Quantifying Hepatic Mitochondrial Fluxes in Humans

Quantitation of Hepatic Mitochondrial Fluxes in Humans With Nonalcoholic Fatty Liver Disease (NAFLD)

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

Study Overview

• Status: Recruiting
• Conditions: Type 2 Diabetes; Non-Alcoholic Fatty Liver Disease; Mitochondrial Metabolism Disorders
• Intervention / Treatment: Drug: Pioglitazone; Other: Placebo

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.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Luke Norton, PhD; Phone Number: 210-567-0739; Email: nortonl@uthscsa.edu
• Study Contact Backup: Name: Andrea Hansis-Diarte, MPH; Phone Number: 210-567-3208; Email: hansisdiarte@uthscs.edu

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78229
      • Recruiting
      • University of Texas Health Science Center at San Antonio
    • San Antonio, Texas, United States, 78207
      • Recruiting
      • Texas Diabetes Institute - University Health System
      • Contact: Luke Norton, PhD; Phone Number: 210-567-0739; Email: hansisdiarte@uthscsa.edu
      • Contact: Andrea Hansis-Diarte, MPh; Phone Number: 210-567-6691; Email: hansisdiarte@uthscsa.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NAFL TZD; T2D with non-alcoholic fatty liver (NAFL), treated with pioglitazone	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 Names: Actos
Placebo Comparator: NAFL Placebo; T2D with non-alcoholic fatty liver (NAFL), treated with placebo	Other: Placebo; Placebo for pioglitazone
Experimental: NASH TZD; T2D with non-alcoholic steatohepatitis (NASH), treated with pioglitazone	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 Names: Actos
Placebo Comparator: NASH Placebo; T2D with non-alcoholic steatohepatitis (NASH), treated with placebo	Other: Placebo; Placebo for pioglitazone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of pioglitazone on hepatic mitochondrial TCA cycle fluxes	Quantitated using a combine stable isotope approach before and after treatment with pioglitazone	Baseline, week 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean absolute change from baseline in liver fat content by magnetic resonance Imaging - Proton Density Fat Fraction (MRI-PDFF)	Mean absolute change from baseline in liver fat content by MRI-PDFF	Baseline, Week 16
Mean change from baseline in body weight	Mean change from baseline in body weight	Baseline, Week 16
Mean change from baseline in body composition	Mean change from baseline in lean and fat mass measured by DEXA	Baseline, Week 16
Quantitate the effect of pioglitazone on liver histology by improvement of fibrosis	Percentage of Participants with ≥1 Point Decrease in Fibrosis Stage with No Worsening of NASH on Liver Histology	Week 16
Quantitate the effect of pioglitazone on NAFLD Activity Score (NAS)	Percentage of Participants that Achieve a ≥2 Point Decrease in NAS on Liver Histology, with ≥1 Point Reduction in at Least 2 NAS Components	Week 16
Examine the effect of pioglitazone on non-invasive markers of NAFLD	Mean change from baseline in Fibrosis-4 (FIB-4), transient elastography (Fibroscan®), NAFLD fibrosis score (NFS), alanine transaminase (ALT) and aspartate transaminase (AST)	Baseline, Week 16
Effect of pioglitazone on the hepatic lipidome	Lipidomics will be carried out using mass-spectrometry methods	Baseline, Week 16
Effect of pioglitazone on hepatic gene regulatory networks	Multimodal RNA-Seq and ATAC-Seq will be used to examine gene regulatory networks in liver samples	Baseline, Week 16

Collaborators and Investigators

• Sponsor: The University of Texas Health Science Center at San Antonio
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Luke Norton, PhD, University of Texas Health Science Center San Antonio

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2022
• Primary Completion (Estimated): March 31, 2027
• Study Completion (Estimated): March 31, 2027

Study Registration Dates

• First Submitted: March 22, 2022
• First Submitted That Met QC Criteria: March 22, 2022
• First Posted (Actual): March 31, 2022

Study Record Updates

• Last Update Posted (Actual): January 9, 2026
• Last Update Submitted That Met QC Criteria: January 7, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Exercise; Diet; NAFLD
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Digestive System Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Liver Diseases; Fatty Liver; Behavior; Nutritional and Metabolic Diseases; Diabetes Mellitus, Type 2; Non-alcoholic Fatty Liver Disease; Motor Activity; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Thiazoles; Azoles; Thiazolidinediones; Pioglitazone
• Other Study ID Numbers: HSC20210284H; 1R01DK129676-01A1 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No