Quantifying Hepatic Mitochondrial Fluxes in Humans

Официальное название

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

Обзор

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

Подробное описание

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.

Вмешательства

• Препарат 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.
• Другое Placebo
  Placebo for pioglitazone

Первичные конечные точки

• Effect of pioglitazone on hepatic mitochondrial TCA cycle fluxes [Срок оценки: Baseline, week 16]

Вторичные конечные точки (8)

• Mean absolute change from baseline in liver fat content by magnetic resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) [Срок оценки: Baseline, Week 16]
• Mean change from baseline in body weight [Срок оценки: Baseline, Week 16]
• Mean change from baseline in body composition [Срок оценки: Baseline, Week 16]
• Quantitate the effect of pioglitazone on liver histology by improvement of fibrosis [Срок оценки: Week 16]
• Quantitate the effect of pioglitazone on NAFLD Activity Score (NAS) [Срок оценки: Week 16]
• Examine the effect of pioglitazone on non-invasive markers of NAFLD [Срок оценки: Baseline, Week 16]
• Effect of pioglitazone on the hepatic lipidome [Срок оценки: Baseline, Week 16]
• Effect of pioglitazone on hepatic gene regulatory networks [Срок оценки: Baseline, Week 16]

Критерии участия

T2D with NAFL

Критерии включения

• 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).

Критерии исключения

• 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

Критерии включения

• 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).

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Простое слепое

Основная цель

Фундаментальное исследование

Центры проведения

США · 2 центра

• Texas Diabetes Institute - University Health System — San Antonio
• University of Texas Health Science Center at San Antonio — San Antonio

Идентификаторы

NCT: NCT05305287 · HSC20210284H · 1R01DK129676-01A1

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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