Alloveda Liver Update: Vicious cycle of fatty liver and diabetes |
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Alloveda Liver Update: Vicious cycle of fatty liver and diabetes

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Type 2 diabetes (T2D) is typified by hyperglycemia and dyslipidemia caused by islet β-cells which lose their ability to secrete adequate insulin in response to different levels of long-standing insulin resistance (IR) in genetically predisposed individuals. This disease is known to pose a huge burden on exploding population by increasing the risk of the multi-organ damage and its direct and indirect costs. It has been observed that diabetes is associated with decreased life expectancy of patients, vascular complications, end-stage renal disease and cirrhosis and hepatocellular carcinoma (HCC). Furthermore, non-alcoholic fatty liver disease (NAFLD), which is considered the most common liver disorder is also responsible for the development of systemic IR. Evidence based observations suggest that there is a vicious circle between NAFLD and diabetes as NAFLD can cause development of T2D via IR and conversely, T2D plays a crucial role in the development of progressive liver disease. 

Primary NAFLD is the hepatic manifestation of metabolic syndrome with a triad of clinical conditions such as hypertension, atherogenic dyslipidemia, T2D and obesity. The association between NAFLD and IR, was proposed initially as “two hit hypothesis” in which the first hit was the accumulation of triglycerides, steatosis, a consequence of systemic IR. The second hit was the result of long-term storage of triglycerides leading to hepatic oxidative stress. This stress in turn, would create an imbalance between glutathione and oxidized equivalents (GSH/GSSH), impaired mitochondrial energy production and dysfunctional β-oxidation of fatty acids. These free radicals along with lipid peroxidation products causes hepatocyte injury by breakage of cell organelles and membranes, resulting in apoptosis and augmented synthesis of inflammatory mediators, causing progression into fibrosis, cirrhosis and/or HCC. Several researches indicate that hyperinsulinemia also known as the first hit triggers the development of fatty liver in humans and the second-hit has been much more refined. However, recent models proposes “four step” theory which throw light into the role of lipid release and hepatic venular obstruction in the advancement of NAFLD into cirrhosis. This model is also helpful in understanding the morphogenesis of disease and conditions other than NAFLD. Another investigators, Tilg and Moschen proposed the “multiple parallel hits hypothesis”, which demonstrated that a number of very diverse parallel processes might play a role in the development of liver inflammation such as extrahepatic tissues such as the gut and/or the adipose tissue, and hepatic inflammation may initiate steatosis, cirrhosis and HCC in some cases. Its advantages include discovery of novel treatment strategies. 

Source: Loria P, Lonardo A, Anania F. Liver and diabetes. A vicious circle. Hepatol Res. 2013;43(1):51-64.

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