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Quantifying Hepatic Mitochondrial Fluxes in Humans

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ClinicalTrials.gov Identifier: NCT05305287
Recruitment Status : Recruiting
First Posted : March 31, 2022
Last Update Posted : August 24, 2023
Sponsor:
Collaborator:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
Luke Norton, The University of Texas Health Science Center at San Antonio

Study Description
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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

Condition or disease Intervention/treatment Phase
Non-Alcoholic Fatty Liver Disease Type 2 Diabetes Mitochondrial Metabolism Disorders Drug: Pioglitazone Other: Placebo Phase 4

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Patients with T2D and NAFL or NASH will be randomly assigned to receive placebo or pioglitazone treatment groups.
Masking: Single (Participant)
Primary Purpose: Basic Science
Official Title: Quantitation of Hepatic Mitochondrial Fluxes in Humans With Nonalcoholic Fatty Liver Disease (NAFLD)
Actual Study Start Date : November 1, 2022
Estimated Primary Completion Date : March 31, 2027
Estimated Study Completion Date : March 31, 2027

Resource links provided by the National Library of Medicine


Arms and Interventions
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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 Name: 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 Name: Actos
Placebo Comparator: NASH Placebo
T2D with non-alcoholic steatohepatitis (NASH), treated with placebo
 Other: Placebo
Placebo for pioglitazone


Outcome Measures
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Primary Outcome Measures :
  1. Effect of pioglitazone on hepatic mitochondrial TCA cycle fluxes [ Time Frame: Baseline, week 16 ]
    Quantitated using a combine stable isotope approach before and after treatment with pioglitazone


Secondary Outcome Measures :
  1. 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 absolute change from baseline in liver fat content by MRI-PDFF

  2. Mean change from baseline in body weight [ Time Frame: Baseline, Week 16 ]
    Mean change from baseline in body weight

  3. Mean change from baseline in body composition [ Time Frame: Baseline, Week 16 ]
    Mean change from baseline in lean and fat mass measured by DEXA

  4. Quantitate the effect of pioglitazone on liver histology by improvement of fibrosis [ Time Frame: Week 16 ]
    Percentage of Participants with ≥1 Point Decrease in Fibrosis Stage with No Worsening of NASH on Liver Histology

  5. Quantitate the effect of pioglitazone on NAFLD Activity Score (NAS) [ Time Frame: 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

  6. Examine the effect of pioglitazone on non-invasive markers of NAFLD [ Time Frame: 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)

  7. Effect of pioglitazone on the hepatic lipidome [ Time Frame: Baseline, Week 16 ]
    Lipidomics will be carried out using mass-spectrometry methods

  8. Effect of pioglitazone on hepatic gene regulatory networks [ Time Frame: Baseline, Week 16 ]
    Multimodal RNA-Seq and ATAC-Seq will be used to examine gene regulatory networks in liver samples


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05305287


Contacts
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Contact: Luke Norton, PhD 210-567-0739 nortonl@uthscsa.edu
Contact: Andrea Hansis-Diarte, MPH 210-567-3208 hansisdiarte@uthscs.edu

Locations
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United States, Texas
Texas Diabetes Institute - University Health System Recruiting
San Antonio, Texas, United States, 78207
Contact: Andrea Hansis-Diarte, MPh    210-567-6691    hansisdiarte@uthscsa.edu   
Contact: Luke Norton, PhD    210-567-0739    hansisdiarte@uthscsa.edu   
University of Texas Health Science Center at San Antonio Recruiting
San Antonio, Texas, United States, 78229
Sponsors and Collaborators
The University of Texas Health Science Center at San Antonio
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
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Principal Investigator: Luke Norton, PhD University of Texas Health Science Center San Antonio
More Information
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Responsible Party: Luke Norton, Assistant Professor, The University of Texas Health Science Center at San Antonio
ClinicalTrials.gov Identifier: NCT05305287    
Other Study ID Numbers: HSC20210284H
1R01DK129676-01A1 ( U.S. NIH Grant/Contract )
First Posted: March 31, 2022    Key Record Dates
Last Update Posted: August 24, 2023
Last Verified: August 2023

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Luke Norton, The University of Texas Health Science Center at San Antonio:
NAFLD
Diet
Exercise
Additional relevant MeSH terms:
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Liver Diseases
Fatty Liver
Non-alcoholic Fatty Liver Disease
Metabolic Diseases
 Digestive System Diseases
Pioglitazone
Hypoglycemic Agents
Physiological Effects of Drugs