Time Past Menopause, Duration of Estrogen Deficiency, and Insulin Action

绝经后时间、雌激素缺乏持续时间和胰岛素作用

• 批准号: 8274766
• 负责人: RACHAEL E VAN PELT
• 金额: $ 44.65万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-07 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8274766
• 关键词: Accounting; Adipose tissue; Advisory Committees; Age; Center for Translational Science Activities; Clinical; Clinical Trials; Cohort Studies; Controlled Study; Crossover Design; Data; Development; Diabetes Mellitus; Distant; Endocrine; Environment; Estradiol; Estrogen Receptors; Estrogen Therapy; Estrogens; Euglycemic Clamping; Fatty acid glycerol esters; Glucose Clamp; Incidence; Insulin; Literature; Measures; Mediating; Mediator of activation protein; Menopause; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Physical activity; Physiological; Placebos; Postmenopause; Randomized; Recording of previous events; Relative (related person); Reporting; Research; Research Personnel; Resource Sharing; Risk; Role; Skeletal Muscle; Societies; Testing; Time; Transdermal substance administration; Woman; aged; base; cardiovascular risk factor; clinically relevant; design; early onset; energy balance; experience; follow-up; glucose disposal; glucose uptake; hormone therapy; improved; insulin sensitivity; metabolic abnormality assessment; population based; prospective; receptor expression; research study; response; sedentary

DESCRIPTION (provided by applicant): Large clinical trials have shown a reduced incidence of type 2 diabetes mellitus (T2DM) in postmenopausal women randomized to estrogen-based hormone therapy (HT) compared to placebo. Moreover, a recent population-based prospective cohort study demonstrated development of T2DM was 69% lower in postmenopausal women who had used HT for more than half of a 5-yr follow-up period compared to women who never used HT. Consistent with this, our preliminary data suggest that the timing of estrogen treatment relative to the menopause may be an important determinant of whether there are favorable effects on insulin action. We observed an inverse association of years since menopause with estradiol (E2)-mediated improvements in insulin-stimulated glucose disposal rate (GDR), such that E2 improved GDR in early postmenopausal women, but decreased GDR in those more than 10 years past menopause. Accumulating data suggest estrogens have divergent effects on cardiovascular risk when initiated close to the onset of menopause rather than distant from the menopause. We hypothesize this is also true for insulin action. The general aim of the current proposal is to determine the effects of time since menopause and duration of estrogen deficiency on the ability of E2 to improve insulin action. As such, we propose to measure GDR (via hyperinsulinemic-euglycemic clamp) in women who are 6 years of the onset of menopause (earlier post menopausal; EPM) or 10 years beyond the menopause (later post menopausal; LPM) and who are naive to HT. All women will be studied with and without short-term (2 weeks) administration of transdermal E2 in a randomized, cross-over design. Our global hypothesis is that the E2-mediated effects on insulin action depend on duration of estrogen deficiency. We postulate that E2 will increase GDR in early postmenopausal women and decrease GDR in late postmenopausal women. Because altered estrogen receptor (ER) expression after prolonged estrogen deficiency could account for reduced ability of E2 to augment insulin action, as an exploratory outcome we will compare ER expression in skeletal muscle and adipose tissue between groups and in response to E2. Confirmation of our hypotheses will provide evidence for a benefit of E2 on insulin action (GDR) when administered early, but not late, after menopause; likely contributing to delayed onset of T2DM.

描述(由申请人提供)：大型临床试验表明，与安慰剂相比，随机接受基于雌激素的激素治疗(HT)的绝经后妇女的2型糖尿病(T2 DM)发病率降低。此外，最近一项基于人群的前瞻性队列研究表明，与从未使用过HT5年的妇女相比，使用HT5年以上的绝经后妇女患T2 DM的几率低69%。与此一致，我们的初步数据表明，雌激素治疗相对于更年期的时机可能是是否对胰岛素作用有有利影响的重要决定因素。我们观察到绝经年限与雌激素(E2)介导的胰岛素刺激的葡萄糖处置速率(GDR)的改善呈负相关，即E2改善了绝经后早期妇女的GDR，但降低了绝经后10年以上的GDR。越来越多的数据表明，雌激素在接近绝经开始时起效，而不是在远离绝经时起效时，对心血管风险有不同的影响。我们假设胰岛素的作用也是如此。目前这项建议的总体目标是确定更年期以来的时间和雌激素缺乏的持续时间对E2改善胰岛素作用的能力的影响。因此，我们建议在绝经后6年(绝经后较早；EPM)或绝经后10年(绝经后较晚；LPM)且对高血压天真的女性中测量GDR(通过高胰岛素-正常血糖钳)。所有女性将以随机、交叉设计接受短期(2周)经皮给药和不经皮给药的研究。我们的总体假设是，雌激素对胰岛素作用的调节依赖于雌激素缺乏的持续时间。我们推测，雌激素会增加绝经后早期妇女的GDR，降低绝经后晚期妇女的GDR。由于长期雌激素缺乏后雌激素受体(ER)表达的改变可能是E2增强胰岛素作用的能力降低的原因，作为探索性结果，我们将比较不同组之间骨骼肌和脂肪组织中ER的表达以及对E2的反应。我们的假说的确认将为绝经后早期而不是晚些时候使用E2对胰岛素作用(GDR)的益处提供证据；可能导致T2 DM的延迟发病。