绝经后妇女性激素环境的改变与胰岛素抵抗
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摘要
胰岛素抵抗(insulin resistance)是指胰岛素在外周组织摄取和利用葡萄糖的能力下降的一种状态。作为心血管疾病、糖尿病、代谢综合征的发病基础,胰岛素抵抗发生率在绝经后升高严重威胁着老年女性健康。近年来的研究发现,绝经后性激素环境的变化可能与胰岛素抵抗有关,但其机制尚未完全明确。绝经后性激素环境的最大变化是卵巢功能逐渐衰退进而E2水平下降,肾上腺来源的脱氢表雄酮/硫酸脱氢表雄酮(DHEA/DHEA-S)在外周组织的转化逐渐成为性激素的主要来源。在这个变化的过程中,调控性激素的关键蛋白性激素结合球蛋白(SHBG)、游离雄激素、DHEA/DHEA-S及其在外周组织的转化可能参与了绝经后胰岛素抵抗的关键环节。
本课题从人群研究、动物实验、细胞实验三个水平探讨了绝经后性激素环境的变化与胰岛素抵抗的关系,研究绝经后性激素环境的变化是否通过影响体脂、血脂、胰岛素抵抗相关细胞因子介导胰岛素抵抗,分析在绝经后早期妇女中应用激素替代疗法能否改善胰岛素抵抗,并进一步研究性激素受体表达的变化、DHEA/DHEA-S的外周转化是否与绝经后胰岛素抵抗有关。
第一部分绝经后妇女性激素环境的改变与胰岛素抵抗
目的研究绝经后早期、晚期性激素环境的不同与胰岛素抵抗之间的关系以及其是否能通过影响体脂、血脂增加胰岛素抵抗的风险,研究在绝经后早期妇女中应用HRT能否通过改善体脂、血脂进而改善胰岛素抵抗。
方法募集绝经后早期妇女(绝经时间≤5年)105名、绝经后晚期妇女(绝经时间≥10年)107名,并进一步根据体重指数(BMI)分为正常体重组(BMI<24kg/m2)、超重肥胖组(BMI≥24kg/m2)。采用双能X线吸收法(DEXA)测定体脂分布情况,抽取空腹血检测SHBG、T、E2、DHEA-S、 Glu、Ins、TC、TG、HDL-c、LDL-c、apoA、apoB水平并计算游离睾酮指数(FAI)和稳态模型胰岛素抵抗指数(HOMA-IR),采用偏相关分析、多元线性回归分析、单因素方差分析等统计方法分析SHBG、FAI、E2、 T、DHEA-S与体脂分布、血脂、胰岛素抵抗的关系。募集25名绝经后早期妇女(绝经时间≤5年)并用戊酸雌二醇(补佳乐)+孕激素(琪宁)周期序贯HRT进行干预一年,每三月随访一次,测定治疗前后体脂、血脂、性激素水平、胰岛素、血糖,采用配对t检验分析HRT对体脂、血脂、胰岛素抵抗的影响。
结果绝经后晚期妇女比绝经后早期妇女脂肪含量、TG、Ins、HOMA-IR更高,DHEA-S、E2、apoA/apoB水平更低(p<0.05)。无论是绝经后早期妇女还是绝经后晚期妇女,超重肥胖组比正常体重组T/L、男性脂肪比例、HOMA-IR、Ins更高而女性脂肪比例、apoA/apoB更低(p<0.05),而血脂其它指标无显著差异(p>0.05)。在绝经后早期妇女中、超重肥胖组比正常体重组SHBG更低而FAI更高(p<0.05)。在绝经后晚期妇女中,超重肥胖组比正常体重DHEA-S、E2更高(p<0.05)。偏相关分析和多元线性回归分析表明：在绝经后早期妇女中,FAI与腹部脂肪堆积成正相关,SHBG与apoA/apoB成正相关,SHBG与Ins、HOMA-IR成负相关,DHEA-S与Glu成正相关(p<0.05)；在绝经后晚期妇女中,DHEA-S与腹部脂肪堆积成正相关而与apoA成负相关,FAI与Glu成正相关(p<0.05)。经过HRT治疗一年后,生活质量明显改善,T/L、男性脂肪比例、HOMA-IR明显下降(p<0.05),而女性脂肪比例明显上升(p<0.05),血脂各项指标之间无显著差异(p>0.05)。
结论绝经后雄激素活性升高与胰岛素抵抗风险增加有关,这种相关性在绝经后不同阶段表现有所不同,主要体现在：低水平SHBG引起的FAI升高、卵巢功能逐渐丧失引起的肥胖妇女体内代偿性DHEA-S升高,而且低SHBG、高FAI与DHEA-S能导致腹部脂肪堆积、apoA下降并进一步影响胰岛素抵抗。绝经后早期妇女进行HRT能显著改善体脂分布和HOMA-IR.
第二部分戊酸雌二醇对去势大鼠胰岛素抵抗的影响及相关核受体机制
目的研究戊酸雌二醇(补佳乐)对去势大鼠性激素水平、体脂、血脂、细胞因子、胰岛素抵抗的影响,进一步探讨戊酸雌二醇(补佳乐)对去势大鼠肝脏组织中SHBG、PPARγ、性激素受体(AR、ERα、ERβ)及DHEA外周转化所需的酶(17β-HSD、芳香化酶)表达的影响。
方法27只雌性SD大鼠分为三组：假手术组(SHAM, n=10)、去势组(OVX,n=8)、去势+补佳乐组(OVX+E2, n=9)。双卵巢切除后OVX+E2组用补佳乐灌胃(800μg/kg-d), SHAM和OVX组蒸馏水灌胃,每两周称重一次,12周后处死动物。腹主动脉抽血检测SHBG、T、E2、DHEA, Glu、Ins、TC、TG、HDL-c、LDL-c、TNF-α、IL-6、脂联素、瘦素水平,摘取内脏脂肪并计算内脏脂肪系数,摘取肝脏组织切片进行HE染色,用Western blot、Real-time PCR检测肝脏组织中SHBG、PPARγ、AR、 ERα、ERβ、17β-HSD、芳香化酶的表达。
结果 与SHAM组相比,OVX组动物E2、SHBG明显下降,FAI、DHEA、体重、VFM、IL-6、HOMA-IR明显上升(p<0.05),肝脏组织中脂肪堆积明显增多；OVX+E2组与OVX组动物相比,E2、SHBG、HDL-c明显上升,FAI、体重、VFM、LDL-c、IL-6、HOMA-IR明显下降(p<0.05),肝脏组织中脂肪堆积明显减少。与此同时,OVX组比SHAM组PPARγ、 AR、17β-HSD、芳香化酶的表达明显升高,而SHBG、ERα的表达明显下降(p<0.05)；采用补佳乐干预后,这种趋势呈现一定程度的逆转(p<0.05)。
结论在动物实验中,补佳乐能逆转由于手术绝经导致的内脏脂肪堆积、IL-6及HOMA-IR升高(这些变化与E2和SHBG下降、FAI升高、DHEA代偿性升高有关)。绝经后胰岛素抵抗风险增加可能与肝脏组织中PPARγ、 AR、DHEA外周转化升高以及SHBG、ERα表达下降有关。
第三部分HepG2细胞中胰岛素抵抗状态下SHBG的表达及DHEA外周转化对胰岛素受体信号通路的影响
目的研究胰岛素抵抗模型下SHBG表达的变化,不同浓度DHEA及其外周转化对胰岛素受体信号通路中的关键分子(IR、IRS-2、GLUT-2)表达的影响。
方法采用高胰岛素诱导方法建立胰岛素抵抗HepG2细胞模型,并检测胰岛素抵抗状态下SHBG的表达；用E2、T、不同浓度DHEA作用于HepG2细胞72h,检测IR、IRS-2、GLUT-2的表达；采用来曲唑(letrizole)、曲洛司坦(trilostane)阻断DHEA外周转化后,检测IR、IRS-2、GLUT-2的表达。
结果浓度为10-6M胰岛素作用于HepG2细胞36h后,细胞达到最大胰岛素抵抗状态,与此同时SHBG蛋白及mRNA表达最低(p<0.05)。高浓度(10-5M)DHEA的作用和T类似,明显下调IR、IRS-2、GLUT-2蛋白与mRNA表达；随着浓度的降低,DHEA的下调作用减弱；10-9M浓度的DHEA作用于细胞后IRS-2、GLUT-2蛋白与mRNA表达较空白对照组上升(类似于E2)；和空白对照组相比,E2明显上调IR、IRS-2、GLUT-2蛋白与mRNA表达(p<0.05)。与单独DHEA作用相比,Letrizole阻断后IR、IRS-2、GLUT-2蛋白和mRNA表达明显下调；与DHEA+Letrizole作用相比,Trilostane阻断后,IR、IRS-2、GLUT-2蛋白和mRNA表达明显上升(p<0.05)。
结论肝细胞中SHBG表达下降、DHEA向雄激素转化较雌激素更多与胰岛素抵抗有关。DHEA对胰岛素抵抗的作用与浓度有关：高浓度DHEA与T作用类似,下调胰岛素受体信号通路中IR、IRS-2、GLUT-2的表达从而促进胰岛素抵抗；而低浓度DHEA与E2作用类似,上调IRS-2、GLUT-2的表达从而改善胰岛素抵抗。
1.绝经后性激素环境的改变(特别是雄激素活性增加)增加了胰岛素抵抗的风险,主要体现在：在绝经后早期,E2下降进而SHBG下降、FAI升高,卵巢逐渐丧失功能从而代偿性高DHEA/DHEA-S;在绝经后晚期,肾上腺来源的DHEA/DHEA-S外周转化增加。
2、内脏脂肪堆积、血脂异常、IL-6升高可能是性激素介导胰岛素抵抗的作用环节。人群调查和动物实验表明,绝经后早期HRT能通过改善体脂、血脂、降低IL-6水平进而改善胰岛素抵抗。
3、肝脏组织中PPARy表达升高引发SHBG下降,ERa表达下降、AR表达升高可能是性激素介导绝经后胰岛素抵抗的受体机制。
4、DHEA在肝脏细胞中向雄激素转化更多与胰岛素抵抗有关。肝细胞中DHEA对胰岛素受体信号通路的作用与浓度有关,高浓度DHEA促进胰岛素抵抗而低浓度DHEA改善胰岛素抵抗。
Insulin resistance is defined as the peripheral tissues'decreased ability of utilizing glucose. As the common risk factor of coronary heart diseases, metabolic syndrome and type2diabetes, the increased incidence of insulin resistance after menopause is detrimental to the health of elderly women.During recent years many researches suggested that the changes of sex hormone environment after menopause were associated with insulin resistance, but the concrete mechanisms are still unknown. The most remarkable changes of sex hormone environment after menopause are the gradually reduced sex hormones originating from ovaries and the peripheral synthesis from dehydroepiandrosterone(DHEA) or dehydroepiandrosterone-sulfate (DHEA-S) originating from the adrenals.In these processes, sex hormone-binding globulin (SHBG) which is the key protein regulating sex hormones,free androgens,DHEA/DHEA-S and their peripheral transformation may mediated the key steps of insulin resistance.
Our studies dicussed the relationships between the changes of sex hormone environment after menopause and insulin resistance according to population based investigation, animal experiment and cell experiment. To determine whether the changes of sex hormone environment after menopause mediate insulin resistance by modulating body fat distribution and blood lipids. We also analyzed whether hormone replacement therapy (HRT) in early postmenopausal women could improve insulin resistance and studied whether the changes of sex hormone receptors and peripheral transformation of DHEA/DHEA-S correlated with insulin resistance.
Part Ⅰ The changes of sex hormone environment and insulin resistance after menopause
Objectives:To determine the relationships between insulin resistance and sex hormone environment which are different between early postmenopause and late postmenopause. To study whether the changes of sex hormone environment could improve insulin resistance by regulating body fat and blood lipids and whether hormone replacement therapy (HRT) in early postmenopausal women could improve insulin resistance.
Methods:We enrolled postmenopausal women consisting of an early group years since menopause, n=105) and an elder group (≥10years since menopause, n=107). Each group was subdivided into normal weight (BMI<24kg/m2) group, overweight and obese (BMI≥24kg/m2) group. Body fat distribution was evaluated by dual-energy X-ray absorptiometry (DEXA). Fasting SHBG, T, E2, DHEA-S, Glu, Ins, TC, TG, HDL-c, LDL-c, apoA, apoB levels were measured and then calculated FAI and HOMA-IR. The relationships among sex hormone environment and body fat, blood lipids and insulin resistance were estimated by partial correlation, multiple linear regression and oneway ANOVA analyses. We also recruited25early postmenopausal women (≤5years since menopause) which accepted HRT (progynova+progesterone, cyclic combined therapy) for one year. Follow up visit were performed every3months. We measured sex hormones, body fat, blood lipids, insulin and glucose before and after therapy.The effects of HRT on body fat, blood lipids and insulin resistance were evaluated by matching t-test.
Results:Compared to early postmenopausal women, late postmenopausal women had higher proportion of body fat, TG, Ins and HOMA-IR but they had lower DHEA-S,E2and apoA/apoB (all p<0.05).Both in early postmenopausal and late postmenopausal groups, overweight and obese women had higher T/L, the proportion of android fat, HOMA-IR and Ins, they had lower apoA/apoB and the proportion of gynoid fat than normal weight women (all p<0.05),but there were no significant differences in other blood lipids between normal weight women and overweight and obese women (p>0.05).In early postmenopausal group, overweight and obese women had lower SHBG and higher FAI than normal weight women (all p<0.05).In late postmenopausal group, overweight and obese women had higher DHEA-S and E2levels (all p<0.05). Partial correlation and multiple linear regression analyses suggested that:In early postmenopausal group, FAI correlated positively with abodominal fat accumulation, SHBG correlated positively with apoA/apoB and negatively with Ins and HOMA-IR, DHEA-S correlated positively with glucose (all p<0.05). In late postmenopausal group, DHEA-S correlated positively with abodominal fat accumulation and negatively with apoA, FAI correlated positively with glucose (all p<0.05).After one-year HRT, the quality of women's life were significantly improved, their T/L, the proportion of android fat and HOMA-IR decreased significantly but the proportion of gynoid fat increased significantly (all p<0.05). There were no significant differences in blood lipids between before and after HRT (all p>0.05)
Conclusions:The increased androgenic activities after menopause are associated with insulin resistance. These correlations are different during the different stages of posmenopause and mainly incarnate in:high FAI caused by low SHBG, compensatory high DHEA-S in obese postmenopausal women caused by gradual cesscation of ovary function. High FAI and DHEA-S and low SHBG may affect insulin resistance according to regulating body fat and apoA. HRT in early postmenopausal women could improve insulin resistance.
Part II The effects of progynova on insulin resistance in ovariectomised rats and their nuclear receptor mechanisms
Objectives:To determine the effects of progynova on sex hormones,body fat,blood lipids and insulin resistance in ovariectomised Sprague-Dawley rats.And then to discusss the effects of progynova on the expressions of SHBG、PPAR、AR、ERα、 ERβ、17β-HSD and aromatase.
Methods:Twenty-seven female SD rats were divided into three groups:SHAM group (n=10), OVX group (n=8) and OVX+E2group (n=9).After ovariectomy OVX+E2group received800μg/kg progynova via gavage daily, SHAM and OVX groups received2ml water via gavage daily. Weight and food intake were recorded every two weeks. All of the animals were euthanized12weeks after ovariectomy, then we collected blood from abdominal aorta, after which their fasting SHBG,T,E2,DHEA,Glu,Ins,TC,TG,HDL-c,LDL-c,TNF-a,IL-6,adiponectin and leptin levels were measured. After euthanising the rats, we opened their abdominal cavities and accessed all of their intra-abdominal fat. We then weighed and calculated their visceral fat mass (VFM=visceral fat weight/body weight,%). Liver tissue slices were stained by hemotoxylin and eosin (HE).We also detected the expressions of SHBG、PPARγ、AR、ERα、ERβ、17β-HSD and aromatase in liver tissue using Western blot and Real-time PCR.
Results:Compared to SHAM group, OVX group had lower E2and SHBG levels,higher FAI,DHEA,body weight,VFM,IL-6and HOMA-IR (all p<0.05),OVX group also had significantly higher fat accumulation in liver. Compared to OVX group,OVX+E2group had higher E2,SHBG and HDL-c levels,lower FAI,DHEA,body weight,VFM,LDL-c,IL-6,HOMA-IR and fat accumulation in liver (all p<0.05). In the meantime, the expressions of PPARy,AR,17β-HSD and aromatase in the liver of OVX group were higher than SHAM group.The expressions of SHBG and ERa in the liver of OVX group were lower than SHAM group (all p<0.05). After progynova therapy, these tendencies were reversed to some extent (all p<0.05)
Conclusions:In animal experiment, progynova can reverse visceral fat accumaltion, high IL-6and HOMA-IR induced by surgical menopause (These changes correlated with low SHBG and E2, high FAI and DHEA-S). The increased incidence of insulin resistance after menopause correlated with high expressions of PPARy and AR, low expressions of SHBG and ERa, peripheral transformation of DHEA.
PartⅢ The expressions of SHBG in the HepG2cell model of insulin resistance and the effects of peripheral transformation of DHEA on insulin receptor signal path
Objectives:To detect the expression of SHBG in cell model of insulin resistance and the effects of different concentrations of DHEA and their peripheral transformation on the key molecule(IR,IRS-2,GLUT-2) of insulin receptor signal path.
Methods:We established cell model of insulin resistance in HepG2cell line induced by high dose of insulin and then detected the expression of SHBG in the condition of insulin resistance. After72h stimulation of E2,T and different concentrations of DHEA,then we detected the expressions of IR,IRS-2and GLUT-2. We used letrizole and trilostane to inhibit peripheral transformation of DHEA in HepG2cell line and then detected the expressions of IR, IRS-2and GLUT-2.
Results:HepG2cells reached the extreme insulin resistance after the stimulation of insulin at a concentration of10-6M for36h. In the meantime, the expressions of SHBG protein and mRNA touched the bottom (p<0.05). High concentration of DHEA (10-5M) down-regulated the expressions of IR, IRS-2and GLUT-2, which was similar to T. As the concentration reduced, the effects of down-regulation were weakened.10-9M concentration of DHEA up-regulated the expressions of IRS-2and GLUT-2, which was similar to E2. Compared to the control group, E2significantly up-regulated the expressions of IR, IRS-2and GLUT-2. After inhibited by letrizole, the expressions of IR, IRS-2and GLUT-2were down-regulated compared with the effects of sole DHEA. The expressions of IR, IRS-2and GLUT-2were up-regulated after inhibited by trilostane than combination of DHEA and letrizole (p<0.05)
Conclusions:There were two factors associated with insulin resistance in HepG2cell line:The expression of SHBG decreased and DHEA-S converted more readily to androgens than to estrogens. The effects of DHEA on insulin resistance correlated with its concentration:High concentration of DHEA down-regulated the expressions of IR, IRS-2and GLUT-2, which was similar to T. Low concentration of DHEA up-regulated the expressions of IRS-2and GLUT-2, which was similar to E2.
1、The changes of sex hormone environment after menopause (especially, the increased androgenic activities) increase the risk of insulin resistance and this correlation mainly incarnates in:In early postmenopause, low SHBG caused by low E2,high FAI caused by low SHBG, compensatory high DHEA induced by gradual cessation of ovarian function; In late postmenopause, the increased peripheral transformation of DHEA/DHEA-S induced by the cessation of ovarian function.
2、Visceral fat accumulation, abnormal blood lipids and increased IL-6levels are the possible aspects of the effects of the changes of sex hormone environment after menopause on insulin resistance.Population based investigation and animal experiment suggested that HRT in early postmenopause could improve insulin resistance by regulating body fat distribution, blood lipids and IL-6levels.
3、The decreased expression of SHBG induced by high PPARy,the decreased expression of ERa, the increased expression of AR are the possible receptor mechanisms which the changes of sex hormone environment mediated insulin resistance.
4、DHEA-S converted more readily to androgens than to estrogens in liver, which correlates with insulin resistance. The effects of DHEA on insulin receptor signal path depending on its concentration:High concentration of DHEA promotes insulin resistance and low concentration of DHEA could improves insulin resistance.
本课题从人群研究、动物实验、细胞实验三个水平探讨了绝经后性激素环境的变化与胰岛素抵抗的关系,研究绝经后性激素环境的变化是否通过影响体脂、血脂、胰岛素抵抗相关细胞因子介导胰岛素抵抗,分析在绝经后早期妇女中应用激素替代疗法能否改善胰岛素抵抗,并进一步研究性激素受体表达的变化、DHEA/DHEA-S的外周转化是否与绝经后胰岛素抵抗有关。
第一部分绝经后妇女性激素环境的改变与胰岛素抵抗
目的研究绝经后早期、晚期性激素环境的不同与胰岛素抵抗之间的关系以及其是否能通过影响体脂、血脂增加胰岛素抵抗的风险,研究在绝经后早期妇女中应用HRT能否通过改善体脂、血脂进而改善胰岛素抵抗。
方法募集绝经后早期妇女(绝经时间≤5年)105名、绝经后晚期妇女(绝经时间≥10年)107名,并进一步根据体重指数(BMI)分为正常体重组(BMI<24kg/m2)、超重肥胖组(BMI≥24kg/m2)。采用双能X线吸收法(DEXA)测定体脂分布情况,抽取空腹血检测SHBG、T、E2、DHEA-S、 Glu、Ins、TC、TG、HDL-c、LDL-c、apoA、apoB水平并计算游离睾酮指数(FAI)和稳态模型胰岛素抵抗指数(HOMA-IR),采用偏相关分析、多元线性回归分析、单因素方差分析等统计方法分析SHBG、FAI、E2、 T、DHEA-S与体脂分布、血脂、胰岛素抵抗的关系。募集25名绝经后早期妇女(绝经时间≤5年)并用戊酸雌二醇(补佳乐)+孕激素(琪宁)周期序贯HRT进行干预一年,每三月随访一次,测定治疗前后体脂、血脂、性激素水平、胰岛素、血糖,采用配对t检验分析HRT对体脂、血脂、胰岛素抵抗的影响。
结果绝经后晚期妇女比绝经后早期妇女脂肪含量、TG、Ins、HOMA-IR更高,DHEA-S、E2、apoA/apoB水平更低(p<0.05)。无论是绝经后早期妇女还是绝经后晚期妇女,超重肥胖组比正常体重组T/L、男性脂肪比例、HOMA-IR、Ins更高而女性脂肪比例、apoA/apoB更低(p<0.05),而血脂其它指标无显著差异(p>0.05)。在绝经后早期妇女中、超重肥胖组比正常体重组SHBG更低而FAI更高(p<0.05)。在绝经后晚期妇女中,超重肥胖组比正常体重DHEA-S、E2更高(p<0.05)。偏相关分析和多元线性回归分析表明：在绝经后早期妇女中,FAI与腹部脂肪堆积成正相关,SHBG与apoA/apoB成正相关,SHBG与Ins、HOMA-IR成负相关,DHEA-S与Glu成正相关(p<0.05)；在绝经后晚期妇女中,DHEA-S与腹部脂肪堆积成正相关而与apoA成负相关,FAI与Glu成正相关(p<0.05)。经过HRT治疗一年后,生活质量明显改善,T/L、男性脂肪比例、HOMA-IR明显下降(p<0.05),而女性脂肪比例明显上升(p<0.05),血脂各项指标之间无显著差异(p>0.05)。
结论绝经后雄激素活性升高与胰岛素抵抗风险增加有关,这种相关性在绝经后不同阶段表现有所不同,主要体现在：低水平SHBG引起的FAI升高、卵巢功能逐渐丧失引起的肥胖妇女体内代偿性DHEA-S升高,而且低SHBG、高FAI与DHEA-S能导致腹部脂肪堆积、apoA下降并进一步影响胰岛素抵抗。绝经后早期妇女进行HRT能显著改善体脂分布和HOMA-IR.
第二部分戊酸雌二醇对去势大鼠胰岛素抵抗的影响及相关核受体机制
目的研究戊酸雌二醇(补佳乐)对去势大鼠性激素水平、体脂、血脂、细胞因子、胰岛素抵抗的影响,进一步探讨戊酸雌二醇(补佳乐)对去势大鼠肝脏组织中SHBG、PPARγ、性激素受体(AR、ERα、ERβ)及DHEA外周转化所需的酶(17β-HSD、芳香化酶)表达的影响。
方法27只雌性SD大鼠分为三组：假手术组(SHAM, n=10)、去势组(OVX,n=8)、去势+补佳乐组(OVX+E2, n=9)。双卵巢切除后OVX+E2组用补佳乐灌胃(800μg/kg-d), SHAM和OVX组蒸馏水灌胃,每两周称重一次,12周后处死动物。腹主动脉抽血检测SHBG、T、E2、DHEA, Glu、Ins、TC、TG、HDL-c、LDL-c、TNF-α、IL-6、脂联素、瘦素水平,摘取内脏脂肪并计算内脏脂肪系数,摘取肝脏组织切片进行HE染色,用Western blot、Real-time PCR检测肝脏组织中SHBG、PPARγ、AR、 ERα、ERβ、17β-HSD、芳香化酶的表达。
结果 与SHAM组相比,OVX组动物E2、SHBG明显下降,FAI、DHEA、体重、VFM、IL-6、HOMA-IR明显上升(p<0.05),肝脏组织中脂肪堆积明显增多；OVX+E2组与OVX组动物相比,E2、SHBG、HDL-c明显上升,FAI、体重、VFM、LDL-c、IL-6、HOMA-IR明显下降(p<0.05),肝脏组织中脂肪堆积明显减少。与此同时,OVX组比SHAM组PPARγ、 AR、17β-HSD、芳香化酶的表达明显升高,而SHBG、ERα的表达明显下降(p<0.05)；采用补佳乐干预后,这种趋势呈现一定程度的逆转(p<0.05)。
结论在动物实验中,补佳乐能逆转由于手术绝经导致的内脏脂肪堆积、IL-6及HOMA-IR升高(这些变化与E2和SHBG下降、FAI升高、DHEA代偿性升高有关)。绝经后胰岛素抵抗风险增加可能与肝脏组织中PPARγ、 AR、DHEA外周转化升高以及SHBG、ERα表达下降有关。
第三部分HepG2细胞中胰岛素抵抗状态下SHBG的表达及DHEA外周转化对胰岛素受体信号通路的影响
目的研究胰岛素抵抗模型下SHBG表达的变化,不同浓度DHEA及其外周转化对胰岛素受体信号通路中的关键分子(IR、IRS-2、GLUT-2)表达的影响。
方法采用高胰岛素诱导方法建立胰岛素抵抗HepG2细胞模型,并检测胰岛素抵抗状态下SHBG的表达；用E2、T、不同浓度DHEA作用于HepG2细胞72h,检测IR、IRS-2、GLUT-2的表达；采用来曲唑(letrizole)、曲洛司坦(trilostane)阻断DHEA外周转化后,检测IR、IRS-2、GLUT-2的表达。
结果浓度为10-6M胰岛素作用于HepG2细胞36h后,细胞达到最大胰岛素抵抗状态,与此同时SHBG蛋白及mRNA表达最低(p<0.05)。高浓度(10-5M)DHEA的作用和T类似,明显下调IR、IRS-2、GLUT-2蛋白与mRNA表达；随着浓度的降低,DHEA的下调作用减弱；10-9M浓度的DHEA作用于细胞后IRS-2、GLUT-2蛋白与mRNA表达较空白对照组上升(类似于E2)；和空白对照组相比,E2明显上调IR、IRS-2、GLUT-2蛋白与mRNA表达(p<0.05)。与单独DHEA作用相比,Letrizole阻断后IR、IRS-2、GLUT-2蛋白和mRNA表达明显下调；与DHEA+Letrizole作用相比,Trilostane阻断后,IR、IRS-2、GLUT-2蛋白和mRNA表达明显上升(p<0.05)。
结论肝细胞中SHBG表达下降、DHEA向雄激素转化较雌激素更多与胰岛素抵抗有关。DHEA对胰岛素抵抗的作用与浓度有关：高浓度DHEA与T作用类似,下调胰岛素受体信号通路中IR、IRS-2、GLUT-2的表达从而促进胰岛素抵抗；而低浓度DHEA与E2作用类似,上调IRS-2、GLUT-2的表达从而改善胰岛素抵抗。
1.绝经后性激素环境的改变(特别是雄激素活性增加)增加了胰岛素抵抗的风险,主要体现在：在绝经后早期,E2下降进而SHBG下降、FAI升高,卵巢逐渐丧失功能从而代偿性高DHEA/DHEA-S;在绝经后晚期,肾上腺来源的DHEA/DHEA-S外周转化增加。
2、内脏脂肪堆积、血脂异常、IL-6升高可能是性激素介导胰岛素抵抗的作用环节。人群调查和动物实验表明,绝经后早期HRT能通过改善体脂、血脂、降低IL-6水平进而改善胰岛素抵抗。
3、肝脏组织中PPARy表达升高引发SHBG下降,ERa表达下降、AR表达升高可能是性激素介导绝经后胰岛素抵抗的受体机制。
4、DHEA在肝脏细胞中向雄激素转化更多与胰岛素抵抗有关。肝细胞中DHEA对胰岛素受体信号通路的作用与浓度有关,高浓度DHEA促进胰岛素抵抗而低浓度DHEA改善胰岛素抵抗。
Insulin resistance is defined as the peripheral tissues'decreased ability of utilizing glucose. As the common risk factor of coronary heart diseases, metabolic syndrome and type2diabetes, the increased incidence of insulin resistance after menopause is detrimental to the health of elderly women.During recent years many researches suggested that the changes of sex hormone environment after menopause were associated with insulin resistance, but the concrete mechanisms are still unknown. The most remarkable changes of sex hormone environment after menopause are the gradually reduced sex hormones originating from ovaries and the peripheral synthesis from dehydroepiandrosterone(DHEA) or dehydroepiandrosterone-sulfate (DHEA-S) originating from the adrenals.In these processes, sex hormone-binding globulin (SHBG) which is the key protein regulating sex hormones,free androgens,DHEA/DHEA-S and their peripheral transformation may mediated the key steps of insulin resistance.
Our studies dicussed the relationships between the changes of sex hormone environment after menopause and insulin resistance according to population based investigation, animal experiment and cell experiment. To determine whether the changes of sex hormone environment after menopause mediate insulin resistance by modulating body fat distribution and blood lipids. We also analyzed whether hormone replacement therapy (HRT) in early postmenopausal women could improve insulin resistance and studied whether the changes of sex hormone receptors and peripheral transformation of DHEA/DHEA-S correlated with insulin resistance.
Part Ⅰ The changes of sex hormone environment and insulin resistance after menopause
Objectives:To determine the relationships between insulin resistance and sex hormone environment which are different between early postmenopause and late postmenopause. To study whether the changes of sex hormone environment could improve insulin resistance by regulating body fat and blood lipids and whether hormone replacement therapy (HRT) in early postmenopausal women could improve insulin resistance.
Methods:We enrolled postmenopausal women consisting of an early group years since menopause, n=105) and an elder group (≥10years since menopause, n=107). Each group was subdivided into normal weight (BMI<24kg/m2) group, overweight and obese (BMI≥24kg/m2) group. Body fat distribution was evaluated by dual-energy X-ray absorptiometry (DEXA). Fasting SHBG, T, E2, DHEA-S, Glu, Ins, TC, TG, HDL-c, LDL-c, apoA, apoB levels were measured and then calculated FAI and HOMA-IR. The relationships among sex hormone environment and body fat, blood lipids and insulin resistance were estimated by partial correlation, multiple linear regression and oneway ANOVA analyses. We also recruited25early postmenopausal women (≤5years since menopause) which accepted HRT (progynova+progesterone, cyclic combined therapy) for one year. Follow up visit were performed every3months. We measured sex hormones, body fat, blood lipids, insulin and glucose before and after therapy.The effects of HRT on body fat, blood lipids and insulin resistance were evaluated by matching t-test.
Results:Compared to early postmenopausal women, late postmenopausal women had higher proportion of body fat, TG, Ins and HOMA-IR but they had lower DHEA-S,E2and apoA/apoB (all p<0.05).Both in early postmenopausal and late postmenopausal groups, overweight and obese women had higher T/L, the proportion of android fat, HOMA-IR and Ins, they had lower apoA/apoB and the proportion of gynoid fat than normal weight women (all p<0.05),but there were no significant differences in other blood lipids between normal weight women and overweight and obese women (p>0.05).In early postmenopausal group, overweight and obese women had lower SHBG and higher FAI than normal weight women (all p<0.05).In late postmenopausal group, overweight and obese women had higher DHEA-S and E2levels (all p<0.05). Partial correlation and multiple linear regression analyses suggested that:In early postmenopausal group, FAI correlated positively with abodominal fat accumulation, SHBG correlated positively with apoA/apoB and negatively with Ins and HOMA-IR, DHEA-S correlated positively with glucose (all p<0.05). In late postmenopausal group, DHEA-S correlated positively with abodominal fat accumulation and negatively with apoA, FAI correlated positively with glucose (all p<0.05).After one-year HRT, the quality of women's life were significantly improved, their T/L, the proportion of android fat and HOMA-IR decreased significantly but the proportion of gynoid fat increased significantly (all p<0.05). There were no significant differences in blood lipids between before and after HRT (all p>0.05)
Conclusions:The increased androgenic activities after menopause are associated with insulin resistance. These correlations are different during the different stages of posmenopause and mainly incarnate in:high FAI caused by low SHBG, compensatory high DHEA-S in obese postmenopausal women caused by gradual cesscation of ovary function. High FAI and DHEA-S and low SHBG may affect insulin resistance according to regulating body fat and apoA. HRT in early postmenopausal women could improve insulin resistance.
Part II The effects of progynova on insulin resistance in ovariectomised rats and their nuclear receptor mechanisms
Objectives:To determine the effects of progynova on sex hormones,body fat,blood lipids and insulin resistance in ovariectomised Sprague-Dawley rats.And then to discusss the effects of progynova on the expressions of SHBG、PPAR、AR、ERα、 ERβ、17β-HSD and aromatase.
Methods:Twenty-seven female SD rats were divided into three groups:SHAM group (n=10), OVX group (n=8) and OVX+E2group (n=9).After ovariectomy OVX+E2group received800μg/kg progynova via gavage daily, SHAM and OVX groups received2ml water via gavage daily. Weight and food intake were recorded every two weeks. All of the animals were euthanized12weeks after ovariectomy, then we collected blood from abdominal aorta, after which their fasting SHBG,T,E2,DHEA,Glu,Ins,TC,TG,HDL-c,LDL-c,TNF-a,IL-6,adiponectin and leptin levels were measured. After euthanising the rats, we opened their abdominal cavities and accessed all of their intra-abdominal fat. We then weighed and calculated their visceral fat mass (VFM=visceral fat weight/body weight,%). Liver tissue slices were stained by hemotoxylin and eosin (HE).We also detected the expressions of SHBG、PPARγ、AR、ERα、ERβ、17β-HSD and aromatase in liver tissue using Western blot and Real-time PCR.
Results:Compared to SHAM group, OVX group had lower E2and SHBG levels,higher FAI,DHEA,body weight,VFM,IL-6and HOMA-IR (all p<0.05),OVX group also had significantly higher fat accumulation in liver. Compared to OVX group,OVX+E2group had higher E2,SHBG and HDL-c levels,lower FAI,DHEA,body weight,VFM,LDL-c,IL-6,HOMA-IR and fat accumulation in liver (all p<0.05). In the meantime, the expressions of PPARy,AR,17β-HSD and aromatase in the liver of OVX group were higher than SHAM group.The expressions of SHBG and ERa in the liver of OVX group were lower than SHAM group (all p<0.05). After progynova therapy, these tendencies were reversed to some extent (all p<0.05)
Conclusions:In animal experiment, progynova can reverse visceral fat accumaltion, high IL-6and HOMA-IR induced by surgical menopause (These changes correlated with low SHBG and E2, high FAI and DHEA-S). The increased incidence of insulin resistance after menopause correlated with high expressions of PPARy and AR, low expressions of SHBG and ERa, peripheral transformation of DHEA.
PartⅢ The expressions of SHBG in the HepG2cell model of insulin resistance and the effects of peripheral transformation of DHEA on insulin receptor signal path
Objectives:To detect the expression of SHBG in cell model of insulin resistance and the effects of different concentrations of DHEA and their peripheral transformation on the key molecule(IR,IRS-2,GLUT-2) of insulin receptor signal path.
Methods:We established cell model of insulin resistance in HepG2cell line induced by high dose of insulin and then detected the expression of SHBG in the condition of insulin resistance. After72h stimulation of E2,T and different concentrations of DHEA,then we detected the expressions of IR,IRS-2and GLUT-2. We used letrizole and trilostane to inhibit peripheral transformation of DHEA in HepG2cell line and then detected the expressions of IR, IRS-2and GLUT-2.
Results:HepG2cells reached the extreme insulin resistance after the stimulation of insulin at a concentration of10-6M for36h. In the meantime, the expressions of SHBG protein and mRNA touched the bottom (p<0.05). High concentration of DHEA (10-5M) down-regulated the expressions of IR, IRS-2and GLUT-2, which was similar to T. As the concentration reduced, the effects of down-regulation were weakened.10-9M concentration of DHEA up-regulated the expressions of IRS-2and GLUT-2, which was similar to E2. Compared to the control group, E2significantly up-regulated the expressions of IR, IRS-2and GLUT-2. After inhibited by letrizole, the expressions of IR, IRS-2and GLUT-2were down-regulated compared with the effects of sole DHEA. The expressions of IR, IRS-2and GLUT-2were up-regulated after inhibited by trilostane than combination of DHEA and letrizole (p<0.05)
Conclusions:There were two factors associated with insulin resistance in HepG2cell line:The expression of SHBG decreased and DHEA-S converted more readily to androgens than to estrogens. The effects of DHEA on insulin resistance correlated with its concentration:High concentration of DHEA down-regulated the expressions of IR, IRS-2and GLUT-2, which was similar to T. Low concentration of DHEA up-regulated the expressions of IRS-2and GLUT-2, which was similar to E2.
1、The changes of sex hormone environment after menopause (especially, the increased androgenic activities) increase the risk of insulin resistance and this correlation mainly incarnates in:In early postmenopause, low SHBG caused by low E2,high FAI caused by low SHBG, compensatory high DHEA induced by gradual cessation of ovarian function; In late postmenopause, the increased peripheral transformation of DHEA/DHEA-S induced by the cessation of ovarian function.
2、Visceral fat accumulation, abnormal blood lipids and increased IL-6levels are the possible aspects of the effects of the changes of sex hormone environment after menopause on insulin resistance.Population based investigation and animal experiment suggested that HRT in early postmenopause could improve insulin resistance by regulating body fat distribution, blood lipids and IL-6levels.
3、The decreased expression of SHBG induced by high PPARy,the decreased expression of ERa, the increased expression of AR are the possible receptor mechanisms which the changes of sex hormone environment mediated insulin resistance.
4、DHEA-S converted more readily to androgens than to estrogens in liver, which correlates with insulin resistance. The effects of DHEA on insulin receptor signal path depending on its concentration:High concentration of DHEA promotes insulin resistance and low concentration of DHEA could improves insulin resistance.
引文
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