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

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.

项目总结