prese
23、nce of glucose in the urine (glucosuria). presence of glucose in the urine (glucosuria). Ancient Hindu writings, many thousands of Ancient Hindu writings, many thousands of years old, document how black ants and flies years old, document how black ants and flies were attracted to the urine of diabet
24、ics. The were attracted to the urine of diabetics. The Indian physician Sushruta in 400 B.C. Indian physician Sushruta in 400 B.C. described the sweet taste of urine from described the sweet taste of urine from affected individuals, and for many centuries affected individuals, and for many centuries
25、 to come, the sweet taste of urine was key to to come, the sweet taste of urine was key to diagnosis.diagnosis. 公元250年左右，第一次运用“diabetes 描画糖尿病 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
26、 affected individual. 完好的“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 diabetics (“as if imbued with honey and sugar). 糖尿病之谜的一个突破是出如今1889年。德国医生Joseph von Mering 和Oskar Mink
27、owski手术切除狗的胰腺后，狗立刻出现糖尿病。 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 diabetes. Now that a link was established between the pancreas gland and diabetes, researc
28、h 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 of isolating a pancreatic extract, he was met with much skepticism. Banting, a surgeo
29、n, 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，用胰腺提取物胜利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 co
30、llected 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进展提取任务。进展提取任务。Dr. J. Collip, a biochemist, was drafted to continue improving the purity of the
31、pancreas extract, and later, Best carried on this work.n到1922年，胜利运用胰岛素治疗第一例糖尿病病人。n It wasnt until 1922 that the first patient was successfully treated with insulin.Four scientists contributed to the discovery of insulinJ. CollipJohn MacloedCharles BestFrederick BantingIn 1923, Banting and Macloed we
32、re awarded the Nobel Prize for the discovery of insulin.BantingMacloednobel.se/medicine/laureates/1923/index.htmCinema: “Glory enough for all共同的荣誉共同的荣誉光彩光彩岁月月 葡萄糖的代谢概略葡萄糖的代谢概略Overview of Glucose Metabolism Glucose is an essential fuel for the body. The amount of glucose in the bloodstream is regulat
33、ed by many hormones, the most important being insulin.血糖受很多激素调理，其中最重要的是胰岛素。血糖受很多激素调理，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从血液中摄取葡萄糖 cells to breakdown glucose, releasing its energy
34、 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)肝和肌肝和肌肉肉细胞合成糖原胞合成糖原 adipose tissue to store glucose as fat (long-term energy reserve)葡萄糖葡萄糖转变为脂肪脂肪 cells to use glucose in protein synthesis在在蛋白蛋白质的合成
35、的合成过程中利用葡萄糖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 metabolize glucose, causing the
36、 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 after a carbohyrate-rich meal (ingested at time 0 minutes).The Story of InsulinInsulin Synthe
37、sis胰岛素的合成胰岛素的合成Insulin Structure胰岛素的构造胰岛素的构造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 the sequence of the amino acids that make up insulin
38、. This marked the first time that a protein had had the order of its amino acids (the primary sequence) determined.nobelprizes/nobel/chemistry/1958a.htmlInsulin 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 disulf
39、ide 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胰腺细胞内葡萄糖程度的升高触发胰岛素释放1. Glucose is transported into the beta cell by type 2 g
40、lucose 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 proceeds, ATP is prod
41、uced 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比例添加，封锁比例添加，封锁 细胞细胞ATP-钾通道，防止带钾通道，防止带正电的钾离子分
42、开正电的钾离子分开 细胞细胞4.The rise in positive charge inside the beta cell causes depolarization. 细胞内正电荷的添加引起细胞去极化细胞内正电荷的添加引起细胞去极化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 calcium concen
43、tration triggers the secretion of insulin via exocytosis细胞内钙离子的添加触发胰岛素经过胞吐作用分泌到细胞外细胞内钙离子的添加触发胰岛素经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. The first is an immediate release of insulin. This is attributable to the release of preformed insulin, which is store
44、d in secretory granules. After a short delay, there is a second, more prolonged release of newly synthesized insulin.胰岛素对葡萄糖反响的的释放有两个阶段胰岛素对葡萄糖反响的的释放有两个阶段第一阶段：立刻释放储存在分泌颗粒中的胰岛素第一阶段：立刻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，继续时间较长第二阶段：释放新合成的胰岛素，继续时间较长Glucose 1GLUT2ATPMETABOLISM2Ca2+ IMMEDIATE SECRETIONCalmodulin
45、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
46、in 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 subuni
47、ts。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 inlHumansThe insulin receptor. Insulin binding to the -chains transmits a signal through the transmembrane domain of the -chain
48、s to activate the tyrosine kinase activity CYTOPLASMEXTRACELLULARNH3+SSSSInsulin-OOC-S-S-+3HNCOO-subunits-subunitsTransmembranedomainTyrosinekinasedomain+3HNNH3+-OOCCOO- PlasmamembraneSSSSExtracellularCytoplasm1insulinbindsLR2IRTK (L)activatedOPOP3IRTK (R)phosphorylated/activatedActivation of the ty
49、rosine kinase domains of the insulin receptor by insulin binding, followed by interchain autophosphorylation PPPPATPsADPsPhosphorylationcatalyzed by IRTK (L)PExtracellularCytoplasm1insulinbindsLR2IRTK (L)activatedOPOP3IRTK (R)phosphorylated/activatedPOPO4IRTK (L)phosphorylatedOPOPPPPPATPsADPsPhospho
50、rylationcatalyzed 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 Transductionqseveral targets are phosphorylated by IRTKqIRS activation is tied to
51、 metabolic responsesq glucose transport (muscle and fat cells)q activation of protein phosphataseqprotein 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
52、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 to the cell surface.Extracellular spaceCytoplasm tyr-OH4 signals Golgi to traffic GLU
53、T-4 tomembraneGOLGI= GLUT-4Active IRTKPOPOOPOP1 IRTKcatalyzed tyr-OPATP ADPactiveIRS tyr-OP2 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 receptor ty
54、rosine kinase; PI-3K, phosphatidyl-inositol kinase; PDK; phospholipid-dependent kinasePKB, protein kinase B tyr-OP tyr-OP tyr-OPPIP2PIP3+ +Insulin stimulated glucose transport (GLUT-4) in adipose or muscle cells Golgi glucose transporter Step1 - insulin binding and signal transduction (signal) -P P-
55、 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
56、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 im
57、mune 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; Gestational diabetesn nMajor defect in individuals with type 2 diabetesn nReduced biological response to insulinn nSt
58、rong predictor of type 2 diabetesn nClosely associated with obesityWhat is insulin resistance?What is -cell dysfunction?n nMajor defect in individuals with type 2 diabetesn nReduced ability of -cells to secrete insulin in response to hyperglycemia Insulin resistance and Insulin resistance and -cell
59、dysfunction are -cell dysfunction are core defects of type 2 diabetescore defects of type 2 diabetesInsulinresistanceGenetic susceptibility,obesity, Western lifestyleType 2 diabetesIR-cell-celldysfunctiondysfunction How do insulin resistance and How do insulin resistance and -cell dysfunction -cell
60、dysfunction combine to cause type 2 diabetes?combine to cause type 2 diabetes?Abnormalglucose toleranceHyperinsulinemia,then -cell failureNormal IGT*Type 2 diabetes Post-prandial glucoseInsulin resistanceIncreased insulinresistanceFasting glucoseHyperglycemiaInsulinsecretion*IGT = impaired glucose t
61、oleranceMore than 80% of patients progressing to type More than 80% of patients progressing to type 2 diabetes are insulin resistant2 diabetes are insulin resistantInsulin resistant;low insulin secretion (54%)Insulin resistant; good insulin secretion (29%)Insulin sensitive;good insulin secretion (1%
62、)Insulin sensitive;low insulin secretion (16%)83%83%Haffner SM, et al. Circulation 2000; 101:975980.Insulin resistance reduced response to Insulin resistance reduced response to circulating insulincirculating insulinInsulinresistance Glucose output Glucose uptake Glucose uptakeHyperglycemiaLiverMusc
63、leAdiposetissueIRIn 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 of diabetes. This form of diabetes can go undiagnosed for many years, but the nu
64、mber 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越年全球糖尿病病人已超越1.94亿，估计到本世纪亿，估计到本世纪2025年这个数字将添加近一倍年这个数字将添加近一倍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
65、associations遗传关联遗传关联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), 11q (I
66、DDM4) 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环境要素环境要素Viruses. Eviden
67、ce 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), pre
68、served meats (containing nitrosamines) and coffee. etiology of type 1 DMImmune markers免疫标志免疫标志 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 islet
69、s. Antibodies against the insulin molecule, the enzyme gamma-amino butyric acid decarboxylase (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
70、. Prevalence of type 2 DM is very high in certain ethnic groups including Pima Indians in Arizona, Naruans in Polynesia, and Indian sub-continent Asians in the UK. The etiology of type 2 diabetes mellitusEnvironmental factors环境要素环境要素Obesity (especially central), aging, physical inactivity. These inc
71、rease insulin resistance. Poor fetal development胎儿发育不良胎儿发育不良. This (the thrifty phenotype hypothesis) is 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 mellitusDiabeticre
72、tinopathyLeading causeof blindnessin working-ageadultsDiabeticnephropathyLeading cause of end-stage renal diseaseCardiovasculardiseaseStroke1.2- to 1.8-fold increase in strokeDiabeticneuropathyLeading cause of non-traumatic lower extremity amputations75% diabetic patients die from CV eventsComplicat
73、ions (并发症并发症 of diabetes. Overall, 75% of patients with type 2 diabetes die from cardiovascular diseaseComplications of DM动脉粥样硬化动脉粥样硬化Insulin resistance is as strong a risk factor for Insulin resistance is as strong a risk factor for cardiovascular disease as smokingcardiovascular disease as smoking0.60.81.01.21.41.61.8Odds ratio for incident CVDAgeSmokingTotal cholesterol:HDL cholesterolInsulinresistanceComplications of DMMacrosomic baby Complications of DMn ndiabeteshealthn ndiabetes.org
