Quantifying Hepatic Mitochondrial Fluxes in Humans
- Conditions
- Non-Alcoholic Fatty Liver DiseaseType 2 DiabetesMitochondrial Metabolism Disorders
- Interventions
- Other: Placebo
- Registration Number
- NCT05305287
- Brief Summary
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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 60
- 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).
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description NASH Placebo Placebo T2D with non-alcoholic steatohepatitis (NASH), treated with placebo NAFL TZD Pioglitazone T2D with non-alcoholic fatty liver (NAFL), treated with pioglitazone NAFL Placebo Placebo T2D with non-alcoholic fatty liver (NAFL), treated with placebo NASH TZD Pioglitazone T2D with non-alcoholic steatohepatitis (NASH), treated with pioglitazone
- Primary Outcome Measures
Name Time Method Effect of pioglitazone on hepatic mitochondrial TCA cycle fluxes Baseline, week 16 Quantitated using a combine stable isotope approach before and after treatment with pioglitazone
- Secondary Outcome Measures
Name Time Method Mean change from baseline in body composition Baseline, Week 16 Mean change from baseline in lean and fat mass measured by DEXA
Quantitate the effect of pioglitazone on liver histology by improvement of fibrosis Week 16 Percentage of Participants with ≥1 Point Decrease in Fibrosis Stage with No Worsening of NASH on Liver Histology
Quantitate the effect of pioglitazone on NAFLD Activity Score (NAS) Week 16 Percentage of Participants that Achieve a ≥2 Point Decrease in NAS on Liver Histology, with ≥1 Point Reduction in at Least 2 NAS Components
Examine the effect of pioglitazone on non-invasive markers of NAFLD Baseline, Week 16 Mean change from baseline in Fibrosis-4 (FIB-4), transient elastography (Fibroscan®), NAFLD fibrosis score (NFS), alanine transaminase (ALT) and aspartate transaminase (AST)
Mean absolute change from baseline in liver fat content by magnetic resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) Baseline, Week 16 Mean absolute change from baseline in liver fat content by MRI-PDFF
Mean change from baseline in body weight Baseline, Week 16 Mean change from baseline in body weight
Effect of pioglitazone on the hepatic lipidome Baseline, Week 16 Lipidomics will be carried out using mass-spectrometry methods
Effect of pioglitazone on hepatic gene regulatory networks Baseline, Week 16 Multimodal RNA-Seq and ATAC-Seq will be used to examine gene regulatory networks in liver samples
Trial Locations
- Locations (2)
Texas Diabetes Institute - University Health System
🇺🇸San Antonio, Texas, United States
University of Texas Health Science Center at San Antonio
🇺🇸San Antonio, Texas, United States