Quantifying Hepatic Mitochondrial Fluxes in Humans

Sponsor

The University of Texas Health Science Center at San Antonio (Other)

Overall Status

Recruiting

CT.gov ID

NCT05305287

Collaborator

(none)

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

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 (i) type 2 diabetic patients with NASH.

Study Design

Study Type:

Interventional

Anticipated 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.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 :

Feb 1, 2022

Anticipated Primary Completion Date :

Feb 1, 2026

Anticipated Study Completion Date :

Feb 1, 2027

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Quantitative hepatic mitochondrial flux [5 hours]
Establishment of a minimally invasive method to quantitate hepatic mitochondrial flux using nuclear magnetic resonance (NMR).
Tricarboxylic Acid Cycle (TCA) Levels [Baseline to 16 weeks]
A measure of change in pyruvate

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 = 18-75 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 = 18-75 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

Locations

	Site	City	State	Country	Postal Code
1	Texas Diabetes Institute - University Health System	San Antonio	Texas	United States	78207
2	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229