Use of Insulin Sensitizers in NASH

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This article briefly discusses nonalcoholic fatty liver disease (NAFLD) and its association with the metabolic syndrome, its pathogenesis and natural history. It then presents a detailed discussion on the efficacy and safety of different insulin sensitizers in patients who have NASH.

Section snippets

Insulin resistance and metabolic syndrome in nonalcoholic fatty liver disease

The close association between metabolic syndrome and NAFLD is described well in the literature. The metabolic syndrome's core cluster includes diabetes, hypertension, dyslipidemia, and obesity. During the last decade, it has become clear that NAFLD is frequently present in patients who have the metabolic syndrome. Depending on the method of detection, up to 40% of patients who have metabolic syndrome have evidence for ongoing NAFLD [2].

Insulin resistance is very common in patients who have

Pathogenesis

The prevailing hypothesis is the two-hit model, with insulin resistance at the core of the pathogenesis. Obesity and diabetes mellitus are associated with increased tissue resistance to insulin; hyperinsulinemia develops and impairs mitochondrial β-oxidation of free fatty acids. Because of this block in fatty acid catabolism, fat accumulates in zone 3 hepatocytes, and thus the development of NAFL. The progression to NASH entails a second hit that is believed to be caused by oxidative stress.

Epidemiology

More than half of the United States population are either overweight (BMI greater than 25 but less than 29 kg/m2) or obese (BMI greater than 29 kg/m2) [13]. It is also estimated that 47 million individuals in the United States have the metabolic syndrome [14]. Thus, a high proportion of the United States population is at risk for NAFLD. NAFLD occurs in 9% of overweight patients and 21% to 33% of those with morbid obesity. Ultrasonography surveys of the general population indicate the presence

Prognosis and natural history

Prognosis of patients who have NAFLD depends on hepatic histology and coexisting comorbidities. Patients with underlying metabolic syndrome are especially at risk for cardiovascular morbidity and mortality. A recent study of 420 patients with NAFLD in the community setting found both liver-related and overall mortality higher than the general population [23]. Studies that included mainly patients who had bland steatosis described a benign long-term prognosis, whereas those that included mainly

Therapy

Improvement of insulin resistance, or insulin sensitivity, has therapeutic potential in preventing the progression of NASH, because the accumulation of triglycerides in hepatocytes is believed to be the first step in the current two-hit hypothesis of the pathophysiological development of NAFLD. The goals of therapy include risk factor modification, avoidance of factors that promote progression of liver disease, and specific treatment of NASH. The ultimate goal is to prevent end-organ damage

Mechanism of action

Thiazolidinediones, more commonly known as glitazones, are a new class of oral antidiabetic drugs that improve insulin sensitivity by acting as selective agonists of the nuclear peroxisome proliferators-activated receptor (PPAR)-γ. Three PPARs, designated PPAR-α, PPAR-δ (also known as PPAR-β), and PPAR-γ, have been identified. PPAR-α is expressed predominantly in muscle, liver, vascular wall, and heart [25]. PPAR-δ is expressed mostly in adipose tissue, skin, brain and hepatic stellate cells,

Mechanism of action

Metformin first was described in the scientific literature in 1957 [62], [63], but it did not receive approval by the US Food and Drug administration (FDA) for type 2 diabetes until 1994. The exact mechanism of action of metformin is uncertain despite its known therapeutic benefits. Its mode of action appears to be reduction of hepatic gluconeogenesis, decreased absorption of glucose from the gastrointestinal (GI) tract, and increased insulin sensitivity. The improvement in insulin sensitivity

Other insulin sensitizers

Exendin-4, a naturally occurring peptide that has 50% identity with the amino acid sequence of glucagon-like peptide 1 (GLP-1), binds to GLP-1 receptor and acts similarly to GLP-1 [74]. Both exendin-4 and GLP-1 augment pancreatic β cell function by enhancing glucose-stimulated insulin secretion, restoring first-phase insulin secretion, and stimulating β cell growth and neogenesis under conditions of increased insulin demand. Also, these compounds promote satiety [75], [76], [77], [78]. Ding and

Summary

NAFLD is very common in the Western world and it can be divided broadly into simple steatosis, which is benign, and NASH, which can progress to cirrhosis and liver failure. Insulin resistance is essential for developing NAFLD, and thus insulin sensitizers are emerging as promising agents to treat NASH. Many preliminary studies have suggested that second generations are effective in improving hepatic histology in patients who have NASH, but many important safety and practical issues need to be

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    Supported in part by K24 DK 069,290 (NC). Authors have no relevant financial conflicts to declare.

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