Mitochondrial Metabolism Disorders, Non-Alcoholic Fatty Liver Disease, Type 2 Diabetes
Conditions
Keywords
NAFLD, Mitochondria, Type 2 diabetes, Insulin resistance
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
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.
Interventions
DRUGPioglitazone
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.
OTHERPlacebo
Placebo for pioglitazone
Sponsors
The University of Texas Health Science Center at San Antonio
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Intervention model description
Patients with confirmed T2D will be screened for NAFL or NASH and will be randomly assigned to receive placebo or pioglitazone treatment groups.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion 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. * Liver cirrhosis (fibrosis stage 4). * 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. * 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. * 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect of pioglitazone on hepatic mitochondrial TCA cycle fluxes | Baseline, week 16 | Quantitated using a combined stable isotope approach before and after treatment with pioglitazone |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of pioglitazone on hepatic gene regulatory networks | Baseline, Week 16 | Multimodal RNA-Seq and ATAC-Seq will be used to examine gene regulatory networks in liver samples |
| Effect of pioglitazone on the hepatic lipidome | Baseline, Week 16 | Lipidomics will be carried out using mass-spectrometry methods |
| Mean absolute change from baseline in liver fat content by magnetic resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) | Baseline, Week 16 | Mean absolute change from baseline in liver fat content by MRI-PDFF |
| Mean change from baseline in body weight | Baseline, Week 16 | Mean change from baseline in body weight |
| Mean change from baseline in body composition | Baseline, Week 16 | Mean change from baseline in lean and fat mass measured by DEXA |
| Quantitate the effect of pioglitazone on liver histology by improvement of fibrosis | Week 16 | Percentage of Participants with ≥1 Point Decrease in Fibrosis Stage with No Worsening of NASH on Liver Histology |
| Examine the effect of pioglitazone on non-invasive markers of NAFLD | 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) |
| Quantitate the effect of pioglitazone on NAFLD Activity Score (NAS) | 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 |
Countries
United States
Contacts
CONTACTLuke Norton, PhD
CONTACTAndrea Hansis-Diarte, MPH
PRINCIPAL_INVESTIGATORLuke Norton, PhD
The University of Texas Health Science Center at San Antonio
Outcome results
None listed