Insulin Resistance in Non-alcoholic Fatty Liver Disease

Insulin Resistance in Non-alcoholic Fatty Liver Disease (Protocol Drug Change From Project Career Development Award (CDA)-2-044-08S)

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.

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.

non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, insulin resistance, pioglitazone, fenofibrate

Liver/Spleen Ratio Measured as the Ratio in Hounsfield Units Between the Liver and the Spleen on Computed Tomography (CT) Scan

Change in Liver/Spleen Ratio Measure by the Density Ratio in Hounsfield Units Between the Liver and the Spleen by CT

Change in the rate of glucose disposal (Rd) during the low dose clamp. During a clamp procedure, insulin is infused at a dose based on body size and a glucose solution is infused and the rate adjusted every 5 minutes based on a blood glucose reading to maintain the blood glucose stable at 90 mg/dl (normal level). Using glucose isotopes and the rate of the glucose infusion, we are then able to calculate how much glucose the liver is producing and how much glucose is being taken up into tissues. This provides a measure of insulin sensitivity.

Hepatic insulin sensitivity was determined using stable glucose isotope measurements during the low dose hyperinsulinemic euglycemic clamp to determine the rate of endogenous glucose production in the fasting state and in response to a low dose glucose infusion. The ability of insulin to suppress glucose, which is mainly produced by the liver, thus provides a measure of hepatic insulin sensitivity and is expressed as a percentage of the basal state. Change in the ability of low dose insulin to suppress endogenous glucose production during a labeled hyperinsulinemic euglycemic clamp.

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

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