Insulin Resistance in Non-alcoholic Fatty Liver Disease
试验速览
- 阶段
- 不适用
- 状态
- 终止
- 入组人数
- 13
- 试验地点
- 1
- 主要终点
- Liver/Spleen Ratio at 6 Months
研究概览
简要总结
The purpose of this study is to determine whether nonalcoholic fatty liver disease (NAFLD) is associated with altered peripheral and hepatic insulin sensitivity and to investigate potential mechanisms underlying insulin resistance in NAFLD by determining associations between hepatic and peripheral insulin sensitivity, hepatic steatosis, dyslipidemia, inflammatory cytokines, glucose metabolism, beta-cell function and body fat distribution.
详细描述
NAFLD and nonalcoholic steatohepatitis (NASH) are common liver disorders that are strongly associated with obesity, type 2 diabetes and dyslipidemia. The underlying pathophysiology of fatty infiltration of the liver is thought to be related to insulin resistance, which is an almost universal finding in patients with NAFLD. It is also possible that fat infiltration and inflammation in the liver may impair insulin sensitivity, either locally in the liver, or peripherally via the actions of inflammatory cytokines. We hypothesize that insulin resistance is a major causal factor leading to fat deposition in the liver and NAFLD, and thus interventions aimed at improving insulin sensitivity will result in a reduction of hepatic inflammation and steatosis.
Specific Aim 1: To determine in a cross-sectional study whether NAFLD is associated with altered peripheral and hepatic insulin sensitivity and to study their relationships with hepatic steatosis, dyslipidemia, inflammatory cytokines, glucose metabolism, -cell function and body fat distribution. Specific Aim 2: To determine in a 6 month placebo-controlled double-blinded treatment study if treatment with rosiglitazone, an insulin sensitizer, or fenofibrate, a triglyceride lowering agent, will improve both hepatic as well as peripheral insulin sensitivity and thereby improve hepatic steatosis and inflammation in subjects with NAFLD.
The results of the proposed study will have important implications for our understanding of the mechanisms underlying insulin resistance and abnormalities in lipid and glucose metabolism in subjects with NAFLD and for the design of future studies aimed at the prevention and treatment of this condition.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Age 18-80 years old Controls:
- •otherwise healthy Case subjects: NAFLD on liver biopsy within the past 3 years or presumed NAFLD with otherwise unexplained elevated ALT and fatty liver by CT or ultrasound
- •Able to comply with taking 3 pills a day for 6 months and follow-up safety visits
排除标准
- •Controls:
- •history or evidence of hepatic steatosis
- •Cirrhosis on liver biopsy or by clinical exam or fibrosis score
- •Causes of liver dysfunction other than NASH
- •Use of medications associated with hepatic steatosis:
- •glucocorticoids
- •estrogens
- •tamoxifen
- •amiodarone
- •sertraline
- •Use of medications that cause insulin resistance:
- •glucocorticoids
- •anti-HIV drugs or atypical antipsychotics
- •Use of lipid-lowering medications except stable dose statin
- •Use of anti-NASH drugs such as:
- •ursodeoxycholic acid
- •betaine milk thistle
- •Use of coumadin
- •Use of nitrates
- •Significant alcohol consumption:
- •Average >20 grams/day
- •In subjects with diabetes
- •a HbA1c >7.5% or use of insulin
- •metformin
- •rosiglitazone or pioglitazone
- •Liver transaminases:
- •Cases: ALT >5x upper limit of normal
- •Controls: ALT or AST above the normal range
- •Iron saturation >50%
- •Creatinine >1.5 mg/dl for men and >1.4 mg/dl for women
- •Hematocrit <33%
- •Pregnancy or lactation
- •Significant weight loss within the past 6 months for controls, or since the liver biopsy for case subjects, history of significant coronary artery disease or congestive heart failure
- •Retinopathy
研究组 & 干预措施
Rosiglitazone Arm
rosiglitazone 4 mg po bid and fenofibrate placebo 1 po qd
干预措施: placebo for fenofibrate (Drug)
Placebo Arm
matching placebo for rosiglitazone, 1 po bid and placebo for fenofibrate 1 po qd
干预措施: placebo for rosiglitazone (Drug)
Placebo Arm
matching placebo for rosiglitazone, 1 po bid and placebo for fenofibrate 1 po qd
干预措施: placebo for fenofibrate (Drug)
Rosiglitazone Arm
rosiglitazone 4 mg po bid and fenofibrate placebo 1 po qd
干预措施: rosiglitazone (Drug)
Fenofibrate Arm
micronized fenofibrate 200 mg 1 po qd and rosiglitazone placebo 1 po bid
干预措施: fenofibrate (Drug)
Fenofibrate Arm
micronized fenofibrate 200 mg 1 po qd and rosiglitazone placebo 1 po bid
干预措施: placebo for rosiglitazone (Drug)
结局指标
主要结局
Liver/Spleen Ratio at 6 Months
时间窗: 6 months
Liver fat was estimated by non-contrast CT scan measuring the density ratio between the liver and spleen by Hounsfield units (liver/spleen ratio), which has been previously correlated with liver fat quantification by magnetic resonance spectroscopy.Ten separate measurements equally distributed throughout the liver and spleen were obtained and the Hounsfield units averaged. In subjects with more than one slice through the liver and spleen, the values for all slices were averaged.
次要结局
- Changes in Intra-abdominal Fat Area From Baseline to 6 Months(6 months)
- Change in Alanine Aminotransferase (ALT) Levels From Baseline to 6 Months(6 months)
- Change in Hepatic Insulin Sensitivity From Baseline to 6 Months(6 months)
- Change in the Liver Spleen Ratio by CT Scan From Baseline to 6 Months as a Measure of Fat in the Liver(6 months)
- Change in Peripheral Insulin Sensitivity From Baseline to 6 Months(6 months)