The Influence of Diabetes in the Pathogenesis and the Clinical Course of Hepatocellular Carcinoma: Recent Findings and New Perspectives

Abstract

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.

Effect of Intramuscular Adipose Tissue Content on Prognosis in Patients Undergoing Hepatocellular Carcinoma Resection

“…39,40 Management of insulin resistance is thus a critical issue for patients with chronic liver disease, both to protect liver function and to prevent hepatocarcinogenesis. Alterations in glucose metabolism also affect fat metabolism, which may result in excess production of lipid peroxide and reactive oxygen species, 41,42 which in turn damages hepatocytes, 15 leading to possible development of HCC.…”

p110α Hot Spot Mutations E545K and H1047R Exert Metabolic Reprogramming Independently of p110α Kinase Activity

“…Furthermore, p110␣ has been shown to be crucial for the metabolic actions of insulin, whereas p110␤ does not appear to be a major contributor to these effects (6)(7)(8). In addition, p110␣ mutations frequently occur in cancers that are closely associated with metabolic dysfunction (45)(46)(47)(48). Based on our data, from the perspective of a tumor cell, the gain-of-function effects of the E545K and H1047R mutations of p110␣ would be largely beneficial for maintaining the ability to grow and divide, as a tumor cell needs a high lipid synthesis rate to form new cell membranes during rapid mitosis.…”

Nonalcoholic steatohepatitis-related hepatocellular carcinoma: is there a role for the androgen receptor pathway?

“…However, the incidence in developed countries has also been increasing owing to the emergence of nonalcoholic steatohepatitis (NASH) as an important risk factor 3,4. In fact, recently, a large retrospective study demonstrated that the proportion of non-virus–related HCC increased from 10% in 1991 to 24.1% in 2010, with most cases related to nonalcoholic fatty liver disease (NAFLD) and diabetes 5–7. In a Japanese study, the 5-year HCC development rates in cirrhosis patients were 11.3% in NAFLD cirrhosis, 12.5% in alcoholic cirrhosis, and 30.5% in hepatitis C virus cirrhosis, showing similar rates of HCC development in both alcoholic and NAFLD-related cirrhosis 8.…”