Insulin resistance: a metabolic pathway to chronic liver disease

none3ABSTRACT Insulin resistance is the pathophysiologic hallmark of nonalcoholic fatty liver disease (NAFLD), one of the most common causes of chronic liver disease in Western countries. In this article, we review the definition, the methods for the quantitative assessment of insulin action, the pathophysiology of insulin resistance and its role in the pathogenesis of chronic liver disease. Increased free fatty acid (FFA) flux from adipose tissue to non-adipose organs, which is a result of abnormal fat metabolism, leads to hepatic triglyceride accumulation and contributes to impaired glucose metabolism and insulin sensitivity in muscle and liver. Several factors secreted or expressed in the adipocyte contribute to the onset of a pro-inflammatory state, which may be limited to the liver or more extensively expressed throughout the body. Insulin resistance is the common soil of the metabolic syndrome and its related features. It is a systemic disease affecting the nervous system, muscle, pancreas, kidney, heart, and the immune system, in addition to the liver. A complex interaction between genes and the environment favors or enhances insulin resistance and the phenotypic expression of NAFLD in individual patients. Advanced fibrotic liver disease is associated with multiple features of the metabolic syndrome and the risk of progressive liver disease should no longer be underestimated in subjects with metabolic disorders. Finally, the ability of insulin-sensitizing, pharmacological agents to treat NAFLD by reducing insulin resistance in the liver (metformin) and in the periphery (thiazolidinediones) are discussed.mixedE. Bugianesi; A. J. McCullough; G. Marchesini ReggianiE. Bugianesi; A. J. McCullough; G. Marchesini Reggian