Impact of GLP-1 on Hepatic Fat and Energy Utilization in Obese Girls with Polycystic Ovarian Syndrome

项目摘要 多囊卵巢综合征(PCOS)影响6%-10%的女性，相关的代谢并发症包括 胰岛素抵抗(IR)、糖尿病和非酒精性脂肪性肝病(NAFLD)，这些都存在于青春期。 尽管多囊卵巢综合征的高患病率和严重并发症，但广泛有效的治疗 没有选择余地。更好地理解PCOS相关代谢性疾病的病理基础是 对推动新疗法的发展至关重要。NAFLD发生在50%患有多囊卵巢综合征的女孩，是 是恶化代谢性疾病的最佳预测指标，因此是改善#年整体健康状况的主要目标 多囊卵巢综合征。我们的初步结果显示，肥胖者存在显著的胰岛素抵抗，NAFLD和糖尿病前期的发生率很高。 患有多囊卵巢综合征的女孩。此外，这些女孩的非酒精性脂肪肝和餐后血糖紊乱似乎与上调有关。 肝脏新生脂肪生成(DNL)、过量游离脂肪酸(FFA)和不足的胰高血糖素样肽-1(GLP-1)- 1)分泌物。当我们使用GLP-1受体激动剂(GLP-1RA)进行短期治疗时，PCOS 女孩的餐后血糖、FFA和DNL标志物较低。目前还没有关于……的作用的工作 长期的GLP-1 RA在患有PCOS的青年患者中，由于发病较早，他们长期处于最高风险 足月发病率和死亡率。有限的成人研究表明，GLP-1RA可降低患者的肝脏脂肪 患有2型糖尿病和非酒精性脂肪肝，并改善患有多囊卵巢综合征的女性的血糖和睾酮浓度， 显示了这种疗法的前景，尽管缺乏机械性的工作。 我们的中心假设是GLP-1RA将直接改善肝脏代谢，减少底物 患有多囊卵巢综合征的肥胖女孩的分娩，与体重减轻无关。本应用程序的目标将在 对50名患有多囊卵巢综合征的未服用药物的肥胖女孩进行随机临床试验。治疗武器将是 为期16周的强化饮食咨询或每周GLP-1 RA艾塞那肽，目标是匹配减肥 跨过治疗臂。我们的目标是：与饮食相比，服用4个月的GLP-1RA可以降低肝脏脂肪 咨询和SA2)评估肝脏葡萄糖和FFA分娩的变化，并探索独特的肝脏 稳定同位素示踪评估DNL和肝脏TCA循环活性的PCOS早期NAFLD机制 用同位素异构体和31P磁共振波谱(31P MRS)进行非侵入性测量。 我们已经成功地招募了100多名类似的人，我们正准备执行这项重要的工作 在以前的试验中，参与者在青年用药的临床试验中经验丰富，并有 在肝脏代谢和包括同位素在内的新方法领域建立了专家团队 示踪剂、同位素分析和31P-MRS。该项目在这两种方法上都是创新的，具有 同位素和MRS的工作，以及一个独特的高危患者群体。结果将大大进步。 不仅全面了解NAFLD在肥胖中的作用机制，而且还将提供必要的 一种新的治疗选择的证据，以改善肥胖的多囊卵巢综合征女孩的近期和长期健康。

Project Summary Polycystic ovary syndrome (PCOS) affects 6-10% of women and related metabolic complications include insulin resistance (IR), diabetes and nonalcoholic fatty liver disease (NAFLD), which all present in adolescence. Despite the high prevalence and gravity of comorbidities associated with PCOS, widely effective therapeutic options are lacking. A better understanding of the pathology underlying PCOS related metabolic disease is critical to inform development of new therapeutics. NAFLD occurs in >50% of girls with PCOS, is one of the best predictors for worsening metabolic disease and is thus a prime target for improving overall health in PCOS. Our preliminary results demonstrate significant IR and high rates of NAFLD and prediabetes in obese girls with PCOS. Further, NAFLD and post-prandial dysglycemia in these girls appear related to upregulated hepatic de novo lipogenesis (DNL), excess free fatty acids (FFA) and inadequate glucagon like peptide-1 (GLP- 1) secretion. When we administered short-duration treatment with a GLP-1 receptor agonist (GLP-1 RA), PCOS girls had lower post-prandial glucose, FFA and markers of DNL. No work has yet been done on the role of longer-term GLP-1 RA in youth with PCOS, who due to the early disease onset are at the highest risk for long term morbidity and mortality. Limited work in adults indicates that GLP-1 RA decreases liver fat in patients with type 2 diabetes and NAFLD and improves glucose and testosterone concentrations in women with PCOS, showing the promise of this therapy, although mechanistic work is lacking. Our central hypothesis is that GLP-1 RA will directly improve hepatic metabolism and decrease substrate delivery in obese girls with PCOS, independent of weight loss. The aims of this application will be performed in the context of a randomized clinical trial in 50 medication-naive obese girls with PCOS. Treatment arms will be intensive dietary counseling or weekly GLP-1 RA exenatide for 16 weeks, with a goal of matching weight loss across treatment arms. We aim to: SA1) lower liver fat with 4 months of GLP-1 RA compared to dietary counseling and SA2) assess changes in hepatic glucose and FFA delivery and probe the unique hepatic mechanisms of early NAFLD in PCOS with stable isotope tracer-assessed DNL and hepatic TCA cycle activity measured non-invasively with isotopomers and 31phosphoprus magnetic resonance spectroscopy (31P MRS). We are uniquely poised to perform this important work as we have successfully enrolled over 100 similar participants in previous trials, are experienced in clinical trials with medications in youth and have an established team of experts in the fields of hepatic metabolism and novel methodologies, including isotope tracers, isotopomer analysis and 31P MRS . The project is innovative in both the approach, with a combination of isotopomer and MRS work, and a unique, high-risk patient population. The results will significantly advance not only the overall mechanistic understanding of NAFLD in obesity, but will also provide the necessary evidence for a new therapeutic option to improve the immediate and long-term health of obese PCOS girls.