胰島素抵抗與多囊卵巢綜合征

1、胰島素抵抗與多囊卵巢綜合征,北京大學(xué)深圳醫(yī)院生殖醫(yī)學(xué)中心李蓉,1921年，Achard 和 Their首先發(fā)現(xiàn)糖代謝異常與高雄激素血癥有關(guān);1935年， Stein and Leventhal首先提出PCOS;1976年，Kahn 和同事發(fā)現(xiàn)高雄激素血癥、胰島素抵抗和黑棘皮癥有關(guān);1980年，Burghen 首先提出PCOS與高雄激素血癥、高胰島素血癥有關(guān);,背 景,Figure 2. Section of a polycy

2、stic ovary with multiple subscapular follicular cysts and stromal hypertrophy (left panel). At higher power (x100) islands of luteinized theca cells are visible in the stroma (right panel). This morphological change is c

3、alled stromal hyperthecosis and appears to be directly correlated with circulating insulin levels.,一、胰島素與卵巢功能的關(guān)系,胰島素通過IGF-1受體刺激卵巢分泌雌激素，雄激素及 孕酮(細(xì)胞色素 p-450c 17α 17 α-羥化酶 )胰島素抑制肝臟分泌SHBG 雄激素的效應(yīng)胰島素抑制肝臟合成 IGF

4、BP-1 IGF-1的效應(yīng)同 Gn相互作用抑制卵泡的凋亡 閉鎖上調(diào) IGF-1受體,,,,,,,,,Figure 1. Possible Mechanisms of Insulin Stimulation of Ovarian Cytochrome P450c17 Activity and Androgen production. In theca cells, insulin may direct

5、ly stimulate (plus signs) ovarian cytochrome P450c17 , resulting in increased 17 -hydroxylase and, to a lesser extent, 17,20-lyase activity. This would lead to increased production of androstenedione, which is then conve

6、rted to testosterone by the enzyme 17 -reductase. Alternatively or in conjunction with this, insulin may stimulate ovarian androgen production indirectly by enhancing the amplitude of serum luteinizing hormone (LH) pulse

7、s, and luteinizing hormone may then stimulate ovarian cytochrome P450c17 activity.,二、胰島素抵抗與PCOS,胰島素及其受體的結(jié)構(gòu),胰島素是胰腺Langerhans小島上的β-細(xì)胞產(chǎn)生多肽，由A鏈(21AAs)和B鏈(30AAs)構(gòu)成。胰島素受體由兩個(gè)α-亞單位（135 kDa）和兩個(gè)β-亞單位(95 kDa)構(gòu)成的異構(gòu)四聚體。 α-亞單位：

8、存在于細(xì)胞膜外，富含半胱氨酸，是胰島素的結(jié)合位點(diǎn)； β-亞單位：三種類型：細(xì)胞膜外、細(xì)胞膜、細(xì)胞漿內(nèi)，后者含有ATP 結(jié)合位點(diǎn)和幾個(gè)酪氨酸自動(dòng)磷酸化位點(diǎn)。,胰島素的作用機(jī)理（1）,,,,,胰島素受體β-亞單位的酪氨酸位點(diǎn)磷酸化,胰島素,胰島素受體α-亞單位,,獲得激酶活性，細(xì)胞內(nèi)蛋白磷酸化,,胰島素受體底物（IRS）,,,突變,胰島素抵抗,基因,OGTTPCOS,高胰島素血癥,,,FIG 1. The IR is a hete

9、rotetramer consisting of two a, b-dimers linked by disulfide bonds. The a-subunit contains the ligand-binding site, and the b-subunit contains a ligand-activated tyrosine kinase. Tyrosine autophosphorylation increases th

10、e receptor’ s tyrosine kinase activity whereas serine phosphorylation inhibits it.,,胰島素的作用機(jī)理（2）,胰島素抵抗的機(jī)理(1),受體與胰島素的結(jié)合或者受體親和力無改變50% PCOS-ser : IR 酪氨酸磷酸化 或 IR 絲氨酸磷酸化 50% PCOS-nl: IR下游信號傳導(dǎo)受阻 (IRS-1 的磷酸化； PI3-K的活性

11、 ）,,,,Figure 9. The tyrosine-phosphorylated IR phosphorylates intracellular substrates, such as IR substrate (IRS)-1 and IRS-2, initiating signal transduction and the plieotropic actions of insulin. The activation of P

12、I3-K (PI3-kinase) by tyrosine-phosphorylated IRS-1 appears to be the pathway for insulin-mediated glucose transport. The Ras-MAP kinase pathway appears to regulate cell growth and glycogen synthesis.,胰島素抵抗的機(jī)理（2）,IR 絲氨酸磷酸

13、化因子IR 酪氨酸激酶抑制因子膜糖蛋白 PC-1/TNF-a,胰島素抵抗的機(jī)理（3）,,,抑制 IR 酪氨酸激酶活性,Figure 14. Insulin resistance in 50% of PCOS women appears to be secondary to a cell membrane-associated factor, presumably a serine/threonine kinase, that

14、serine-phosphorylates the IR-inhibiting signaling. Serine phosphorylation of IRS-1 appears to be the mechanism for TNF -mediated insulin resistance. The membrane glycoprotein PC-1 also inhibits IR kinase activity, but it

15、 does not cause serine phosphorylation of the receptor. These are examples of a recently appreciated mechanism for insulin resistance secondary to factors regulating the receptor’s tyrosine kinase activity.,胰島素抵抗的機(jī)理（4）,F

16、IG.2. a normal (control), a PCOS woman with normal insulin-stimulated tyrosine phosphorylation (PCOS-nl) and a PCOS woman with high basal autophosphorylation on serine residues (PCOS-ser); S-serine, Y-tyrosine. Basal aut

17、ophosphorylation is increased and there is minimal further insulin-stimulated phosphorylation in the PCOS-ser b-subunits. The high basal phosphorylation represents phosphoserine, and phosphotyrosine content does not incr

18、ease in response to insulin in the PCOS-ser b-subunits.,FIG. 3. a striking increase in phosphoserine content and a marked decrease in insulin-stimulated phosphotyrosine content after mixing hIR with PCOS-ser lectin elua

19、tes as compared with mixing hIR with control lectin eluates or in the absence of mixing.,NIDDM IR 數(shù)目/IR磷酸化 / 葡萄糖轉(zhuǎn)運(yùn) 胰島素刺激的肌糖原合成 高血糖癥代償,PCOS 與NIDDM的關(guān)系(1),,,,,,PC

20、OS IR 傳導(dǎo)信號起始階段異常 IR磷酸化獨(dú)特類型 PCOS-相關(guān)的胰島素抵抗 與其它 NIDDM 基因相區(qū)別,PCOS 與NIDDM的關(guān)系（2）,,,,PCOS 是 NIDDM的一個(gè)獨(dú)特的亞型,對患有PCOS的絕經(jīng)后婦女，PCOS 及葡萄糖不耐受的研究顯示 PCOS-相關(guān)的胰島素抵抗使患NIDDM的

21、危險(xiǎn)顯著增加。,,降低雄激素水平不能完全恢復(fù)胰島素敏感性。雄激素不引起或引起輕度胰島素抵抗。,雄激素能引起胰島素抵抗?,高胰島素血癥能引起高雄激素血癥？,在PCOS病人，高胰島素血癥能增加雄激素水平。胰島素通過IR直接介導(dǎo)，而不是占據(jù)了IGF-I 受體。類固醇合成異常。降低胰島素水平卻未改變高雄激素 的異常。,FIG. 6 A single factor that causes serine phosphorylati

22、on of the IR and serine phosphorylation of P450c17, the key regulatory enzyme controlling androgen biosynthesis, could produce both the insulin resistance and the hyperandrogenism characteristic of PCOS. It is also possi

23、ble that the insulin resistance and the reproductive abnormalities reflect separate genetic defects and that the insulin resistance unmasks the syndrome in genetically susceptible women. Recent studies suggest that insul

24、in acting through its own receptor augments steroidogenesis and LH release. Androgens amplify the associated insulin resistance.,三、PCOS的診斷,PCOS的定義(1)（1990年NIH標(biāo)準(zhǔn)）,慢性無排卵（Chronic anovalation）高雄激素血癥（Hyperandrogenism） （

25、臨床或生化） (clinical or biochemical)排除其他代謝異常（Exclusion of other etiologies）,PCOS的定義(2)（2003年標(biāo)準(zhǔn)）,少或無排卵（Oligo and/or anovulation）高雄激素血癥（Hyperandrogenism） (clinical and/or biochemical)多囊卵巢（Pol

26、ycystic ovaries） (2 out of 3 criteria) 排除其他代謝異常（Exclusion of other etiologies）,PCOS的定義(3),高雄激素血癥（Hyperandrogenism） 卵巢功能異常（Ovulatory dysfunction）排除其他代謝異常（The exclusion of specific diso

27、rders）PCO不是必需的診斷要求LH/FSH 比值也不是必需的診斷要求,胰島素抵抗的診斷,,餐后2小時(shí)胰島素水平＞100μU/ml GLU/INS ＞4.5 INS/GLU＜0.3重疊臨床檢測與胰島素水平并不完全相關(guān) 所有的 PCOS病人

28、 所有的肥胖婦女,,四、胰島素抵抗的處理,雙胍類藥物二甲雙胍(如格華止)血管緊張素轉(zhuǎn)換酶抑制劑(如開博通、蒙諾)胰島素增敏劑(如羅格列酮)飲食和運(yùn)動(dòng),降低胰島素抵抗的方法,飲食和運(yùn)動(dòng)療法,限制熱量或減輕體重的飲食胰島素敏感性Gn 和 雄激素代謝P450 和 17α-羥化酶活性,,肥胖和缺乏運(yùn)動(dòng)胰島素抵抗,,α-葡萄糖苷酶抑制劑的作用機(jī)理,延緩碳水化合物及二糖的消化,,葡萄糖的吸收,,葡萄糖苷酶抑制劑的用法

29、,阿卡波糖: 100mg tid ，3-6月 （之前或同時(shí)服用格華止/胰島素）,增加血管平滑肌的 IR酪氨酸激酶活性;降低循環(huán)血中的胰島素;增加 SHBG 、LH 和雄激素;降低 17-OHP 對 GnRH的過度反應(yīng);抑制雄激素;降低高胰島素血癥;降低垂體 LH分泌、 膜細(xì)胞雄激素分泌及SHBG的增加。,Metformin 的作用機(jī)理,500 mg , tid, 3-6月 同時(shí)服用 CC / Gn ，或者