Insulin Resistance in Non-alcoholic Fatty Liver Disease

Not Applicable

Terminated

• Conditions: Fatty Liver; Insulin Resistance
• Interventions: Drug: rosiglitazone; Drug: placebo for rosiglitazone; Drug: fenofibrate; Drug: placebo for fenofibrate

• Registration Number: NCT00252499
• Lead Sponsor: US Department of Veterans Affairs

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Study Start: 2005-10
• Study First Submitted: 2005-11-09
• Study First Submitted QC: 2005-11-09
• Study First Posted: 2005-11-11
• Primary Completion: 2010-08
• Study Completion: 2010-08
• Results First Submitted: 2013-11-12
• Results First Submitted QC: 2014-03-05
• Results First Posted: 2014-04-11
• Status Verified: 2014-08
• Last Update Submitted: 2014-08-18
• Last Update Posted: 2014-08-20

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 13

Inclusion Criteria

• Age 18-80 years old Controls:

  • otherwise healthy Case subjects: NAFLD on liver biopsy within the past 3 years or presumed NAFLD with otherwise unexplained elevated ALT and fatty liver by CT or ultrasound

• Able to comply with taking 3 pills a day for 6 months and follow-up safety visits

Read More

Exclusion Criteria

• Controls:

  • history or evidence of hepatic steatosis

• Cases:

  • Cirrhosis on liver biopsy or by clinical exam or fibrosis score
  • Causes of liver dysfunction other than NASH

• Use of medications associated with hepatic steatosis:

  • glucocorticoids
  • estrogens
  • tamoxifen
  • amiodarone
  • accutane
  • sertraline

• Use of medications that cause insulin resistance:

  • niacin
  • glucocorticoids
  • anti-HIV drugs or atypical antipsychotics

• Use of lipid-lowering medications except stable dose statin

• Use of anti-NASH drugs such as:

  • ursodeoxycholic acid
  • betaine milk thistle

• Use of coumadin

• Use of nitrates

• Significant alcohol consumption:

  • Average >20 grams/day

• In subjects with diabetes

  • a HbA1c >7.5% or use of insulin
  • metformin
  • rosiglitazone or pioglitazone

• Liver transaminases:

  • Cases: ALT >5x upper limit of normal
  • Controls: ALT or AST above the normal range

• Iron saturation >50%

• Creatinine >1.5 mg/dl for men and >1.4 mg/dl for women

• Hematocrit <33%

• Pregnancy or lactation

• Significant weight loss within the past 6 months for controls, or since the liver biopsy for case subjects, history of significant coronary artery disease or congestive heart failure

• Retinopathy

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo Arm	placebo for fenofibrate	matching placebo for rosiglitazone, 1 po bid and placebo for fenofibrate 1 po qd
Rosiglitazone Arm	rosiglitazone	rosiglitazone 4 mg po bid and fenofibrate placebo 1 po qd
Placebo Arm	placebo for rosiglitazone	matching placebo for rosiglitazone, 1 po bid and placebo for fenofibrate 1 po qd
Rosiglitazone Arm	placebo for fenofibrate	rosiglitazone 4 mg po bid and fenofibrate placebo 1 po qd
Fenofibrate Arm	fenofibrate	micronized fenofibrate 200 mg 1 po qd and rosiglitazone placebo 1 po bid
Fenofibrate Arm	placebo for rosiglitazone	micronized fenofibrate 200 mg 1 po qd and rosiglitazone placebo 1 po bid

Primary Outcome Measures

Name	Time	Method
Liver/Spleen Ratio at 6 Months	6 months	Liver fat was estimated by non-contrast CT scan measuring the density ratio between the liver and spleen by Hounsfield units (liver/spleen ratio), which has been previously correlated with liver fat quantification by magnetic resonance spectroscopy.Ten separate measurements equally distributed throughout the liver and spleen were obtained and the Hounsfield units averaged. In subjects with more than one slice through the liver and spleen, the values for all slices were averaged.

Secondary Outcome Measures

Name	Time	Method
Changes in Intra-abdominal Fat Area From Baseline to 6 Months	6 months	Unenhanced CT scan images were obtained on a General Electric Discovery HD750 CT scanner. Intra-abdominal (IAF) areas were measured at the top of the iliac crest and quantified using the Tomovision program (SliceOMatic V4.3) by one trained technologist.
Change in Alanine Aminotransferase (ALT) Levels From Baseline to 6 Months	6 months
Change in Hepatic Insulin Sensitivity From Baseline to 6 Months	6 months	Hepatic insulin sensitivity was determined as the percent suppression of endogenous glucose production (EGP) at the end of the low dose insulin clamp.
Change in the Liver Spleen Ratio by CT Scan From Baseline to 6 Months as a Measure of Fat in the Liver	6 months
Change in Peripheral Insulin Sensitivity From Baseline to 6 Months	6 months	A two-step stable isotope labeled, hyperinsulinemic-euglycemic clamp procedure was performed with a low dose insulin infusion (20 mU/m2/min) for 3 hours followed by a primed high dose insulin infusion (160 mU/m2/min x 5 minutes then 80 mU/m2/min) for two hours. D20 was infused and adjusted to maintain the blood glucose at 90 mg/dl. Samples for glucose, insulin and 6,6 2d glucose were drawn every 15 minutes during the final half hour of the basal, low dose and high dose insulin periods. Whole body insulin sensitivity was calculated as the rate of glucose disposal (Rd)/lean body mass during the high dose insulin infusion.

Trial Locations

Locations (1)

VA Puget Sound Health Care System, Seattle; 🇺🇸 Seattle, Washington, United States