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

描述（由申请人提供）：大型临床试验显示，与安慰剂相比，绝经后妇女随机接受基于雌激素的激素治疗（HT）可降低2型糖尿病（T2DM）的发病率。此外，最近一项基于人群的前瞻性队列研究表明，与从未使用过激素治疗的妇女相比，在5年随访期间使用激素治疗超过一半的绝经后妇女中，2型糖尿病的发病率降低了69%。与此一致，我们的初步数据表明，雌激素治疗的时间相对于绝经期可能是是否对胰岛素作用有有利影响的重要决定因素。我们观察到绝经后的年数与雌二醇（E2）介导的胰岛素刺激葡萄糖处置率（GDR）的改善呈负相关，例如E2改善了早期绝经后妇女的GDR，但降低了绝经后10年以上妇女的GDR。越来越多的数据表明，雌激素在接近更年期而不是远离更年期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。当前建议的总体目的是确定绝经后时间和雌激素缺乏持续时间对E2改善胰岛素作用能力的影响。因此，我们建议在绝经前6年（绝经后较早；EPM）或绝经后10年（绝经后较晚；LPM）和未接受HT治疗的妇女中测量GDR（通过高胰岛素-血糖钳夹法）。所有女性将在随机交叉设计中接受或不接受短期（2周）透皮E2治疗。我们的总体假设是e2介导的胰岛素作用取决于雌激素缺乏的持续时间。我们假设E2会增加早期绝经后妇女的GDR，降低晚期绝经后妇女的GDR。由于雌激素长期缺乏后雌激素受体（ER）表达的改变可以解释E2增强胰岛素作用能力的降低，作为一项探索性结果，我们将比较两组之间骨骼肌和脂肪组织中的ER表达以及对E2的反应。我们的假设的证实将为E2对胰岛素作用（GDR）的益处提供证据，如果在绝经后早期而不是晚期给药；可能导致T2DM延迟发病。

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. PUBLIC HEALTH RELEVANCE: One of the reported benefits of estrogen therapy in postmenopausal women is reduced incidence of diabetes, but the reason for this is unknown. This study is designed to test whether estrogens improve insulin sensitivity and whether this effect depends on how long after menopause treatment is initiated. It is expected that estrogens improve insulin sensitivity when given early, but not late, after menopause; likely delaying the onset of diabetes.