Insulin resistance: A metabolic pathway to chronic liver disease

Abstract

Insulin resistance (IR) is the pathophysiological hallmark of nonalcoholic fatty liver disease (NAFLD), one of the most common causes of chronic liver disease in Western countries. We review the definition of IR, the methods for the quantitative assessment of insulin action, the pathophysiology of IR, and the role of IR in the pathogenesis of chronic liver disease. Increased free fatty acid flux from adipose tissue to nonadipose organs, a result of abnormal fat metabolism, leads to hepatic triglyceride accumulation and contributes to impaired glucose metabolism and insulin sensitivity in muscle and in the liver. Several factors secreted or expressed in the adipocyte contribute to the onset of a proinflammatory state, which may be limited to the liver or more extensively expressed throughout the body. IR is the common characteristic of the metabolic syndrome and its related features. It is a systemic disease affecting the nervous system, muscles, pancreas, kidney, heart, and immune system, in addition to the liver. A complex interaction between genes and the environment favors or enhances IR 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 not be underestimated in individuals with metabolic disorders. Finally, the ability of insulin-sensitizing, pharmacological agents to treat NAFLD by reducing IR in the liver (metformin) and in the periphery (thiazolidinediones) are discussed. (HEPATOLOGY 2005;42:987-1000.)

Visceral adiposity and insulin resistance are independent predictors of the presence of non-cirrhotic NAFLD-related portal hypertension

“…Available data indicate that the onset of NAFLD is an early event in the development of IR and might predict the presence or future development of the MS. 46 On the other hand, IR is often considered as a key etiological mechanism in the development of NASH, and is a possible therapeutic target. 47,48 In diabetic patients, NAFLD is an important source of morbidity and mortality. 49 In patients with type 2 diabetes, cirrhosis and its complications are the second cause of disease-specific mortality.…”

“…46,47,52 Previous studies showed that that the severity of fatty liver was positively correlated with visceral fat accumulation and insulin resistance. 42,48 However, the exact causal relation between IR, visceral fat and steatosis remains unclear.…”

Research on the protection effect of pioglitazone for non-alcoholic fatty liver disease (NAFLD) in rats

“…But the pathogenesis of NAFLD remains unknown. NAFLD is considered one of the clinical features of the metabolic syndrome in which insulin resistance plays a central role (Bugianesi et al, 2005;Machado and Cortez-Pinto, 2005). Marchesini et al(2001) and Sanyal et al(2001) using euglycemic-hyperinsulinemic clamping showed that insulin resistance is present in both fatty liver and NASH.…”

Metabolic syndrome and nonalcoholic fatty liver disease: Is insulin resistance the link?

“…Insulin resistance, defined as the failure of insulin to stimulate glucose transport into its target cells, plays a central etiological role in MetS and is harmful for the liver since it likely promotes NAFLD (Bugianesi et al, 2005). Insulin is a pleiotropic hormone that regulates several cell functions among which stimulation of glucose transport, cell growth, energy balance and regulation of gene expression (de Luca and Olefsky, 2008).…”