Insulin Resistance in Non-alcoholic Fatty Liver Disease

VA Office of Research and Development

Status: Terminated

Conditions: Fatty Liver

Treatments: Drug: fenofibrate; Drug: placebo; Drug: pioglitazone

Study type: Interventional

Funder types: Other U.S. Federal agency

Identifiers

NCT01289639

CDA-2-044-08S-2

Details and patient eligibility

About

The study is designed to investigate the relationship between insulin resistance and non-alcoholic fatty liver disease (NAFLD) 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.

Full 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, beta-cell function and body fat distribution. Specific Aim 2: To determine in a 6 month placebo-controlled double-blinded treatment study if treatment with pioglitazone, 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.

Enrollment: 11 patients

Sex: All

Ages: 18 to 80 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

Control subjects: nl liver enzymes and no history of liver disease Case subjects: NAFLD on liver biopsy within the past 3 years or presumed NAFLD with otherwise unexplained elevated alanine aminotransferase (ALT) and fatty liver by computerized tomography (CT) scan or ultrasound

• Able to comply with taking 1 pill a day for 6 months and follow-up safety visits

Exclusion criteria

• 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 hemoglobin A1c (HbA1c) >7.5% or use of insulin, metformin, rosiglitazone or pioglitazone

• Liver transaminases: ALT >5x upper limit of normal,

• 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 or since the liver biopsy

• History of significant coronary artery disease or congestive heart failure, retinopathy

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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11 participants in 3 patient groups, including a placebo group

Placebo

Placebo Comparator group

Description:

matching placebo 1 po qd

Treatment:

Drug: placebo

Fenofibrate

Experimental group

Description:

micronized fenofibrate 200 mg 1 po qd

Treatment:

Drug: fenofibrate

Pioglitazone

Experimental group

Description:

pioglitazone 30 mg po qd

Treatment:

Drug: pioglitazone