Quantifying Hepatic Mitochondrial Fluxes in Humans

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

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.

Eligibility 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