Insulin Resistance in Non-alcoholic Fatty Liver Disease
The purpose of this study is to determine whether nonalcoholic fatty liver disease (NAFLD) is associated with altered peripheral and hepatic insulin sensitivity and to investigate potential mechanisms underlying insulin resistance in NAFLD by determining associations between hepatic and peripheral insulin sensitivity, hepatic steatosis, dyslipidemia, inflammatory cytokines, glucose metabolism, beta-cell function and body fat distribution.
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Basic Science
|Official Title:||Insulin Resistance in Non-alcoholic Fatty Liver Disease|
- The 2 primary outcome measures are: change in ALT levels and liver/spleen ratio [ Time Frame: 6 months ] [ Designated as safety issue: No ]
- 1.Change in alanine aminotransferase (ALT) levels as a marker of hepatic inflammation [ Time Frame: 6 months ] [ Designated as safety issue: No ]
- 2.Change in the liver spleen ration by CT scan as a measure of fat in the liver [ Time Frame: 6 months ] [ Designated as safety issue: No ]
- 3. Peripheral insulin sensitivity Hepatic insulin sensitivity Inflammatory cytokines Lipid profile Glucose tolerance Beta-cell function [ Time Frame: 6 months ] [ Designated as safety issue: No ]
- 4. Changes in body fat distribution [ Time Frame: 6 months ] [ Designated as safety issue: No ]
- 5. Changes in beta-cell function [ Time Frame: 6 months ] [ Designated as safety issue: No ]
|Study Start Date:||October 2005|
|Study Completion Date:||August 2010|
|Primary Completion Date:||August 2010 (Final data collection date for primary outcome measure)|
No Intervention: Arm 1
matching placebo for rosiglitazone, 1 po bid and placebo for fenofibrate 1 po qd
Experimental: Arm 2
rosiglitazone 4 mg po bid and fenofibrate placebo 1 po qd
PPAR-gamma agonist, insulin sensitizer
Experimental: Arm 3
micronized fenofibrate 200 mg 1 po qd and rosiglitazone placebo 1 po bid
PPAR-alpha agonist, reduces triglycerides
NAFLD and nonalcoholic steatohepatitis (NASH) are common liver disorders that are strongly associated with obesity, type 2 diabetes and dyslipidemia. The underlying pathophysiology of fatty infiltration of the liver is thought to be related to insulin resistance, which is an almost universal finding in patients with NAFLD. It is also possible that fat infiltration and inflammation in the liver may impair insulin sensitivity, either locally in the liver, or peripherally via the actions of inflammatory cytokines. We hypothesize that insulin resistance is a major causal factor leading to fat deposition in the liver and NAFLD, and thus interventions aimed at improving insulin sensitivity will result in a reduction of hepatic inflammation and steatosis.
Specific Aim 1: To determine in a cross-sectional study whether NAFLD is associated with altered peripheral and hepatic insulin sensitivity and to study their relationships with hepatic steatosis, dyslipidemia, inflammatory cytokines, glucose metabolism, -cell function and body fat distribution. Specific Aim 2: To determine in a 6 month placebo-controlled double-blinded treatment study if treatment with rosiglitazone, an insulin sensitizer, or fenofibrate, a triglyceride lowering agent, will improve both hepatic as well as peripheral insulin sensitivity and thereby improve hepatic steatosis and inflammation in subjects with NAFLD.
The results of the proposed study will have important implications for our understanding of the mechanisms underlying insulin resistance and abnormalities in lipid and glucose metabolism in subjects with NAFLD and for the design of future studies aimed at the prevention and treatment of this condition.
|United States, Washington|
|VA Puget Sound Health Care System, Seattle|
|Seattle, Washington, United States, 98108|
|Principal Investigator:||Kristina Marie Utzschneider, MD||VA Puget Sound Health Care System, Seattle|