Obesity and Nonalcoholic Fatty Liver Disease

The primary goal of this study is to provide a better understanding of: 1) the pathogenesis and pathophysiology of non-alcoholic fatty liver disease (NAFLD) in obese subjects, and 2) the effect of marked weight loss on the histologic and metabolic abnormalities associated with NAFLD. The following hypotheses will be tested:

1. obesity causes hepatic fat accumulation because of excessive fatty acid release from fat tissue and increased free fatty acid availability,
2. increased hepatic (liver) fat content causes insulin-resistant glucose (sugar) production by the liver and altered liver protein synthesis,
3. increased hepatic fat content causes increased lipid (fat) peroxidation, hepatic inflammation, necrosis and fibrosis, and
4. marked weight loss improves NAFLD once patients are weight stable.

Study Overview

• Status: Completed
• Conditions: Non-alcoholic Fatty Liver Disease
• Intervention / Treatment: Drug: Niacin; Drug: fenofibrate; Drug: placebo

Detailed Description

Obesity is a major risk factor for non-alcoholic fatty liver disease (NAFLD), which represents a spectrum of liver diseases. NAFLD is a major health problem in the US because of its high prevalence and causal relationship with serious liver abnormalities. However, the mechanism(s)responsible for developing NAFLD in obese persons and the effects on liver function are not known. This gap in knowledge has made it difficult to identify effective therapy. The results from these studies will lay the groundwork for the development of novel therapeutic interventions for NAFLD in obese patients.

• Study Type: Interventional
• Enrollment (Actual): 51
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

All

• 18 - 45 years old
• Class I obesity, i.e. Body Mass Index (BMI) between 30 and 45.
• weight less than 300 lbs.

Exclusion Criteria:

• Active or previous infection with hepatitis B or C, as well as other liver disease.
• History of alcohol abuse
• Diabetes
• Medications that cause liver damage or steatosis.
• Women who are pregnant or lactating.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NAFLD-Niacin; Subjects, having previously diagnosed with NAFLD, were given Niacin for 16 weeks. The dosage was 500mg/day for week 1, 1000mg/day for week 2, 1500mg/day for week three and 2000mg/day for weeks 4 through 16.	Drug: Niacin; Subjects randomized to Niacin therapy will be treated with Niacin at night for 16 wks to reduce plasma free fatty acid concentrations. The dose of medication will be gradually increased: 500 mg/day during week 1, 1000 mg/day during week 2, 1500 mg/day during week 3, and 2000mg/day during weeks 4-16.; Other Names: niaspan
No Intervention: Control; Subjects were found to have intrahepatic triglyceride levels below the threshold for Non-Alcoholic Fatty Liver Disease (NAFLD). For this study that threshold was set at 10% intrahepatic triglyceride content as determined by magnetic resonance spectroscopy. These control subjects did not participate in any intervention. Only baseline features were characterized for this arm.
Experimental: NAFLD-fenofibrate; Subjects diagnosed with NAFLD were randomized to fenofibrate, an oral medication, nightly for eight weeks. Subjects will be given a dose of 200mg/day.	Drug: fenofibrate; Subjects randomized to fenofibrate will be treated with 200 mgs per day for eight weeks.; Other Names: Tricor
Placebo Comparator: NAFLD-placebo; These subjects were diagnosed with Non-Alcoholic Fatty Liver Disease (NAFLD) and received an 8 week course of a placebo pill. Their baseline characteristics were averaged into the overall NAFLD baseline characteristics along with the baseline data for the two intervention groups.	Drug: placebo; Subjects randomized to placebo will be treated with one placebo pill per day for eight weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hepatic Insulin Sensitivity Index (HISI)	Hepatic insulin sensitivity, assessed as a function of glucose production rate and plasma insulin concentration. The Hepatic Insulin Sensitivity Index(HISI) is the reciprocal of glucose rate of appearance [10000/(μmol/min)] multiplied by insulin concentration[mU/L]. The 10000 in the formula is a conventional adjustment so that insulin sensitivity measures are more readable. As yet there is no normal range for HISI, since is a surrogate marker for hepatic insulin sensitivity that has not yet been validated.	baseline cross-sectional data
Percent Increase in Skeletal Muscle Insulin Sensitivity During Insulin Infusion.	A precise measure of the ability of insulin to stimulate glucose uptake by skeletal muscle. Skeletal muscle insulin sensitivity, measured as the increase from baseline in skeletal muscle glucose uptake during insulin infusion(percentage)as part of a nine hour euglycemic hyperinsulinemic clamp study.	baseline cross-sectional data pre and post nine hour euglycemic clamp
Adipose Tissue Insulin Sensitivity	The ability of insulin to suppress the release of fatty acids from adipose tissue: Adipose tissue insulin sensitivity, measured as the suppression from baseline of free fatty acid release from adipose tissue (lipolysis) during insulin infusion as part of a nine hour euglycemic hyperinsulinemic clamp study.	baseline cross-sectional data pre and post nine hour euglycemic clamp
Hepatic Fat Content for Fenofibrate and Niacin Groups	Hepatic fat content as measured by magnetic resonance spectroscopy. A PRESS sequence was used. The results from three 10 cubic centimeter voxels positioned within the liver were averaged. The measure is a ratio of triglyceride signal to total signal.	baseline to post intervention: 8 weeks (fenofibrate), 16 weeks (niacin)
Adipose Tissue Insulin Sensitivity in Fenofibrate and Niacin Groups	The baseline and post-treatment measures of adipose tissue insulin sensitivity (ATIS) were compared. ATIS at both timepoints is the suppression from fasting levels of free fatty acid release from adipose tissue (lipolysis) during an insulin infusion as part of a euglycemic clamp study. It is the percent decrease from time zero to the end of the nine hour euglycemic hyperinsulinemic clamp	baseline to post intervention: 8 weeks (fenofibrate), 16 weeks (niacin)
Change From Baseline in Skeletal Muscle Insulin Sensitivity	Changes in skeletal muscle insulin sensitivity (SMIS). SMIS was measured as the increase in skeletal muscle glucose uptake from time zero to the end of a nine hour euglycemic clamp and insulin infusion study. This increase is the percentage change from time zero to end of insulin infusion at nine hours.	baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin)
Change From Baseline in Hepatic Insulin Sensitivity Index	Hepatic insulin sensitivity, assessed as a function of glucose production rate and plasma insulin concentration. The Hepatic Insulin Sensitivity Index (HISI) is measured as the reciprocal of glucose rate of appearance [10000/(μmol/min)] multiplied by insulin concentration[mU/L]. The 10000 in the formula is a conventional adjustment so that insulin sensitivity measures are more readable. As yet there is no normal range for HISI, since is a surrogate marker for hepatic insulin sensitivity that has not yet been validated.	baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Very Low Density Lipoprotein - Triglyceride Production Rate	Very low density lipoprotein triglyceride (VLDL-TG) production rate, a measure of hepatic secretion of VLDL-triglyceride per liter of plasma per minute (μmol/L/min).	baseline cross-sectional data
Change From Baseline in Very Low Density Lipoprotein Apolipoprotein B Production Rate	VLDL-apolipoprotein B (apoB) concentrations were measured as part of a VLDL metabolism study utilizing stable isotope tracers. VLDL apoB production rate, a measure of hepatic secretion of VLDL-apolipoproteinB-100 per liter of plasma per minute.	baseline to post intervention: 8 weeks (fenofibrate), 16 weeks (niacin)
Change From Baseline in VLDL-Tg Clearance Rate	Very low density lipoprotein triglyceride (VLDL-Tg) clearance rate, a measure of VLDL-triglyceride removal from plasma per minute.	baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin)
Change From Baseline in VLDL-Tg Production Rate	VLDL-TG production rate, a measure of hepatic secretion of VLDL-triglyceride per liter of plasma per minute.	baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin)
Change From Baseline in Very Low-density Lipoprotein Triglyceride Concentration	Change from baseline in very low-density lipoprotein triglyceride concentration (VLDL-Tg)	baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin)

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study record dates

Study Major Dates

• Study Start: October 1, 2004
• Primary Completion (Actual): December 1, 2008
• Study Completion (Actual): December 1, 2008

Study Registration Dates

• First Submitted: December 6, 2005
• First Submitted That Met QC Criteria: December 6, 2005
• First Posted (Estimate): December 7, 2005

Study Record Updates

• Last Update Posted (Actual): July 11, 2018
• Last Update Submitted That Met QC Criteria: June 13, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: obesity; non-alcoholic fatty liver disease; fatty liver disease
• Additional Relevant MeSH Terms: Digestive System Diseases; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Liver Diseases; Obesity; Fatty Liver; Non-alcoholic Fatty Liver Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Antimetabolites; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Vitamins; Vitamin B Complex; Fenofibrate; Niacin
• Other Study ID Numbers: DK37948; R01DK037948 (U.S. NIH Grant/Contract)