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1、胰岛素抵抗与多囊卵巢综合征,北京大学深圳医院生殖医学中心 李蓉,1921年，Achard 和 Their首先发现糖代谢异常与高雄激素血症有关; 1935年， Stein and Leventhal首先提出PCOS; 1976年，Kahn 和同事发现高雄激素血症、胰岛素抵抗和黑棘皮症有关; 1980年，Burghen 首先提出PCOS与高雄激素血症、高胰岛素血症有关;,背 景,Figure 2. Section of a polycystic ovary with multiple subscapular follicular cysts and stromal hypertrophy (lef
2、t panel). At higher power (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、胰岛素与卵巢功能的关系,胰岛素通过IGF-1受体刺激卵巢分泌雌激素，雄激素及孕酮(细胞色素 p-450c 17 17 -羟
3、化酶 ) 胰岛素抑制肝脏分泌SHBG 雄激素的效应 胰岛素抑制肝脏合成 IGFBP-1 IGF-1的效应 同 Gn相互作用 抑制卵泡的凋亡 闭锁 上调 IGF-1受体,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
4、in increased 17 -hydroxylase 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 in
5、directly by enhancing the amplitude of serum luteinizing hormone (LH) pulses, and luteinizing hormone may then stimulate ovarian cytochrome P450c17 activity.,二、胰岛素抵抗与PCOS,胰岛素及其受体的结构,胰岛素是胰腺Langerhans小岛上的-细胞产生多肽，由A链(21AAs)和B链(30AAs)构成。胰岛素受体由两个-亚单位（135 kDa）和两个-亚单位(95 kDa)构成的异构四聚体。-亚单位：存在于细胞膜外，富含半胱氨酸，是胰
6、岛素的结合位点；-亚单位：三种类型：细胞膜外、细胞膜、细胞浆内，后者含有ATP 结合位点和几个酪氨酸自动磷酸化位点。,胰岛素的作用机理（1）,胰岛素受体-亚单位的酪氨酸位点磷酸化,胰岛素,胰岛素受体-亚单位,获得激酶活性，细胞内蛋白磷酸化,胰岛素受体底物（IRS）,突变,胰岛素抵抗,基因,OGTT PCOS,高胰岛素血症,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,
7、 and the b-subunit contains a ligand-activated tyrosine kinase. Tyrosine autophosphorylation increases the receptor s tyrosine kinase activity whereas serine phosphorylation inhibits it.,胰岛素的作用机理（2）,胰岛素抵抗的机理(1),受体与胰岛素的结合或者受体亲和力无改变50% PCOS-ser : IR 酪氨酸磷酸化 或 IR 丝氨酸磷酸化 50% PCOS-nl: IR下游信号传导受阻 (IRS-1 的磷
8、酸化； PI3-K的活性 ）,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 PI3-K (PI3-kinase) by tyrosine-phosphorylated IRS-1 appears to be the path
9、way for insulin-mediated glucose transport. The Ras-MAP kinase pathway appears to regulate cell growth and glycogen synthesis.,胰岛素抵抗的机理（2）,IR 丝氨酸磷酸化因子 IR 酪氨酸激酶抑制因子膜糖蛋白 PC-1/TNF-a,胰岛素抵抗的机理（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-a
10、ssociated factor, presumably a serine/threonine kinase, 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 ser
11、ine phosphorylation of the receptor. These are examples of a recently appreciated mechanism for insulin resistance secondary to factors regulating the receptors tyrosine kinase activity.,胰岛素抵抗的机理（4）,FIG.2. a normal (control), a PCOS woman with normal insulin-stimulated tyrosine phosphorylation (PCOS
12、-nl) and a PCOS woman with high basal autophosphorylation 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, a
13、nd phosphotyrosine content does not increase 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 eluates as compared with mixing hIR with cont
14、rol lectin eluates or in the absence of mixing.,NIDDM IR 数目/IR磷酸化 / 葡萄糖转运胰岛素刺激的肌糖原合成高血糖症代偿,PCOS 与NIDDM的关系(1),PCOSIR 传导信号起始阶段异常IR磷酸化独特类型PCOS-相关的胰岛素抵抗与其它 NIDDM 基因相区别,PCOS 与NIDDM的关系（2）,PCOS 是 NIDDM的一个独特的亚型,对患有PCOS的绝经后妇女，PCOS 及葡萄糖不耐受的研究显示 PCOS-相关的胰岛素抵抗使患NIDDM的危险显著增加。,降低雄激素水平不能完全恢复胰岛素敏感性。雄激素不引起或引起轻度胰岛素抵抗
15、。,雄激素能引起胰岛素抵抗?,高胰岛素血症能引起高雄激素血症？,在PCOS病人，高胰岛素血症能增加雄激素水平。胰岛素通过IR直接介导，而不是占据了IGF-I 受体。类固醇合成异常。降低胰岛素水平却未改变高雄激素 的异常。,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 th
16、e insulin resistance and the hyperandrogenism characteristic 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 steroidogenesis and LH release. Androgens amplify the associated insulin resistance.,
