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），这些都出现在青春期。 尽管与PCOS相关的合并症的患病率和严重性很高， 缺乏选择。更好地了解PCOS相关代谢疾病的病理基础是 这对新疗法的开发至关重要。NAFLD发生在>50%的PCOS女孩中， 代谢疾病恶化的最佳预测因子，因此是改善整体健康的主要目标， PCOS。我们的初步研究结果表明，肥胖患者IR显著，NAFLD和前驱糖尿病发生率高， PCOS的女孩此外，这些女孩的NAFLD和餐后营养不良似乎与上调的 肝脏新生脂肪生成（DNL）、过量游离脂肪酸（FFA）和胰高血糖素样肽-1（GLP-1）不足 1)分泌物当我们用GLP-1受体激动剂（GLP-1 RA）进行短期治疗时， 女孩的餐后血糖、FFA和DNL标记物较低。尚未就下列方面的作用开展工作： PCOS青年患者的长期GLP-1 RA，由于早期疾病发作，长期处于最高风险 长期发病率和死亡率。成人中的有限研究表明GLP-1 RA可降低患者的肝脏脂肪 2型糖尿病和NAFLD，并改善PCOS女性的葡萄糖和睾酮浓度， 显示了这种疗法的前景，尽管缺乏机械的工作。 我们的中心假设是GLP-1 RA将直接改善肝脏代谢， PCOS肥胖女孩分娩，与体重减轻无关。本申请的目的将在 在50名未接受过药物治疗的肥胖PCOS女孩中进行的随机临床试验。治疗组将 强化饮食咨询或每周一次GLP-1 RA exenetry，持续16周，目标是匹配体重减轻 在治疗组之间。我们的目标是：SA 1）与饮食相比，GLP-1 RA治疗4个月可降低肝脏脂肪 咨询和SA 2）评估肝脏葡萄糖和FFA输送的变化，并探测独特的肝脏 稳定同位素示踪剂评估DNL和肝脏TCA循环活性的PCOS早期NAFLD机制 用同位素和31磷核磁共振波谱（31 P MRS）非侵入性测量。 我们是独一无二的准备执行这项重要的工作，因为我们已经成功地招募了100多个类似的 以前试验的参与者，在青年药物临床试验中有经验， 建立了肝脏代谢和新方法学（包括同位素）领域的专家团队 示踪剂、同位素分析和31 P MRS。该项目是创新的方法，与组合 同位素和MRS的工作，以及独特的，高风险的患者群体。结果将大大推进 不仅全面了解NAFLD在肥胖症中的机制，而且还将提供必要的 为改善肥胖PCOS女孩的近期和长期健康提供新的治疗选择的证据。

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.