Insulin Resistance in Nonalcoholic Fatty Liver Disease: A Case Control Study

Purpose of the study:

To date, no case control study evaluating insulin resistance (IR) in nonalcoholic fatty liver disease (NALFD) has been published. We hypothesize that IR is characteristic of NAFLD as compared to age, gender, non-diabetic BMI-matched control subjects, both healthy and those with non-cirrhotic, non-steatotic liver disease. The following aims test this central hypothesis:

Specific Aim 1: Measure IR and insulin clearance using intravenous glucose tolerance testing and Bergman's Minimal Modeling in patients with NAFLD as compared to matched controls (healthy and those with non-steatotic hepatitis). This aim tests the postulate that IR is necessary for the development of hepatic steatosis as compared to healthy (non-steatotic livers). It will also test the postulate that IR is not present as a confounding factor (impaired hepatic clearance) in NAFLD as compared to those with non-steatotic forms of hepatitis.

Specific Aim 2: Determine if IR is associated with altered parameters of lipid metabolism as compared to matched controls. This aim addresses whether IR (if present) is associated with abnormal lipid parameters in NAFLD or can be observed irrespective of the presence of hepatic steatosis.

Specific Aim 3: Measure the differential effects of IR and lipid metabolism on peripheral mononuclear cell (PBMC) inflammatory response and the associated hepatocyte mitochondrial ultrastructure and measures of oxidative stress. Since increased oxidative stress and bioenergetic failure have been associated with hepatic steatosis, this aim will address whether IR and/or steatosis results in impaired inflammatory response and increased oxidative stress as compared to controls. Changes in innate immune response will be determined by measuring inflammatory indices thought to correlate with obesity, IR, and/or chronic hepatitis: 1) interleukins (IL-2, IL-4, IL-6, IL-10, IL-12, IL-18) 2) C-reactive protein, 3) TNF-a and TGF-B 4) IFN-A & IFN-g, and 5) adiponectin. Changes in oxidative stress will be determined by measuring key indices of oxidative stress and damage. These include, a) reduced and oxidized glutathione (GSH and GSSG); oxidation/reduction status), b) malondialdehyde (MDA;lipid peroxidation), c) nitrotyrosine (NO damage), and d) 8OHdG and 8OHG (DNA damage).