Clinical Trial: Obesity and Nonalcoholic Fatty Liver Disease

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Obesity and Nonalcoholic Fatty Liver Disease

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:

  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.

Detailed Summary: 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.
Sponsor: Washington University School of Medicine

Current Primary Outcome:

  • 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.
  • 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.
  • 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.
  • Hepatic Fat Content for Fenofibrate and Niacin Groups [ Time Frame: baseline to post intervention:

    Original Primary Outcome:

    • 1. VLDL-TG and protein kinetics
    • 2. Insulin sensitivity in adipose tissue, liver and skeletal muscle
    • 3. Hepatic fat content
    • 4. Hepatic, subcutaneous fat, and intraabdominal fat cytokine production
    • 5. Arterial, portal venous, and peripheral blood lymphocyte cytokine production
    • 6. Body composition analysis


    Current Secondary Outcome:

    • Very Low Density Lipoprotein - Triglyceride Production Rate [ Time Frame: baseline cross-sectional data ]
      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).
    • Change From Baseline in Very Low Density Lipoprotein Apolipoprotein B Production Rate [ Time Frame: baseline to post intervention: 8 weeks (fenofibrate), 16 weeks (niacin) ]
      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.
    • Change From Baseline in VLDL-Tg Clearance Rate [ Time Frame: baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin) ]
      Very low density lipoprotein triglyceride (VLDL-Tg) clearance rate, a measure of VLDL-triglyceride removal from plasma per minute.
    • Change From Baseline in VLDL-Tg Production Rate [ Time Frame: baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin) ]
      VLDL-TG production rate, a measure of hepatic secretion of VLDL-triglyceride per liter of plasma per minute.
    • Change From Baseline in Very Low-density Lipoprotein Triglyceride Concentration [ Time Frame: baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin) ]
      Change from baseline in very low-density lipoprotein triglyceride concentration (VLDL-Tg)


    Original Secondary Outcome:

    Information By: Washington University School of Medicine

    Dates:
    Date Received: December 6, 2005
    Date Started: October 2004
    Date Completion:
    Last Updated: July 2, 2010
    Last Verified: July 2010