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

GLP-1 对患有多囊卵巢综合症的肥胖女孩肝脏脂肪和能量利用的影响

• 批准号: 10212375
• 负责人: Melanie G Cree
• 金额: $ 54.34万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212375
• 关键词: Acyl Coenzyme A; Adipose tissue; Adolescence; Adult; Affect; Agonist; Androgens; Animals; Body Weight decreased; Body mass index; Carbon; Citric Acid Cycle; Clinical; Clinical Trials; Consumption; Counseling; Data; Development; Diabetes Mellitus; Diet; Diet therapy; Dietary Intervention; Disease; Dose; Energy Metabolism; Enrollment; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Female Adolescents; Future; GLP-I receptor; Gene Expression; Glucose; Glycerol; Goals; Health; Hepatic; High Prevalence; Hormonal; Hypergravity; Hyperinsulinism; Insulin; Insulin Resistance; Intervention; Isotopes; Life; Liver; Liver Fibrosis; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Mediating; Metabolic; Metabolic Diseases; Methodology; Methods; Modeling; Morbidity - disease rate; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Onset of illness; Oral; Outcome; Participant; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Polycystic Ovary Syndrome; Prediabetes syndrome; Prevalence; Prevention; Production; Quality of life; Randomized; Randomized Clinical Trials; Reactive Oxygen Species; Research; Risk; Role; Serum; Severity of illness; Testing; Testosterone; Tracer; Triglycerides; Unhealthy Diet; Water; Woman; Work; Youth; base; cohort; comorbidity; dietary; disorder risk; elastography; exenatide; experience; girls; glucagon-like peptide; glucagon-like peptide 1; glucose metabolism; high risk; impaired glucose tolerance; improved; innovation; insulin sensitivity; intrahepatic; lipid biosynthesis; liver injury; liver metabolism; mortality; non-alcoholic fatty liver disease; novel; novel therapeutics; patient population; prevent; stable isotope; sugar; therapeutically effective; treatment arm; treatment duration; Acyl Coenzyme A; Adipose tissue; Adolescence; Adult; Affect; Agonist; Androgens; Animals; Body Weight decreased; Body mass index; Carbon; Citric Acid Cycle; Clinical; Clinical Trials; Consumption; Counseling; Data; Development; Diabetes Mellitus; Diet; Diet therapy; Dietary Intervention; Disease; Dose; Energy Metabolism; Enrollment; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Female Adolescents; Future; GLP-I receptor; Gene Expression; Glucose; Glycerol; Goals; Health; Hepatic; High Prevalence; Hormonal; Hypergravity; Hyperinsulinism; Insulin; Insulin Resistance; Intervention; Isotopes; Life; Liver; Liver Fibrosis; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Mediating; Metabolic; Metabolic Diseases; Methodology; Methods; Modeling; Morbidity - disease rate; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Onset of illness; Oral; Outcome; Participant; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Polycystic Ovary Syndrome; Prediabetes syndrome; Prevalence; Prevention; Production; Quality of life; Randomized; Randomized Clinical Trials; Reactive Oxygen Species; Research; Risk; Role; Serum; Severity of illness; Testing; Testosterone; Tracer; Triglycerides; Unhealthy Diet; Water; Woman; Work; Youth; base; cohort; comorbidity; dietary; disorder risk; elastography; exenatide; experience; girls; glucagon-like peptide; glucagon-like peptide 1; glucose metabolism; high risk; impaired glucose tolerance; improved; innovation; insulin sensitivity; intrahepatic; lipid biosynthesis; liver injury; liver metabolism; mortality; non-alcoholic fatty liver disease; novel; novel therapeutics; patient population; prevent; stable isotope; sugar; therapeutically effective; treatment arm; treatment duration

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.

项目摘要 多囊卵巢综合征（PCOS）影响6-10％的女性和相关代谢并发症包括 胰岛素抵抗（IR），糖尿病和非酒精性脂肪肝病（NAFLD），它们都属于青春期。 尽管与PCOS相关的合并症的患病率高和严重性，但有效的治疗率很高 缺乏选择。更好地了解与PCOS相关的代谢疾病的病理学是 为开发新的治疗剂而言至关重要。 NAFLD发生在> 50％的PCOS女孩中，是 恶化代谢疾病的最佳预测因素，因此是改善整体健康的主要目标 PCOS。我们的初步结果表明，肥胖中的NAFLD和糖尿病前期的高率很高 PCOS的女孩。此外，这些女孩中的NAFLD和餐后血糖症似乎与上调有关 肝脂肪生成（DNL），过量的游离脂肪酸（FFA）和胰高血糖素（如肽-1）（GLP- 1）分泌。当我们使用GLP-1受体激动剂（GLP-1 RA）进行短期处理时，PCOS 女孩的餐后葡萄糖，FFA和DNL的标记较低。尚未完成有关角色的工作 PCOS青年的长期GLP-1 RA，由于早期疾病发作，长期的风险最高 术语发病率和死亡率。成人的工作有限表明，GLP-1 RA可减少患者的肝脏脂肪 使用2型糖尿病和NAFLD，并改善PCOS女性的葡萄糖和睾丸激素浓度， 尽管缺乏机械工作，但表现出这种疗法的希望。 我们的中心假设是GLP-1 RA将直接改善肝代谢并减少底物 在患有PCOS的肥胖女孩中分娩，独立于减肥。该应用程序的目的将在 在50种药物肥胖的女孩中，一项随机临床试验的背景。治疗臂将是 密集的饮食咨询或每周GLP-1 RA烯肽16周，目的是减肥 跨治疗臂。我们的目标是：SA1）与饮食相比，GLP-1 RA 4个月的肝脂肪较低 咨询和SA2）评估肝葡萄糖和FFA的变化，并探测独特的肝 具有稳定的同位素示踪剂DNL和肝TCA周期活动的PCOS早期NAFLD的机制 用同位素和31磷磁共振光谱法（31p MRS）非侵入性测量。 我们已经独特地准备执行这项重要工作，因为我们已经成功招募了100多个类似的工作 以前试验的参与者是在青年中接受药物治疗的临床试验中经验的 肝代谢和新方法的既定专家团队，包括同位素 示踪剂，同位素分析和31p MRS。该项目在两种方法上都是创新的，结合了 同位素和MRS的工作，以及独特的高风险患者人群。结果将大大提高 不仅在肥胖症中对NAFLD的总体机械理解，还将提供必要的 一种新的治疗选择的证据，以改善肥胖的PCOS女孩的直接和长期健康状况。