Obesity and Nonalcoholic Fatty Liver Disease

Non-alcoholic Fatty Liver Disease Clinical Trial

Official title:

Obesity and Nonalcoholic Fatty Liver Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00262964
• Other study ID #: DK37948
• Secondary ID: R01DK037948
• Status: Completed
• Phase: N/A
• Start date: October 2004
• Est. completion date: December 2008

Study information

• Verified date: June 2018
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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:

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 51
• Est. completion date: December 2008
• Est. primary completion date: December 2008
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 45 Years

Eligibility

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.

Related Conditions & MeSH terms

• Fatty Liver
• Liver Diseases
• Non-alcoholic Fatty Liver Disease
• Obesity

Intervention

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.
• fenofibrate
Subjects randomized to fenofibrate will be treated with 200 mgs per day for eight weeks.
• placebo
Subjects randomized to placebo will be treated with one placebo pill per day for eight weeks.

Locations

Country	Name	City	State
United States	Washington University School of Medicine	Saint Louis	Missouri

Sponsors (2)

Lead Sponsor	Collaborator
Washington University School of Medicine	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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)
Primary	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)
Primary	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)
Primary	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	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)