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The influence of diabetes in the pathogenesis and the clinical course of hepatocellular carcinoma: recent findings and new perspectives.

Up to 50% of patients with hepatocellular carcinoma (HCC) have the so-called "cryptogenic cirrhosis." Most of them are affected by at least one of the condition characterizing the metabolic syndrome, as obesity or diabetes. Recent observations found that type-2 diabetes mellitus (DM) confers a three-fold risk of HCC. Main molecular feature of the conditions of metabolic syndrome is insulin resistance, i.e. the reduced sensitivity to insulin action and, as consequence, increased secretion of this hormone. Insulin resistance and hyperinsulinemia influence hepatocarcinogenesis via several molecular pathways, such as phosphatase and tensin homolog (PTEN)/P13K/Akt and MAPK kinase (MAPKK). Diabetes also seems to influence negatively the prognosis and the clinical course of HCC patients, independently from the cause of the underlying cirrhosis. It's well known that insulin-sensitizing drugs may reduce the incidence of HCC. Metformin activates 5-adenosine monophosphate-activated protein kinase (AMPK), that has growth inhibition effects on human cancer cell lines via inhibition of its downstream target mammalian target of rapamycin (mTOR), and decreases the expression of Livin, a protein involved in both cell proliferation and survivalexpressed at high level in neoplastic cell. Also thiazolidinediones seem to prevent tumor formation in the liver via the inhibition of peroxisome proliferator-activated receptor gamma-independent regulation of nucleophosmin. More debated is the role of sulfonylureas in decreasing HCC incidence in diabetic patients. Further investigations are needed to define reliable indications to therapy and surveillance in patients with diabetes or insulin resistance.