• The link between diabetes mellitus type 2 and hepatocellular carcinoma; metformin treatment review article
  • Rabeeh Mehdigholian,1 Saman Hakimian,2,*
    1. Bachelor of Microbiology Rasht Azad University
    2. M.sc student of Microbiology Islamic Azad University Central Tehran Branch, Iran, Tehran


  • Introduction: The term “HepatoCellular carcinoma (HCC)” has come to be used to refer to primary liver cancer that appears from a mutation of a cellular gene and causes the cells to reproduce in a disorderly and unusual way. Also, it is recognized as being the sixth most common cancer worldwide responsible for the diagnosis of more than half a million people around the globe every year. For many years Type 2 diabetes mellitus (T2MD) has been considered an independent risk factor for HCC and interestingly the correlation is related to non-alcoholic fatty liver disease (NAFLD); a major cause of liver-related mortality. An increasing number of studies have found that obesity and insulin resistance are the strongest indicators that exist between T2DM and NAFLD. This theorem states that adipose tissue in obese people goes through changes that cause the release of a hormone called adipokine. In the condition of obesity, adipose tissue produces a higher amount of adipokine which causes insulin resistance (IR) in most cases. Insulin resistance is a common trait in NAFLD patients and it is evaluated as the major contributor to the development and advancement of the disease.
  • Methods: Insulin resistance is a common trait in NAFLD patients and it is evaluated as the major contributor to the development and advancement of the disease. Insulin resistance and compensatory hyperinsulinemia cause elevated manufacturing of insulin-like growth factor1, which in addition promotes hepatic cellular proliferation and inhibits cellular apoptosis in the liver. Further analysis shows that IR is affected in the progression of hepatic steatosis and hepatic fibrosis by the existence of increased circulating levels of free fatty acids which stimulate NAFLD. As mentioned previously unnatural glucose and lipid metabolism, hyperinsulinemia, and insulin resistance cause intrahepatic fat assemblage which boosts the development of HCC.
  • Results: More recent evidence reveals that the metformin may have direct and indirect mechanisms. The direct mechanism developed by metformin is the reduction of plasma insulin levels. On the other hand, the inhibition of carcinogenesis, the induction of cellular apoptosis, and the stimulation of the immune system are posed as indirect mechanisms of metformin.
  • Conclusion: Many attempts have been made to improve insulin sensitivity and reduce its resistance as well as hyperinsulinemia. There is a considerable amount of literature on the association between the use of metformin and a lower risk of HCC while the use of insulin has been related to a higher risk of HCC. Metformin is identified as a drug that functions as an endothelial protector that hampers tumor growth, and metastasis via a signaling network. Compared with exogenous insulin which increases plasma insulin levels and promotes body weight gain, metformin reduces body weight and hyperinsulinemia, improves hepatic insulin resistance, decreases steatosis, and improves liver enzymes. Metformin treatment has been independently associated with decreasing the proceeding of HCC and liver-related deaths.
  • Keywords: Hepatocellular carcinoma, Diabete mellitus type 2,Insulin, NAFLD, Metformin