The Effect of Sex Hormones on Cardiometabolic Outcomes in Men and Women with Diabetes: The Look AHEAD (Action for Health in Diabetes) Study

虽然女性和男性的2型糖尿病（DM）患病率大致相同，但DM在临床上对女性和男性的糖尿病患者造成了严重的影响。 冠心病（高44%）、中风（高27%）和血管性心脏病的相对风险显著增加。 痴呆症（女性比男性高19%）。了解这些性别差异可以告诉我们， 研究以改善女性和男性的DM结果。“女性处于不利地位”的假定原因 包括不利心脏代谢特征（特别是更严重的肥胖）和 CV预防性治疗（例如使用他汀类药物）。此外，内源性性激素的差异，包括 雌二醇（E2）、睾酮（T）和性激素结合球蛋白（SHBG）可能导致过度风险 由DM授予的女性。虽然生活方式的改变（饮食，锻炼和减肥）是 糖尿病管理，不知道减肥和更健康的生活方式是否可以调节性生活的轨迹 激素随时间的变化，以及这些激素变化对心脏代谢危险因素的作用。的动作 糖尿病健康（展望未来）研究是一项在5,145名超重者中进行的随机对照试验 肥胖和2型糖尿病患者，旨在评估强化生活方式干预（ILI）的效果 与对照组相比，发生CVD事件。展望未来的一个主要优势是它能够 解决因果关系的问题，因为研究参与者被随访了8年（约3000人， 性激素测量的纵向生物标本），具有显著且特征良好的变化 体重和判定的临床结果。在这个提议中，我们将首先分析储存的生物标本 性激素（E2，T），SHBG和白蛋白。然后，我们将1）测试ILI是否改善内源性 激素随时间的变化，以及ILI的影响是否受性别的调节; 2）评估纵向 内源性激素与心血管代谢危险因素（HbA 1c、血脂水平、体质量）之间的相关性 质量指数和体重、腰围、身体成分、血压）（主要结局）; 3）测试 内源性性激素的时间轨迹对改善心脏代谢危险因素的作用， 8年内的长期DM结局（即CVD、卒中、慢性肾病和血管性痴呆） 后续行动，以及是否存在性别差异。我们的总体假设是ILI提高了性激素 一个不利的性激素概况，即女性游离T高，男性游离T低， 与不良心脏代谢风险特征相关。最终，了解性的生物学作用 糖尿病患者的激素可以靶向治疗，特别是生活方式的改变，并告知CVD的预防 和其他糖尿病并发症，以降低女性和男性的糖尿病相关发病率和死亡率。

Although women and men have about an equal prevalence of type 2 diabetes (DM), DM imposes a clinically significant excess relative risk of coronary heart disease (44% higher), stroke (27% higher) and vascular dementia (19% higher) in women compared to men. Understanding these sex differences could inform research to improve DM outcomes for both women and men. Postulated reasons for the “female disadvantage” include an adverse cardiometabolic profile (particularly greater obesity) and disparities in aggressiveness of CV preventive treatments (e.g. use of statins). In addition, differences in endogenous sex hormones, including estradiol (E2), testosterone (T) and sex hormone binding globulin (SHBG), may contribute to the excess risk for women conferred by DM. Although lifestyle changes (diet, exercise and weight loss) are the cornerstone of diabetes management, it is not known if weight loss and healthier lifestyle can modulate the trajectory of sex hormones over time, and the role of these hormonal changes on cardiometabolic risk factors. The Action for Health In Diabetes (Look AHEAD) Study was a randomized controlled trial among 5,145 overweight individuals with obesity and type 2 diabetes designed to evaluate the effect of an Intensive Lifestyle Intervention (ILI) compared to a control group on incident CVD events. A major strength of Look AHEAD is its capacity to address questions of causation, because study participants were followed over 8 years (~3000 with longitudinal biospecimens for sex hormone measurements), with significant and well-characterized alterations in weight and with adjudicated clinical outcomes. In this proposal, we will first analyze the stored biospecimens for sex hormones (E2, T), SHBG and albumin. We will then 1) Test whether the ILI improves endogenous sex hormones over time and whether the effect of ILI is moderated by sex; 2) Evaluate the longitudinal associations between endogenous sex hormones and cardiometabolic risk factors (HbA1c, lipid levels, body mass index and weight, waist circumference, body composition, blood pressure) (primary outcomes); 3) Test the effect of the time-trajectory of endogenous sex hormones on improving cardio-metabolic risk factors and long term DM outcomes (i.e. CVD, stroke, chronic kidney disease and vascular dementia) over 8 years of followup, and whether differences exist by sex. Our overall hypothesis is that ILI improves the sex hormone profile, and that an unfavorable sex hormone profile, i.e. high free T in women and low free T in men, is associated with an adverse cardiometabolic risk profile. Ultimately, understanding the biological role of sex hormones in DM could target treatments, particularly lifestyle modification, and inform the prevention of CVD and other DM complications, to reduce DM-related morbidity and mortality for both women and men.