Role of Mitochondrial Dysfunction in Non-Alcoholic Fatty Liver Disease
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 70
- 试验地点
- 2
- 主要终点
- Change in Measurement of percentage of Liver Fat by MRI
研究概览
简要总结
One-third of the US population has non-alcoholic fatty liver disease (NAFLD) due to obesity and ~8 million of these individuals have a progressive form of the disease, non-alcoholic steatohepatitis (NASH). Currently, there are no noninvasive ways to determine which individuals with NAFLD will develop NASH. This is of medical importance since NASH can be a prelude to the development of end-stage liver disease.
The study of NAFLD has been limited by several factors, including the difficulties associated with studying liver metabolism in vivo in humans. Our group has pioneered new methods that use nuclear magnetic resonance (NMR) to measure intermediary hepatic metabolism in humans with a goal of directly studying the pathophysiology of bland steatosis and NASH. In this study, these noninvasive methods will be used to characterize and compare the metabolic alterations that accompany bland steatosis and NASH and test the hypothesis that detects if hepatic mitochondrial metabolism contribute to both disorders. Such characterization is fundamental to establishing a rational approach to the prevention and treatment of NAFLD and may provide simple, non-invasive methods to differentiate benign and progressive forms of NAFLD.
This proposal will be addressed via separate isotopic studies occurring at different time points during a prolonged fast. In subjects with NAFLD, these studies will be carried out before and after treatment with Vitamin E or placebo.
Healthy subjects will participate in initial baseline studies only without Vitamin E or placebo intervention.
The study is designed to harness the physiologic changes that occur with short- and long-term fasting to provide a rapid and cost-effective method to accomplish the aims of the application.
详细描述
Study Procedures (Healthy and NAFLD/NASH Subjects) Screening (Week -2) Prior to initiation of the timeline, all potential study participants will be evaluated by a research nurse to obtain informed consent, a brief medical history, height, weight, body mass index, waist/hip circumference, vital signs, approximately 20mls. of blood for screening labs and urine for analysis. NAFLD/NASH subjects with no available liver serologies will have an additional 25 mls of blood drawn. This visit will take approximately 60 minutes and will include a screening questionnaire for family history of disease, activities of daily living (ADL), and alcohol consumption. Diabetic subjects will also withhold their oral diabetic agent prior to the fasting screening labwork.
Teaching Visit: (Week -2 or prior to week -1): A research nurse will give diabetic subjects a 30-minute refresher course on diabetes that will include the signs and symptoms of hyper and hypoglycemia. A teaching booklet will be given to each diabetic subject. Some type 2 diabetic (T2DM) patients only on oral medication do not regularly check their blood sugar. If the patient does not have a glucometer, we will provide a glucometer, supplies and instructions for use by our diabetic study volunteers during their study participation.
Prior to the initiation of standardized diet, subjects will maintain their normal dietary routine. For three to four days prior to the protocol procedures, subjects will be placed on a standardized diet provided by the CTRC metabolic kitchen. In addition, participants will refrain from physical exercise at least 3 days prior to the procedures. Also, T2DM participants will withhold their oral diabetic agents for 3-4 days prior to the protocol procedures.
Phenotyping (Week -1) Participants will be asked to write down food and beverage consumption for three days prior to this visit. This food log will be turned into the dietician at the Clinical Translational Research Center (CTRC) for calculation of proteins, carbohydrates and fats in order to calculate a tailored 3.5 day meal plan to be consumed just prior to the overnight Fast.
Participants will be asked not to eat or drink anything after midnight prior to this visit in preparation for the day's study procedures.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •NAFLD/NASH SUBJECTS
- •Male and Female, Age 18-65 years of all racial and ethnic origins
- •Hepatic steatosis by radiologic study with or without liver enzyme elevation
- •BMI < 35 kg/m2
- •English or Spanish language
- •Females of childbearing potential must be willing to practice an acceptable form of birth control throughout the protocol
- •May also have Type 2 Diabetes (T2DM) with:
- •Hemoglobin A1C < 8.5 % of total Prior, current or no oral antidiabetic medication usage
- •CONTROL SUBJECTS:
- •Age 18-65 years.
- •BMI ≤ 35 kg/m2
- •English or Spanish language
- •Females of childbearing potential must be willing to practice an acceptable form of birth control throughout the protocol
- •May also have T2DM with:
- •Hemoglobin A1C < 8.5 % of total Prior, current or no oral antidiabetic medication usage
排除标准
- •ALL SUBJECTS:
- •Diabetes type 1
- •Diabetes type 2 with:
- •Hemoglobin A1C < 8.5 % of total Current or prior insulin usage
- •Medications or conditions that confound the diagnosis of NAFLD
- •Excessive alcohol intake (>30 g/day in men and >20 g/day in women)
- •Chronic liver disease other than NAFLD/NASH
- •Glucocorticoids
- •Medications or conditions that alter hepatic metabolism
- •Autoimmune disorders
- •Current or chronic infection
- •Other endocrine disorders
- •Recent weight loss (> 10 lbs. within the past 3 months)
- •Prescription weight-loss medications
- •Medical conditions likely to increase the risk of intervention Renal insufficiency (creatinine > 1.4 mg/dL) Baseline metabolic acidosis Congestive heart failure
- •Conditions or behaviors likely to affect the conduct of the study Pregnancy and breastfeeding confirmed by urine pregnancy test prior to all imaging or invasive procedure such as the euglycemic clamp, stable isotope studies, as well as prior to initiation of Vitamin E.
- •Concurrent participation in another research project
- •Inability to accept treatment assignment
- •Major psychiatric disorder or substance abuse
- •CONTROL SUBJECTS (in addition to the above):
- •Liver disease Elevated liver function tests Hepatic steatosis
- •Metabolic syndrome Hypertriglyceridemia (fasting plasma triglycerides > 150 mg/dL). Systolic blood pressure > 140 mmHg Diastolic blood pressure > 80 mmHg
- •Exercise above activities of daily living
结局指标
主要结局
Change in Measurement of percentage of Liver Fat by MRI
时间窗: baseline, 4 weeks, 8 weeks, 12 weeks, and 16 weeks
Measurement of percentage of Liver Fat by MRI at baseline, 4 weeks, 8 weeks, 12 weeks, and 16 weeks.
Change in Measurement of glucose metabolism turnover by non-radioactive isotopic infusion and recovery
时间窗: 4 months
Measurement of glucose metabolism turnover (ug/Kg/min) in the liver by non-radioactive isotopic infusion and recovery @ baseline and 16 weeks.
Change in Measurement of Insulin Sensitivity via Hyperinsulinemic glucose clamp
时间窗: 4 months
Measurement of insulin sensitivity by glucose disposal rate (mg/Kg/min) via hyperinsulinemic glucose clamp @ baseline and 16 weeks.
次要结局
未报告次要终点
研究者
Jeffrey Browning
Associate Professor of Internal Medicine
University of Texas Southwestern Medical Center