Quantifying Hepatic Mitochondrial Fluxes in Humans
For patients and families
In plain language
An automatic summary of structured registry data. It is an orientation aid, not a substitute for the official protocol or a physician assessment.
- What is being studied
- The protocol lists: Pioglitazone, Placebo.
- Who it may be relevant to
- Registry conditions: Non-Alcoholic Fatty Liver Disease, Type 2 Diabetes, Mitochondrial Metabolism Disorders. Basic parameters: 18 years — 80 years · All.
- What needs checking
- Age, condition and sex are only basic indicators. Prior treatment, laboratory values and other mandatory requirements appear in the eligibility criteria below.
- Where it takes place
- United States
- Next step
- Save the trial, show it to the treating physician, and confirm current recruitment with the study center. Costs, documents and travel →
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Official title
Quantitation of Hepatic Mitochondrial Fluxes in Humans With Nonalcoholic Fatty Liver Disease (NAFLD)
Overview
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
Detailed description
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.
Interventions
- Drug Pioglitazone
An insulin sensitizer and anti-diabetic agent. Participants will be started on 15 mg/day, increased to 30 mg/day at week 2 and then to 45 mg/day at week 4. - Other Placebo
Placebo for pioglitazone
Primary outcome measures
- Effect of pioglitazone on hepatic mitochondrial TCA cycle fluxes [Time frame: Baseline, week 16]
Secondary outcome measures (8)
- Mean absolute change from baseline in liver fat content by magnetic resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) [Time frame: Baseline, Week 16]
- Mean change from baseline in body weight [Time frame: Baseline, Week 16]
- Mean change from baseline in body composition [Time frame: Baseline, Week 16]
- Quantitate the effect of pioglitazone on liver histology by improvement of fibrosis [Time frame: Week 16]
- Quantitate the effect of pioglitazone on NAFLD Activity Score (NAS) [Time frame: Week 16]
- Examine the effect of pioglitazone on non-invasive markers of NAFLD [Time frame: Baseline, Week 16]
- Effect of pioglitazone on the hepatic lipidome [Time frame: Baseline, Week 16]
- Effect of pioglitazone on hepatic gene regulatory networks [Time frame: Baseline, Week 16]
Eligibility criteria
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).
Exclusion criteria
- Alcohol consumption >14 units/week for women and >21 units/week for men.
- Cirrhosis (fibrosis stage 4).
- 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.
- 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.
- 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.
- Cirrhosis (fibrosis stage 4).
- 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.
- 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.
- History of NY Class III-IV heart failure
Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.
Healthy volunteers: No
Study design
- Allocation
- Randomized
- Model
- Parallel assignment
- Masking
- Single blind
- Primary purpose
- Basic science
Study locations
United States · 2 centers
- Texas Diabetes Institute - University Health System — San Antonio
- University of Texas Health Science Center at San Antonio — San Antonio
Identifiers
NCT: NCT05305287 · HSC20210284H · 1R01DK129676-01A1