胰島素抵抗與多囊卵巢綜合征解析

1、胰島素抵抗與多囊卵巢綜合征解析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 polycystic ovary with multiple subscapular follicular cysts and stromal hypertrophy (left panel). At higher po

2、wer (x100) islands of luteinized theca cells are visible in the stroma (right panel). This morphological change is called 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(guò)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 17 17 -羥化酶 )胰島素抑制肝臟分泌SHBG 雄激素的

3、效應(yīng)胰島素抑制肝臟合成 IGFBP-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 directly stimulate (plus signs) ovarian cytochrome P450c17 , resulting in increased 17 -hydroxylase

4、 and, to a lesser extent, 17,20-lyase activity. This would lead to increased production of androstenedione, which is then converted to testosterone by the enzyme 17 -reductase. Alternatively or in conjunction with this, insulin may stimulate ovarian androgen production indirectly by enhancing the am

5、plitude of serum luteinizing hormone (LH) pulses, 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-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)-亞單位（135 kDa）和兩個(gè)-亞單位(95 kDa)構(gòu)成的異構(gòu)四聚體。 -亞單位：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)； -亞單位：三種類(lèi)型：細(xì)胞膜外、細(xì)胞膜、細(xì)

6、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-亞單位的酪氨酸位點(diǎn)磷酸化胰島素胰島素受體-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 heterotetramer 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-acti

7、vated tyrosine kinase. Tyrosine autophosphorylation increases the 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(wú)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(hào)傳導(dǎo)受阻 (IRS-1 的磷酸化； PI3-K的活性 ）Figure 9. The tyrosine-phospho

8、rylated 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 PI3-K (PI3-kinase) by tyrosine-phosphorylated IRS-1 appears to be the pathway for insulin-mediated glucose transport. T

9、he 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 ki

10、nase, that 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 does not cause serine phosphorylation of the receptor. These are exa

11、mples of a recently appreciated mechanism for insulin resistance secondary to factors regulating the receptors tyrosine kinase activity. 胰島素抵抗的機(jī)理（4）FIG.2. a normal (control), a PCOS woman with normal insulin-stimulated tyrosine phosphorylation (PCOS-nl) and a PCOS woman with high basal autophosphory

12、lation on serine residues (PCOS-ser); S-serine, Y-tyrosine. Basal autophosphorylation 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 increase in res

13、ponse 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 eluates as compared with mixing hIR with control lectin eluates or in the absence of mixing. NIDD

14、M 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) PCOS IR 傳導(dǎo)信號(hào)起始階段異常 IR磷酸化獨(dú)特類(lèi)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(duì)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

15、平。胰島素通過(guò)IR直接介導(dǎo)，而不是占據(jù)了IGF-I 受體。類(lèi)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 phosphorylation of the IR and serine phosphorylation of P450c17, the key regulatory enzyme controlling androgen biosynthesis, could produce both the insulin resistance and the hyperandrogenism characte

16、ristic of PCOS. It is also possible 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 insulin acting through its own receptor augments ster

17、oidogenesis 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(wú)排卵（Chronic anovalation）高雄激素血癥（Hyperandrogenism） （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(wú)排卵（Oligo and/or anovulation）高雄激素血癥（Hyperandr

18、ogenism） (clinical and/or biochemical)多囊卵巢（Polycystic 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 disorders）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100U/ml重疊臨床檢測(cè)與胰島素