胰岛素抵抗和多囊卵巢综合征详解演示文稿

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 的磷酸化； PI3-K的活性 ）
胰岛素抵抗的机理（2）
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 tyrosinephosphorylated 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.
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
Figure 1. Possible Mechanisms of Ie 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,
胰岛素受体α-亚单位
胰岛素受体β-亚单位的酪氨酸位点磷酸化
获得激酶活性，细胞内蛋白磷酸化
突变
胰岛素抵抗
胰岛素受体底物（IRS）
基因
高胰岛素血症
OGTT PCOS
胰岛素的作用机理（2）
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 serine phosphorylation inhibits it.
胰岛素抵抗的机理（3）
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
抑制 IR 酪氨酸激酶活性
胰岛素抵抗的机理（4）
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 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 examples of a recently appreciated mechanism for insulin resistance secondary to factors regulating the receptor’s tyrosine kinase activity.
胰岛素抵抗和多囊卵巢综合征 详解演示文稿
（优选）胰岛素抵抗和多囊卵 巢综合征
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