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

尽管女性和男性的2型糖尿病(DM)患病率大致相同，但在临床上，DM对 冠心病(高44%)、中风(高27%)和血管疾病的相对风险显著超标 女性的痴呆症(比男性高19%)。了解这些性别差异可能会让人们 研究以改善女性和男性的糖尿病结果。“女性劣势”的假设原因 包括不利的心脏代谢特征(特别是更严重的肥胖)和侵袭性方面的差异 心血管预防治疗(如使用他汀类药物)。此外，内源性性激素的差异，包括 雌二醇(E_2)、睾酮(T)和性激素结合球蛋白(SHBG)可能是导致额外风险的原因 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，目前尚不清楚减肥和更健康的生活方式是否可以调节性行为的轨迹 荷尔蒙随着时间的推移，以及这些荷尔蒙变化对心脏代谢危险因素的作用。针对以下方面的行动 糖尿病健康(展望)研究是一项对5145名超重者进行的随机对照试验 肥胖和2型糖尿病旨在评估强化生活方式干预(ILI)的效果 与事件CVD事件的对照组进行比较。展望未来的一个主要优势是它有能力 解决因果关系问题，因为研究参与者被跟踪了8年多(约3000人，其中 用于性激素测量的纵向生物显微镜)，具有显著和良好特征的变化 体重和临床结果的判断。在这份提案中，我们将首先分析储存的生物制品 性激素(E2、T)、SHBG和白蛋白。然后我们将测试ILI是否改善了内源性性行为 激素随时间的变化以及ILI的影响是否受性别的影响；2)评估纵向 内源性性激素与心脏代谢危险因素(糖化血红蛋白、血脂、体重)的关系 体重指数和体重、腰围、身体成分、血压)(主要结果)；3)测试 内源性性激素改善心脏代谢危险因素的时间轨迹及临床意义 糖尿病患者8年的长期预后(如心血管疾病、中风、慢性肾脏疾病和血管性痴呆) 随访，以及性别是否存在差异。我们的总体假设是ILI可以改善性激素 以及不利的性激素谱，即女性的高游离T和男性的低游离T是 与不利的心脏代谢风险相关联。归根结底，了解性行为的生物学作用 糖尿病中的激素可以针对治疗，特别是改变生活方式，并提供预防心血管疾病的信息 以及其他糖尿病并发症，以减少女性和男性与糖尿病相关的发病率和死亡率。

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.