1、內(nèi)分泌及代謝疾病,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,生長發(fā)育,生殖衰老,Endocrine System,內(nèi)分泌學發(fā)展三階段,腺體內(nèi)分泌學 Organic Endocrinology 組織內(nèi)分泌學 Histological Endocrinology 分子內(nèi)分泌學 Moleculer Endocrinology,腺體內(nèi)分泌學,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充給切除了內(nèi)分泌腺的動物，觀察其恢復情況 從內(nèi)分泌腺提取激素，了解其化學結(jié)構(gòu)，制備同類物與拮抗物,組織內(nèi)分泌學,放免的創(chuàng)建，可測量微量激素 （

2、1960年 Yalow 首次用放免法測量血漿胰島素）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,激素及其受體的基因 基因的表達、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 激素作用機制 激素與細胞代謝、增生、分化、凋亡等,細胞信息傳遞方式, 通過相鄰細胞的直接接觸, 通過細胞分泌各種化學物質(zhì)來調(diào)節(jié)其他細胞的代謝和功能,信息物質(zhì)(signal molecules),跨膜信號轉(zhuǎn)導的一般步驟,特定的細胞釋放信息物質(zhì),信息物質(zhì)經(jīng)擴散或血循環(huán)到達靶細胞,與靶細胞的受體特異性結(jié)合,受體對信號進行轉(zhuǎn)換并啟動細胞內(nèi)信使系統(tǒng),靶細胞

3、產(chǎn)生生物學效應,（一）神經(jīng)遞質(zhì) 又稱突觸分泌信號(synaptic signal),根據(jù)細胞分泌信息物質(zhì)的方式，將細胞間信息物質(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 deriv

4、atives)： 兒茶酚胺類（腎上腺素、去甲腎上腺素） 脂肪酸衍生物(Fatty acid derivatives ): 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,激素的作用機制,與膜受體結(jié)合 G蛋白偶聯(lián) 發(fā)揮生物效應,（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)揮生物學效應 （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,激素的作用機制,激素信息在細胞內(nèi)的信號傳導,Coris: 發(fā)

5、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。 Sutherland: 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說 獲得1971年諾貝爾生理醫(yī)學獎。 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 embedded 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 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 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,糖尿病的診斷,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過1.94億，預計到本世紀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

21、5.6，型糖尿病占93.7，其它類型糖尿病僅占0.7。,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

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（環(huán)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（免疫標記） 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（遺傳關(guān)聯(lián)） 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（環(huán)境因素）Obesity (especially central), aging, physical inactivity. These increase insulin resistance. Poor fetal development（胎兒發(fā)育不良）. This (the thrifty phenotype hypothesis) is thought to lead to metabolic sequelae pr