Association of Nonalcoholic Fatty Liver Disease with Insulin Resistance Giulio Marchesini, MD, Mara Brizi, MD, Antonio M. Morselli-Labate, PhD, Giampaolo Bianchi, MD, Elisabetta Bugianesi, MD, Arthur J. McCullough, MD, Gabriele Forlani, MD, Nazario Melchionda, MD BACKGROUND AND PURPOSE: Nonalcoholic fatty liver disease is frequently associated with type 2 diabetes mellitus, obesity, and dyslipidemia, but some patients have normal glu- cose tolerance or normal weight. We tested the hypothesis that there is an association between nonalcoholic fatty liver disease and insulin resistance that is independent of diabetes and obe- sity. SUBJECTS AND METHODS: We measured anthropometric and metabolic variables in 46 patients with chronically elevated serum aminotransferase levels, “bright liver” on ultrasound scan, and normal glucose tolerance. Indexes of insulin resis- tance and secretion were determined using the homeostasis model assessment method. They were compared with 92 nor- mal subjects who were matched for age and sex. RESULTS: Patients with nonalcoholic fatty liver disease were characterized by fasting and glucose-induced hyperinsulin- emia, insulin resistance, postload hypoglycemia, and hypertri- glyceridemia. Insulin resistance [odds ratio (OR) = 15 per per- cent increase, 95% confidence interval (CI): 3.0 to 70], fasting triglyceride level (OR = 3.1 per mmol/liter increase, 95% CI: 1.1 to 8.9), 180-minute blood glucose level (OR = 4.3 per mmol/ liter decrease, 95% CI: 1.6 to 12), and average insulin concen- tration in response to oral glucose (OR = 3.0 per 100 pmol/liter increase, 95% CI: 1.5 to 6.2) were independently associated with nonalcoholic fatty liver disease. The exclusion of overweight and obese subjects did not change the results. CONCLUSION: Nonalcoholic fatty liver disease is associated with insulin resistance and hyperinsulinemia even in lean sub- jects with normal glucose tolerance. Genetic factors that reduce insulin sensitivity and increase serum triglyceride levels may be responsible for its development. Am J Med. 1999;107: 450 – 455. 1999 by Excerpta Medica, Inc. L ess than 20 years ago, Ludwig et al (1) coined the term “nonalcoholic steatohepatitis” to identify a syndrome characterized by fatty liver and lobular hepatitis in patients who had negligible alcohol intake. Patients have chronically elevated serum alanine amino- transferase levels that indicate ongoing liver injury that may progress to fibrosis, cirrhosis, and hepatocellular failure. The syndrome, recognized as a clinical entity since 1962 (2), is mainly associated with obesity (3,4), diabetes (3,5–7), and dyslipidemia (5–9). More recently, the spectrum of disease has been expanded to fatty liver with or without inflammation, and the term “nonalco- holic fatty liver disease” is used to include all patients with hepatic steatosis, whether or not there is active inflamma- tion. In earlier studies, fatty liver was considered to be an incidental pathologic finding that was without clinical significance. More recent studies have challenged this idea. Approximately half of the patients with nonalco- holic steatohepatitis develop liver fibrosis, 15% develop cirrhosis, and 3% may progress to liver failure or liver transplantation (10). In 15% to 50% of patients, liver fibrosis or cirrhosis may be diagnosed at presentation (11). Although type 2 diabetes mellitus and fatty liver are associated, the prevalence of steatosis in patients with type 2 diabetes is unknown, because there has not been a systematic study that included liver biopsies. From 21% to 78% of diabetic patients have fatty liver seen with ul- trasound examination (11,12), and serum alanine ami- notransferase levels are frequently increased (13,14). However, attempts to link nonalcoholic fatty liver disease to altered glucose tolerance have been unsuccessful. The prevalence of type 2 diabetes varies from 2% to 55% in patients with nonalcoholic fatty liver disease (15), and the amount of steatosis is more closely related to the degree of obesity (3). In addition, some patients with nonalcoholic fatty liver disease are lean, have normal fasting glucose levels with normal glucose tolerance, and do not have increased plasma lipid levels (7). Because type 2 diabetes, obesity, and dyslipidemia are all associated with decreased sensitivity to insulin, this study was designed to determine the association between nonalcoholic fatty liver disease and insulin resistance, while adjusting for the effects of diabetes and obesity. Insulin sensitivity and -cell function were estimated by the homeostasis model assessment method (16), which From the Department of Internal Medicine and Gastroenterology (GM, MB, AMM-L, NM), Cattedra di Malattie del Metabolismo (GM, MB, GB, EB, GF, NM), Universita ` di Bologna, Bologna, Italy, and Division of Gastroenterology (AJM), MetroHealth Medical Center, Cleveland, Ohio. Requests for reprints should be addressed to Giulio Marchesini, MD, Cattedra di Malattie del Metabolismo, Universita ` di Bologna, Azienda Ospedaliera S. Orsola-Malpighi, Via Massarenti 9, I-40138 Bologna, Italy. Manuscript submitted October 13, 1998, and accepted in revised form May 26, 1999. 450 1999 by Excerpta Medica, Inc. 0002-9343/99/$–see front matter All rights reserved. PII S0002-9343(99)00271-5