Quantifying Hepatic Mitochondrial Fluxes in Humans

Type 2 Diabetes Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05305287
• Other study ID #: HSC20210284H
• Secondary ID: 1R01DK129676-01A
• Status: Recruiting
• Phase: Phase 4
• Start date: November 1, 2022
• Est. completion date: March 31, 2027

Study information

• Verified date: August 2023
• Source: The University of Texas Health Science Center at San Antonio
• Contact: Luke Norton, PhD
• Phone: 210-567-0739
• Email: nortonl[@]uthscsa.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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 information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: March 31, 2027
• Est. primary completion date: March 31, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Fatty Liver
• Liver Diseases
• Metabolic Diseases
• Mitochondrial Metabolism Disorders
• Non-Alcoholic Fatty Liver Disease
• Type 2 Diabetes

Intervention

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

Locations

Country	Name	City	State
United States	Texas Diabetes Institute - University Health System	San Antonio	Texas
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas

Sponsors (2)

Lead Sponsor	Collaborator
The University of Texas Health Science Center at San Antonio	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Mean change from baseline in body weight	Mean change from baseline in body weight	Baseline, Week 16
Secondary	Mean change from baseline in body composition	Mean change from baseline in lean and fat mass measured by DEXA	Baseline, Week 16
Secondary	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
Secondary	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
Secondary	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
Secondary	Effect of pioglitazone on the hepatic lipidome	Lipidomics will be carried out using mass-spectrometry methods	Baseline, Week 16
Secondary	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