Quantifying Hepatic Mitochondrial Fluxes in Humans

The University of Texas System (UT)

Status and phase: Enrolling; Phase 4

Conditions: Type 2 Diabetes; Mitochondrial Metabolism Disorders; Non-Alcoholic Fatty Liver Disease

Treatments: Other: Placebo; Drug: Pioglitazone

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT05305287

1R01DK129676-01A1 (U.S. NIH Grant/Contract)

HSC20210284H

Details and patient eligibility

About

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

Full 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.

Enrollment: 60 estimated patients

Sex: All

Ages: 18 to 80 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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60 participants in 4 patient groups, including a placebo group

NAFL TZD

Experimental group

Description:

T2D with non-alcoholic fatty liver (NAFL), treated with pioglitazone

Treatment:

Drug: Pioglitazone

NAFL Placebo

Placebo Comparator group

Description:

T2D with non-alcoholic fatty liver (NAFL), treated with placebo

Treatment:

Other: Placebo

NASH TZD

Experimental group

Description:

T2D with non-alcoholic steatohepatitis (NASH), treated with pioglitazone

Treatment:

Drug: Pioglitazone

NASH Placebo

Placebo Comparator group

Description:

T2D with non-alcoholic steatohepatitis (NASH), treated with placebo

Treatment:

Other: Placebo