Obesity and Nonalcoholic Fatty Liver Disease
Overview
- Phase
- Not Applicable
- Intervention
- Niacin
- Conditions
- Non-alcoholic Fatty Liver Disease
- Sponsor
- Washington University School of Medicine
- Enrollment
- 51
- Locations
- 1
- Primary Endpoint
- Change From Baseline in Skeletal Muscle Insulin Sensitivity
- Status
- Completed
- Last Updated
- 7 years ago
Overview
Brief Summary
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:
- obesity causes hepatic fat accumulation because of excessive fatty acid release from fat tissue and increased free fatty acid availability,
- increased hepatic (liver) fat content causes insulin-resistant glucose (sugar) production by the liver and altered liver protein synthesis,
- increased hepatic fat content causes increased lipid (fat) peroxidation, hepatic inflammation, necrosis and fibrosis, and
- marked weight loss improves NAFLD once patients are weight stable.
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •18 - 45 years old
- •Class I obesity, i.e. Body Mass Index (BMI) between 30 and
- •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
- •Medications that cause liver damage or steatosis.
- •Women who are pregnant or lactating.
Arms & Interventions
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.
Intervention: Niacin
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.
Intervention: fenofibrate
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.
Intervention: placebo
Outcomes
Primary Outcomes
Change From Baseline in Skeletal Muscle Insulin Sensitivity
Time Frame: baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin)
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.
Percent Increase in Skeletal Muscle Insulin Sensitivity During Insulin Infusion.
Time Frame: baseline cross-sectional data pre and post nine hour euglycemic clamp
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.
Hepatic Fat Content for Fenofibrate and Niacin Groups
Time Frame: baseline to post intervention: 8 weeks (fenofibrate), 16 weeks (niacin)
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.
Adipose Tissue Insulin Sensitivity
Time Frame: baseline cross-sectional data pre and post nine hour euglycemic clamp
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.
Adipose Tissue Insulin Sensitivity in Fenofibrate and Niacin Groups
Time Frame: baseline to post intervention: 8 weeks (fenofibrate), 16 weeks (niacin)
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
Hepatic Insulin Sensitivity Index (HISI)
Time Frame: baseline cross-sectional data
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.
Change From Baseline in Hepatic Insulin Sensitivity Index
Time Frame: baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin)
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.
Secondary Outcomes
- Change From Baseline in VLDL-Tg Clearance Rate(baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin))
- Change From Baseline in Very Low-density Lipoprotein Triglyceride Concentration(baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin))
- Very Low Density Lipoprotein - Triglyceride Production Rate(baseline cross-sectional data)
- Change From Baseline in VLDL-Tg Production Rate(baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin))
- Change From Baseline in Very Low Density Lipoprotein Apolipoprotein B Production Rate(baseline to post intervention: 8 weeks (fenofibrate), 16 weeks (niacin))