Insulin sensitizers in nonalcoholic fatty liver disease and steatohepatitis: Current status

Abstract

Nonalcoholic fatty liver disease (NAFLD), first described in 1980, is now recognized as one of the most common causes of elevated liver enzymes and chronic liver disease in Western countries. The incidence of NAFLD in both adults and children is rising, in conjunction with the burgeoning epidemics of obesity and type 2 diabetes mellitus. NAFLD often coexists with other sequelae of the metabolic syndrome: central obesity, type 2 diabetes, hypertension, and hyperlipidemia. NAFLD encompasses a spectrum of pathologic liver diseases ranging from simple hepatic steatosis to a predominant lobular necro-inflammation, with or without centrilobular fibrosis (called nonalcoholic steatohepatitis or NASH). NASH can progress to cirrhosis, decompensated liver disease, and hepatocellular carcinoma. Though the natural history of NASH is still not clearly defined, it has been observed to progress to cirrhosis in 15%-220% of those affected. Insulin resistance is nearly universal in NASH and is thought to play an important role in its pathogenesis leading to dysregulated lipid metabolism. The prevalence of insulin resistance is reported in the general population to be approaching 45%, suggesting that NAFLD and NASH will contin nue to be an important public health concern. To date, NASH has proven to be a difficult disease to treat. Front-line therapy with lifestyle modifications resulting in weight loss through decreased caloric intake and moderate exercise is generally believed to be beneficial in patients with NASH, but is often difficult to maintain long term. Given that insulin resistance plays a dominant role in the pathogenesis, many studies have examined the use of insulin sensitizers: the biguanides (metformin), thiazolidinediones (pioglitazone, troglitazone, and rosiglitazone), glucagon-like peptide-1-receptor agonists, or incretins (exenatide)in NASH. This review will provide an overview of insulin resistance in NAFLD and provide a detailed summary on the clinical data regarding the use of insulin sensitizers in NASH.

Clinical Syndromes and Consequences of Antiretroviral-Related Hepatotoxicity5, 1, 3

“…Lifestyle modifications resulting in weight loss through decreased caloric intake and moderate exercise is generally believed to be beneficial in patients with NASH, but is often difficult to maintain in the long term. 133 Given that insulin resistance plays a dominant role in the pathogenesis of NASH, many studies have examined the use of insulin sensitizers. Results with metformin (a biguanide) have been heterogeneous, most studies have been small and have flaws in the design, and its effect may be largely related to its ability to induce weight loss.…”

“…[139][140][141][142] However, it is unclear whether a thiazolidinedione-associated increase in adiposity and weight gain would ultimately limit its benefits. 133 In addition, long-term toxicities of these agents include a potential for cardiovascular events and fracture risk. Therefore, we need more information regarding the efficacy and safety of these agents before recommendations for safe use can be made.…”

Effects of a combination of puerarin, baicalin and berberine on the expression of proliferator-activated receptor-γ and insulin receptor in a rat model of nonalcoholic fatty liver disease

“…NAFLD develops progressively from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis (2,3). Previous studies have suggested a 'two-hit' theory for the pathogenesis of NAFLD, including insulin resistance, oxidative stress, lipid peroxidation and mitochondrial dysfunction (4,5), with insulin resistance considered the major factor.…”

Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice

“…Furthermore, up to 15-25% of people with NASH may progress to having cirrhosis over 10 to 20 yr (3,25,29) The current standard of care for NAFLD/NASH is limited to ameliorating components of the metabolic syndrome, primarily through weight loss and/or improving insulin sensitivity with lifestyle interventions or surgery (22,30). Improving insulin sensitivity by the use of thiazolidinediones is being investigated in a growing number of trials (4,36). However, this strategic approach appears to be inadequate as these agents display only modest and variable efficacy for NAFLD/NASH (27).…”