| Outcome Measures: |
Primary: Liver Histology (Using Kleiner et al Criteria, Hepatology 2005), Number of patients with reduction of at least 2 points in the nonalcoholic fatty liver disease activity score (NAS) (with reduction in at least 2 different histological categories) without worsening of fibrosis. NAS is the sum of the separate scores for steatosis (0-3), hepatocellular ballooning (0-2) and lobular inflammation (0-3), and ranges from 0-8 . The scoring system is based on the following grading: Steatosis: 0 = \<5%; 1 = 5-33%; 2 = \>33-66%; 3 = \>66%. Lobular Inflammation: 0 = No foci 1 = \<2 foci/200x; 2 = 2-4 foci/200x, 3 = \>4 foci/200x. Hepatocyte Ballooning: 0 = None; 1 = Few balloon cells; 2 = Many cells/prominent ballooning. Fibrosis: 0 = None; 1 = Perisinusoidal or periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis., At 18 months | Secondary: Number of Participants With Resolution of NASH, Resolution of NASH was defined as absence of NASH after 18 months of therapy in patients with definite NASH (presence of zone 3 accentuation of macrovesicular steatosis of any grade, hepatocellular ballooning of any degree, and lobular inflammatory infiltrates of any amount) at baseline., Month 18|Mean Individual Histological Scores, Mean change in individual scores compared to baseline. Steatosis: 0 = \<5%; 1 = 5-33%; 2 = \>33-66%; 3 = \>66%. Lobular Inflammation: 0 = No foci 1 = \<2 foci/200x; 2 = 2-4 foci/200x, 3 = \>4 foci/200x. Hepatocyte Ballooning: 0 = None; 1 = Few balloon cells; 2 = Many cells/prominent ballooning. Fibrosis: 0 = None; 1 = Perisinusoidal or periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis, Baseline and Month 18|Individual Histological Scores, Number of patients with improvement of at least 1 grade in each of the histological parameters. Steatosis: 0 = \<5%; 1 = 5-33%; 2 = \>33-66%; 3 = \>66%. Lobular Inflammation: 0 = No foci 1 = \<2 foci/200x; 2 = 2-4 foci/200x, 3 = \>4 foci/200x. Hepatocyte Ballooning: 0 = None; 1 = Few balloon cells; 2 = Many cells/prominent ballooning. Fibrosis: 0 = None; 1 = Perisinusoidal or periportal, 1A = Mild, zone 3, perisinusoidal "delicate" fibrosis; 1B = Moderate, zone 3, perisinusoidal "dense" fibrosis; 1C = Portal/periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis, Month 18|Mean Individual Histological Scores, Steatosis: 0 = \<5%; 1 = 5-33%; 2 = \>33-66%; 3 = \>66%. Lobular Inflammation: 0 = No foci 1 = \<2 foci/200x; 2 = 2-4 foci/200x, 3 = \>4 foci/200x. Hepatocyte Ballooning: 0 = None; 1 = Few balloon cells; 2 = Many cells/prominent ballooning. Fibrosis: 0 = None; 1 = Perisinusoidal or periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis, Month 36|Liver Transaminases (AST and ALT)., 18 and 36 months|Liver Fat by Magnetic Resonance and Spectroscopy (MRS)., Liver fat content was calculated as the fat fraction: 100\*(area under the curve \[AUC\] of fat peak / \[AUC of fat peak + AUC of water peak\])., 18 months|Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), Homeostatic model assessment of insulin resistance (HOMA-IR) is a method for assessing insulin resistance (IR) from basal fasting plasma glucose (FPG) and fasting plasma insulin (FPI). It is calculated as (FPG x FPI)/405., 18 and 36 months|Hepatic Insulin Sensitivity, Suppression of endogenous glucose production (Supp EGP) by low dose insulin (i.e., percentage of reduction of EGP with low dose insulin infusion compared to the baseline state). This was calculated as: 100\*((EGP without insulin - EGP with insulin infusion)/EGP without insulin). All measurements are obtained at the same time point during an euglycemic insulin clamp., 18 months|Adipose Tissue Insulin Sensitivity, Suppression of free fatty acids by low dose insulin (i.e., percentage of reduction of plasma FFA with low dose insulin infusion compared to the baseline state). This was calculated as: 100\*((plasma FFA without insulin - plasma FFA with insulin infusion)/plasma FFA without insulin). All measurements are obtained at the same time point during an euglycemic insulin clamp., 18 months|Skeletal Muscle Insulin Sensitivity, Rate of glucose disappearance (Rd) during high-dose insulin infusion. The rate of plasma glucose disappearance was calculated using Steele's non-steady-state equation., 18 months|Body Mass Index (BMI), Months 18 and 36|Total Body Fat, Total body fat measured by dual-energy x-ray absorptiometry (DXA), Months 18|Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (Adiponectin)., 18 and 36 months|Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (CK-18)., 18 and 36 months|Prevention of the Onset of T2DM and/or Reversal From IFG/IGT to NGT in Non-diabetics., Number of patients developing T2DM and number of patients regressing to NGT among patients with prediabetes (IFG/IGT)., 18 months|Osteoporotic Fractures, Number of patients with osteoporotic fractures, 18 and 36 months|Molecular Pathways of Liver Glucose and Lipid Signaling; Inflammatory Pathways; Oxidative Stress; Other., At 18 (2nd liver biopsy) and 36 (3rd liver biopsy) months.|Bone Mineral Density, Bone mineral density measured at the levels of spine, femoral neck, hip, and wrist by DXA., 18 and 36 months
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