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Role of Insulin Resistance and Diabetes in the Pathogenesis and Treatment of Nonalcoholic Fatty Liver Disease

ByCrossFitNovember 22, 2019

Fatty liver disease and insulin resistance are strongly associated. This 2014 review assesses how fatty liver disease directly contributes to the progression of insulin resistance and vice versa.

Fatty liver disease has become the most common cause of liver disease in adults worldwide. As fatty liver progresses, it moves from nonalcoholic fatty liver disease (NAFLD) — which indicates liver fat accumulation but no additional damage — to NASH, or nonalcoholic steatohepatitis. With the latter condition, the liver becomes inflamed, oxidized, and fibrotic. NASH can directly progress to cirrhosis and liver failure, though the most common cause of death in patients with NASH is cardiovascular disease.

NAFLD and NASH incidence has risen alongside the obesity and diabetes epidemics. An estimated 60% of obese non-diabetics and over 80% of obese diabetics have significant liver fat accumulation, with more than two-thirds of diabetics also showing inflammation and oxidative damage (NASH). More than half of obese, diabetic patients show fibrotic damage and progression toward cirrhosis. Across the population as a whole, the prevalence of NASH is estimated to be between 34% and 46% (1).

Fatty liver disease exacerbates insulin resistance. As the liver accumulates fat, it becomes less responsive to insulin. The liver produces glucose to maintain blood glucose levels; insulin suppresses this glucose production. As the liver becomes insulin resistant, this insulin-derived glucose suppression breaks down. Thus, glucose levels remain elevated. As a result, liver fat directly leads to chronic hyperglycemia and hyperinsulinemia as well as insulin resistance in other tissues such as muscle and fat cells.

Simultaneously, insulin resistance in these other tissues can drive liver fat accumulation. As fat and muscle cells become insulin resistant, fatty acid oxidation decreases and the release of fatty acids into the bloodstream increases. As the liver is exposed to increasing fatty acid loads, it accumulates fat, and as this process continues, NAFLD develops and progresses to NASH over time.

Once fatty liver disease is present, the liver is no longer able to perform another key function: clearing insulin from the blood. Liver insulin clearance is decreased with even mild liver steatosis, and the hyperinsulinemia often seen alongside NASH may be the result of impaired insulin clearance as much as increased insulin production.

The result is a vicious cycle in which fat accumulation in the liver drives increased peripheral insulin resistance that further increases fat accumulation in the liver. Insulin resistance leads to diabetes, while liver fat accumulation (which affects lipid production in the liver) leads to a more atherogenic (i.e., higher-risk) blood lipid profile.

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