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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,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,分子内分泌学,激素及其受体的基因
2、 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(
3、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 derivatives)： 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（Cholestero
4、l 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 （c
5、AMP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. 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 in
6、sulin 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 subunit， subunit - tyrosine kinase activity Localized to 19th chromosome in Humans,The insu
7、lin 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,-subunits,Transmembrane domain,Tyrosine kinase domain,+3HN,-OOC,COO-,Plasma membrane,Extrace
8、llular,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 of the tyrosine kinase domains of the insulin receptor by insulin binding, followed by
9、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 phosphatase protein phosphatase removes phosphates from proteins phosphorylated by protei
10、n 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 increases the activity of these transporters and increases their numbers by stimulating their re
11、cruitment 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 activated by docking active IRS,Hypothetical mechanism for insulin to mobilize GLUT-4 transport
12、er 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, protein kinase B,PDK,+,Insulin stimulated glucose transport (GLUT-4) in adipose or muscle cell
13、s,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 criteria World Health Organization (1980) 1. Symptoms of diabetes plus a plasma glucose c
14、oncentration 11.1 mmol/l obtained at any time of day and without regard to meals, OR 2. Fasting plasma glucose 7.8 mmol/l, OR 3. A plasma glucose concentration 11.1 mmol/l 2 h after 75 g of oral glucose,糖尿病的诊断,Classification,Diabetes is classified by underlying cause. The categories are: Type 1 diab
15、etesan 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; 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 Reduced
