quantifying hepatic mitochondrial fluxes in humans

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

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

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

Keywords: nafld diet exercise