1、胰岛素抵抗胰岛素抵抗(dkng)(dkng)与多囊卵巢综合与多囊卵巢综合征征北京大学深圳医院(yyun)生殖医学中心李蓉第一页，共三十七页。v19211921年，年，Achard Achard 和和 Their Their首先首先(shuxin)(shuxin)发现糖代发现糖代谢异常与高雄激素血症有关谢异常与高雄激素血症有关;v19351935年，年，Stein and Leventhal Stein and Leventhal首先提出首先提出PCOS;PCOS;v19761976年，年，Kahn Kahn 和同事发现高雄激素血症、胰和同事发现高雄激素血症、胰岛素抵抗和黑棘皮症有关岛素抵抗和黑
2、棘皮症有关;v19801980年，年，Burghen Burghen 首先提出首先提出PCOSPCOS与高雄激素与高雄激素血症、高胰岛素血症有关血症、高胰岛素血症有关;背背 景景第二页，共三十七页。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(ri
3、ght panel).This morphological change is called stromal hyperthecosis and appears to be directly correlated with circulating insulin levels.第三页，共三十七页。一、胰岛素与卵巢功能的关系一、胰岛素与卵巢功能的关系(gun x)(gun x)第四页，共三十七页。v胰岛素通过胰岛素通过IGF-1受体刺激卵巢分泌雌激素，雄激素及受体刺激卵巢分泌雌激素，雄激素及 孕酮孕酮(细胞色素细胞色素 p-450c 17 17-羟化酶羟化酶 )v胰岛素抑制胰岛素抑制(yzh)肝
4、脏分泌肝脏分泌SHBG 雄激素的效应雄激素的效应v胰岛素抑制肝脏合成胰岛素抑制肝脏合成 IGFBP-1 IGF-1的效应的效应v同同 Gn相互作用相互作用v抑制卵泡的凋亡抑制卵泡的凋亡 闭锁闭锁v上调上调 IGF-1受体受体第五页，共三十七页。Figure 1.Possible Mechanisms of Insulin Stimulation of Ovarian Cytochrome P450c17 Activity and Androgen production.In theca cells,insulin may directly stimulate(plus signs)ovaria
5、n 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
6、 androgen production indirectly by enhancing the amplitude of serum luteinizing hormone(LH)pulses,and luteinizing hormone may then stimulate ovarian cytochrome P450c17 activity.第六页，共三十七页。二、胰岛素抵抗二、胰岛素抵抗(dkng)(dkng)与与PCOSPCOS第七页，共三十七页。胰岛素及其受体的结构胰岛素及其受体的结构(jigu)(jigu)v胰岛素是胰腺胰岛素是胰腺LangerhansLangerhans小岛
7、上的小岛上的-细胞产生多肽，细胞产生多肽，由由A A链链(21AAs)(21AAs)和和B B链链(30AAs)(30AAs)构成。构成。v胰岛素受体由两个胰岛素受体由两个-亚单位（亚单位（135 kDa135 kDa）和两个）和两个-亚单位亚单位(95 kDa)(95 kDa)构成的异构四聚体。构成的异构四聚体。-亚单位亚单位：存在于细胞膜外，富含：存在于细胞膜外，富含半胱氨酸半胱氨酸，是胰岛素的结合，是胰岛素的结合位点；位点；-亚单位亚单位：三种类型：细胞膜外、细胞膜、细胞浆内，后者含：三种类型：细胞膜外、细胞膜、细胞浆内，后者含有有(hn yu)(hn yu)ATP ATP 结合位点和几
8、个结合位点和几个酪氨酸酪氨酸自动磷酸化位点。自动磷酸化位点。第八页，共三十七页。胰岛素的作用胰岛素的作用(zuyng)(zuyng)(zuyng)(zuyng)机理（机理（1 1）胰岛素受体胰岛素受体-亚单位亚单位(dnwi)(dnwi)的的酪氨酸酪氨酸位点磷酸化位点磷酸化胰岛素胰岛素胰岛素受体胰岛素受体-亚单位亚单位(dnwi)(dnwi)获得激酶活性，细胞内蛋白磷酸化获得激酶活性，细胞内蛋白磷酸化胰岛素受体底物（胰岛素受体底物（IRSIRS）突变突变胰岛素抵抗胰岛素抵抗基因基因OGTTOGTTPCOSPCOS高胰岛素血症高胰岛素血症第九页，共三十七页。FIG 1.The IR is a h
9、eterotetramer 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.
10、胰岛素的作用胰岛素的作用(zuyng)(zuyng)(zuyng)(zuyng)机理（机理（2 2）第十页，共三十七页。胰岛素抵抗胰岛素抵抗(dkng)(dkng)的机理的机理(1)v受体与胰岛素的结合或者受体与胰岛素的结合或者(huzh)受体亲和力受体亲和力无无改改变变v50%PCOS-ser:IR 酪氨酸磷酸化酪氨酸磷酸化 或或 IR 丝丝氨酸磷酸化氨酸磷酸化 v50%PCOS-nl:IR下游信号传导受阻下游信号传导受阻(IRS-1 的磷酸化；的磷酸化；PI3-K的活性的活性 ）第十一页，共三十七页。Figure 9.The tyrosine-phosphorylated IR phosp
11、horylates 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.The Ras-MAP kinase pathw
12、ay appears to regulate cell growth and glycogen synthesis.胰岛素抵抗胰岛素抵抗(dkng)(dkng)的机理（的机理（2）第十二页，共三十七页。IR 丝氨酸磷酸化因子丝氨酸磷酸化因子(ynz)IR 酪氨酸激酶抑制因子酪氨酸激酶抑制因子膜糖蛋白膜糖蛋白 PC-1/TNF-a胰岛素抵抗胰岛素抵抗(dkng)(dkng)的机理（的机理（3）抑制抑制(yzh)IR 酪氨酸激酶活性酪氨酸激酶活性第十三页，共三十七页。Figure 14.Insulin resistance in 50%of PCOS women appears to be sec
13、ondary 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
14、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 receptors tyrosine kinase activity.胰岛素抵抗胰岛素抵抗(dkng)(dkng)的机理的机理（4）第十四页，共三十七页。FIG.2.a normal(control),a PCOS woman with normal ins
15、ulin-stimulated tyrosine phosphorylation(PCOS-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 phos
16、phorylation represents phosphoserine,and phosphotyrosine content does not increase in response to insulin in the PCOS-ser b-subunits.第十五页，共三十七页。FIG.3.astrikingincreaseinphosphoserinecontentandaastrikingincreaseinphosphoserinecontentandamarkeddecreaseininsulin-stimulatedphosphotyrosinemarkeddecreaseininsulin-stimulatedphosphotyrosinecontentaftermixinghIRwithPCOS-serlectineluatesascontentaftermixinghIRwithPCOS-serlectineluatesascomparedwithmixinghIRwithcontrollectineluatesorcomparedwithmixinghIRwi
