内分泌的分子生物学final.ppt

1、内分泌及代谢疾病,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,Endocrine System,内分泌学发展三阶段,腺体内分泌学 Organic Endocrinology 组织内分泌学 Histological Endocrinology 分子内分泌学 Moleculer Endocrinology,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,组织内分泌学,放免的创建，可测量微量激素 （

2、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,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,细胞信息传递方式, 通过相邻细胞的直接接触, 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(signal molecules),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

3、产生生物学效应,（一）神经递质 又称突触分泌信号(synaptic signal),根据细胞分泌信息物质的方式，将细胞间信息物质分为四类：,（二） 内分泌激素 又称内分泌信号(endocrine signal),（三）局部化学介质 又称旁分泌信号(paracrine signal,（四）气体信号 (Gas signal),激素的分泌方式,内分泌 旁分泌 自分泌,激素的种类 Hormones,肽类/蛋白类激素 （Protein or peptide) : ACTH,LH, FSH, PHT, TSH, Insulin ,Glucagon, IGFs 氨基酸衍生物（Amino Acid deriv

4、atives)： 儿茶酚胺类（肾上腺素、去甲肾上腺素） 脂肪酸衍生物(Fatty acid derivatives ): 前列腺素类、视黄酸 胆固醇衍生物（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,激素的作用机制,激素信息在细胞内的信号传导,Coris: 发

5、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 DAG: diacylglycerol,6,Insulinase found in the liver and kidneys breaks down insulin circulating in the plasma Insulin has a half-life of only about 6 minutes.

6、 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,Insulin Receptor（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 subunits。 胰岛素受体是跨膜受体，由两个亚基和两个亚基组成。,Two and two subunits Receptor tyrosine kinase Hormone binding site on sub

7、unit， subunit - tyrosine kinase activity Localized to 19th chromosome in Humans,The insulin receptor. Insulin binding to the -chains transmits a signal through the transmembrane domain of the -chains to activate the tyrosine kinase activity,CYTOPLASM,EXTRACELLULAR,NH3+,-OOC,-S-S-,+3HN,-subunits,-sub

8、units,Transmembrane domain,Tyrosine kinase domain,+3HN,-OOC,COO-,Plasma membrane,Extracellular,Cytoplasm,Activation of the tyrosine kinase domains of the insulin receptor by insulin binding, followed by interchain autophosphorylation,P,P,P,P,ATPs,ADPs,P,Extracellular,Cytoplasm,P,P,P,P,P,P,Activation

9、 of the tyrosine kinase domains of the insulin receptor by insulin binding, followed by interchain autophosphorylation,Insulin Signal Transduction,several targets are phosphorylated by IRTK IRS activation is tied to metabolic responses glucose transport (muscle and fat cells) activation of protein p

10、hosphatase protein phosphatase removes phosphates from proteins phosphorylated by protein kinase A counter-regulation of glucagon,Insulin Action（胰岛素的作用）,Insulin promotes the uptake of glucose into many tissues that express GLUT4 glucose transporters, such as skeletal muscle and fat. Insulin increase

11、s the activity of these transporters and increases their numbers by stimulating their recruitment from an intracellular pool to the cell surface.,Extracellular space Cytoplasm,4 signals Golgi to traffic GLUT-4 to membrane,PKB,GOLGI,= GLUT-4,Active IRTK,1 IRTK catalyzed,active IRS,PI-3K,p85,2 activat

12、ed by docking active IRS,Hypothetical mechanism for insulin to mobilize GLUT-4 transporter to the plasma membrane in muscle and adipose tissue. IRS, insulin-receptor substrate; IRTK, insulin receptor tyrosine kinase; PI-3K, phosphatidyl-inositol kinase; PDK; phospholipid-dependent kinase PKB, protei

13、n kinase B,PDK,+,Insulin stimulated glucose transport (GLUT-4) in adipose or muscle cells,Golgi,glucose,transporter,(signal),-,P,P,-,Step 2 translocation From Golgi,Step 3 Binding and fusion,Step 4 Glucose transport,Step 5 Receptor inactivation,Step 6 translocation back to Golgi,Glucose,Diagnostic c

14、riteria World Health Organization (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,糖尿病的诊断,Class

15、ification,Diabetes is classified 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 secr

16、etion may be seen; Gestational diabetes,Major defect in individuals with type 2 diabetes Reduced biological response to insulin Strong predictor of type 2 diabetes Closely associated with obesity,What is insulin resistance?,What is -cell dysfunction?,Major defect in individuals with type 2 diabetes

17、Reduced ability of -cells to secrete insulin in response to hyperglycemia,Insulin resistance and -cell dysfunction are core defects of type 2 diabetes,How do insulin resistance and -cell dysfunction combine to cause type 2 diabetes?,More than 80% of patients progressing to type 2 diabetes are insuli

18、n resistant,Insulin 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 circulatin

19、g insulin,Insulin resistance, Glucose output, Glucose uptake, Glucose uptake,Hyperglycemia,Liver,Muscle,Adiposetissue,In 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 fo

20、r 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 of a diabetes epidemic.,Epidemiology,2003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. 型糖尿病占

21、5.6，型糖尿病占93.7，其它类型糖尿病仅占0.7。,Genetic associations（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

22、on chromosomes 15q (IDDM3), 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 DM,Environme

23、ntal factors（环境因素） Viruses. Evidence 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 (con

24、taining bovine serum albumin), preserved meats (containing nitrosamines) and coffee.,etiology of type 1 DM,Immune markers（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 circula

25、ting antibodies against the islets. 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 DM,Genetic associations（遗传关联） Studies in twins indicate that approximately 30-90% of the r

26、isk of type 2 diabetes is genetic. 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 mellitus,Environmental factors（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 thought to lead to metabolic sequelae pr