title: Type 2 Diabetes in Non-Alcoholic Fatty Liver Disease and Hepatitis C Virus Infection--Liver: The "Musketeer" in the Spotlight.
abstract: The pathogenesis of type 2 diabetes (T2D) involves chronic hyperinsulinemia due to systemic and hepatic insulin resistance (IR), which if uncorrected, will lead to progressive pancreatic beta cell failure in predisposed individuals. Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of fatty (simple steatosis and steatohepatitis) and non-fatty liver changes (NASH-cirrhosis with or without hepatocellular carcinoma (HCC)) that are commonly observed among individuals with multiple metabolic derangements, notably including visceral obesity, IR and T2D. Hepatitis C virus (HCV) infection is also often associated with both hepatic steatosis and features of a specific HCV-associated dysmetabolic syndrome. In recent years, the key role of the steatotic liver in the development of IR and T2D has been increasingly recognized. Thus, in this comprehensive review we summarize the rapidly expanding body of evidence that links T2D with NAFLD and HCV infection. For each of these two liver diseases with systemic manifestations, we discuss the epidemiological burden, the pathophysiologic mechanisms and the clinical implications. To date, substantial evidence suggests that NAFLD and HCV play a key role in T2D development and that the interaction of T2D with liver disease may result in a "vicious circle", eventually leading to an increased risk of all-cause mortality and liver-related and cardiovascular complications. Preliminary evidence also suggests that improvement of NAFLD is associated with a decreased incidence of T2D. Similarly, the prevention of T2D following HCV eradication in the era of direct-acting antiviral agents is a biologically plausible result. However, additional studies are required for further clarification of mechanisms involved.
authors.affiliation: Operating Unit Internal Medicine, Pavullo General Hospital, Azienda USL Modena, ViaSuore di San Giuseppe Benedetto Cottolengo, 5, Pavullo, 41026 Modena, Italy. stefanoballestri@tiscali.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Ballestri
authors.affiliation: Outpatient Liver Clinic and Operating Unit Internal Medicine, NOCSAE, Azienda USL Modena, Via P. Giardini, 1355, 41126 Modena, Italy. fabio.nascimbeni@libero.it.|Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via P. Giardini, 1355, 41126 Modena, Italy. fabio.nascimbeni@libero.it.
authors.forename: Fabio
authors.initials: F
authors.lastname: Nascimbeni
authors.affiliation: Outpatient Liver Clinic and Operating Unit Internal Medicine, NOCSAE, Azienda USL Modena, Via P. Giardini, 1355, 41126 Modena, Italy. danter1@alice.it.
authors.forename: Dante
authors.initials: D
authors.lastname: Romagnoli
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via P. Giardini, 1355, 41126 Modena, Italy. enrica.baldelli@unimore.it.
authors.forename: Enrica
authors.initials: E
authors.lastname: Baldelli
authors.affiliation: Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani, 1, 37126 Verona, Italy. giovanni.targher@univr.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Targher
authors.affiliation: Outpatient Liver Clinic and Operating Unit Internal Medicine, NOCSAE, Azienda USL Modena, Via P. Giardini, 1355, 41126 Modena, Italy. a.lonardo@libero.it.
authors.forename: Amedeo
authors.initials: A
authors.lastname: Lonardo
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000209:etiology; D006526:Hepatitis C / Q000453:epidemiology* / Q000209:etiology; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D065626:Non-alcoholic Fatty Liver Disease / Q000453:epidemiology* / Q000209:etiology
keywords: NASH; cirrhosis; clinical implications; direct acting antivirals; epidemiology; fibrosis; hepatocellular carcinoma; insulin resistance; pathophysiology