胰岛素抵抗和多囊卵巢综合征课件.pptVIP

胰岛素抵抗和多囊卵巢综合征 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 (left 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 17α 17 α-羟化酶 ) 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 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 indirectly 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β-细胞产生多肽，由A链(21AAs)和B链(30AAs)构成。 胰岛素受体由两个α-亚单位（135 kDa）和两个β-亚单位(95 kDa)构成的异构四聚体。 α-亚单位：存在于细胞膜外，富含半胱氨酸，是胰岛素的结合位点； β-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β-亚单位的酪氨酸位点磷酸化 胰岛素 胰岛素受体α-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, and the b-subunit contains a ligand-activated tyrosine kinase. Tyrosine autophosphorylation increases the receptor’ s tyrosine kinase activity whereas serin