Quantitation of Hepatic Mitochondrial Fluxes in Humans With Nonalcoholic Fatty Liver Disease (NAFLD)
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 60
- 试验地点
- 2
- 主要终点
- Effect of pioglitazone on hepatic mitochondrial TCA cycle fluxes
研究概览
简要总结
In this study the investigators will quantitate hepatic mitochondrial fluxes in T2D patients with NAFL and NASH before and after 16-weeks treatment with the insulin sensitizer pioglitazone
详细描述
The study team will examine hepatic mitochondrial TCA flux and pyruvate cycling (oral [U-13C]-propionate), hepatic gluconeogenesis (oral 2H2O), and hepatic insulin sensitivity (intravenous [3,4-13C2]-glucose with euglycemic insulin clamp) before and after 16 weeks treatment with the FDA approved insulin sensitizer pioglitazone. These studies will be performed in (i) type 2 diabetic subjects with NAFL but without evidence of fibrosis, and (ii) type 2 diabetic patients with NASH. Liver biopsies will be obtained before and after treatment for the diagnosis of NAFL/NASH and for molecular analyses.
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
- Single (Participant)
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
- 否
入选标准
- •T2D with NAFL
- •Inclusion Criteria:
- •Confirmed T2D based on OGTT (2 h glucose ≥200 mg/dl).
- •Treated with diet, metformin, and/or sulfonylurea and in good general health determined by medical history, physical exam, and routine blood chemistries;
- •age = 18-80 years;
- •BMI = 25-40 kg/m2;
- •HbA1c = 7-10%; stable body weight (±4 pounds) over the preceding 3-months;
- •not taking any medication known to affect glucose metabolism other than antidiabetic medications.
- •Evidence of moderate/severe fatty liver (steatosis; grade S2/S3 on FibroScan corresponding to ≥10% fat on MRI-PDFF) and no/minimal hepatic fibrosis (grade F0/F1 on FibroScan).
排除标准
- •Alcohol consumption >14 units/week for women and >21 units/week for men.
- •Liver cirrhosis (fibrosis stage 4).
- •Evidence of other forms of chronic liver disease, including alcoholic liver disease, hepatitis B and C, primary biliary cholangitis, suspected/proven liver cancer and any other liver disease other than NAFLD.
- •Type 1 diabetes and/or GAD positive subjects.
- •Subjects not drug naive or have been on metformin more than 3 months.
- •Presence of proliferative retinopathy.
- •Urine albumin excretion > 300 mg/day.
- •History of NY Class III-IV heart failure
- •T2D with NASH
- •Inclusion Criteria:
- •Confirmed T2D based on OGTT (2 h glucose ≥200 mg/dl).
- •Treated with diet, metformin, and/or sulfonylurea and in good general health determined by medical history, physical exam, and routine blood chemistries;
- •age = 18-80 years;
- •BMI = 25-40 kg/m2;
- •HbA1c = 7-10%;
- •stable body weight (±4 pounds) over the preceding 3-months;
- •not taking any medication known to affect glucose metabolism other than antidiabetic medications.
- •Evidence of moderate/severe fatty liver (steatosis; grade S2/S3 on FibroScan corresponding to ≥10% liver fat on MRI-PDFF) and moderate/severe hepatic fibrosis (grade F2/F3 on FibroScan).
- •Exclusion Criteria:
- •Alcohol consumption >14 units/week for women and >21 units/week for men.
- •Liver cirrhosis (fibrosis stage 4).
- •Evidence of other forms of chronic liver disease, including alcoholic liver disease, hepatitis B and C, primary biliary cholangitis, suspected/proven liver cancer and any other liver disease other than NAFLD.
- •Type 1 diabetes and/or GAD positive subjects.
- •Subjects not drug naive or have been on metformin more than 3 months.
- •Presence of proliferative retinopathy.
- •Urine albumin excretion > 300 mg/day.
- •History of NY Class III-IV heart failure
研究组 & 干预措施
T2D + NAFL and placebo
Type 2 diabetes with non-alcoholic fatty liver (NAFL), treated with placebo
干预措施: Placebo (Other)
T2D + NASH and placebo
Type 2 diabetes with non-alcoholic steatohepatitis (NASH), treated with placebo
干预措施: Placebo (Other)
T2D + NAFL and pioglitazone
Type 2 diabetes with non-alcoholic fatty liver (NAFL), treated with pioglitazone
干预措施: Pioglitazone (Drug)
T2D + NASH and pioglitazone
Type 2 diabetes with non-alcoholic steatohepatitis (NASH), treated with pioglitazone
干预措施: Pioglitazone (Drug)
结局指标
主要结局
Effect of pioglitazone on hepatic mitochondrial TCA cycle fluxes
时间窗: Baseline, week 16
Quantitated using a combined stable isotope approach before and after treatment with pioglitazone
次要结局
- Effect of pioglitazone on the hepatic lipidome(Baseline, Week 16)
- Effect of pioglitazone on hepatic gene regulatory networks(Baseline, Week 16)
- Mean absolute change from baseline in liver fat content by magnetic resonance Imaging - Proton Density Fat Fraction (MRI-PDFF)(Baseline, Week 16)
- Mean change from baseline in body weight(Baseline, Week 16)
- Mean change from baseline in body composition(Baseline, Week 16)
- Quantitate the effect of pioglitazone on liver histology by improvement of fibrosis(Week 16)
- Quantitate the effect of pioglitazone on NAFLD Activity Score (NAS)(Week 16)
- Examine the effect of pioglitazone on non-invasive markers of NAFLD(Baseline, Week 16)
研究者
Luke Norton
Assistant Professor
The University of Texas Health Science Center at San Antonio