title: Insulin resistance: mechanism and implications for carcinogenesis and hepatocellular carcinoma in NASH.
abstract: BACKGROUND
  The effects of insulin resistance in human diseases are of paramount importance. Since the original proposal by the WHO indicating insulin resistance as the common substrate of the metabolic syndrome, large data are now available on its significance in cardiovascular diseases, nonalcoholic fatty liver disease and cancer risk.
  
  
  METHODS
  We reviewed the evidence linking hyperinsulinemia to insulin resistance and ultimately to increased cancer risk. Insulin resistance, by reducing substrate flux along the PI3-K pathway, is followed by compensatory hyperinsulinemia, considered a potential stimulus for cancerogenesis along the MAP-K pathway. Adaptive mechanisms of fat storage, promoted by insulin resistance, chronically maintained in an obesiogenic environment, may lead to oxidative stress and inflammation and modify the immune responses, further increasing the carcinogenic potential. The increased cancer risk associated with obesity, type 2 diabetes and nonalcoholic fatty liver may thus be fueled by hyperinsulinemia. Insulin secretagogs and insulin treatment, by raising circulating insulin levels, further increase cancer risk, whereas insulin sensitizers are associated with decreased cancer risk (all sites) and specifically decrease hepatocellular carcinoma. Likewise, drugs related to the incretin system, which are weight neutral or even reduce whole-body and hepatic fat, improve insulin sensitivity and potentially reduce the cancer risk.
  
  
  CONCLUSIONS
  New diabetes treatments might thus help decrease the future burden of diabetes-associated cancer and particularly of hepatocellular carcinoma.
authors.affiliation: Unit of Metabolic Diseases and Clinical Dietetics, "Alma Mater Studiorum" University, Bologna, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Montesi
authors.affiliation: Unit of Metabolic Diseases and Clinical Dietetics, "Alma Mater Studiorum" University, Bologna, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Mazzotti
authors.affiliation: Unit of Metabolic Diseases and Clinical Dietetics, "Alma Mater Studiorum" University, Bologna, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Moscatiello
authors.affiliation: Unit of Metabolic Diseases and Clinical Dietetics, "Alma Mater Studiorum" University, Bologna, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Forlani
authors.affiliation: Unit of Metabolic Diseases and Clinical Dietetics, "Alma Mater Studiorum" University, Bologna, Italy. giulio.marchesini@unibo.it.|Unit of Clinical Dietetics, "Alma Mater Studiorum" University, Policlinico S. Orsola, Via Massarenti, 9, 40138, Bologna, Italy. giulio.marchesini@unibo.it.
authors.forename: Giulio
authors.initials: G
authors.lastname: Marchesini
keywords: Drug treatment; Glucagon-like peptide 1; Insulin; Insulin secretagogs; Insulin sensitizers