Insulin Resistance in Non-alcoholic Fatty Liver Disease

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.

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
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 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