Nonalcoholic fatty liver disease: cause or consequence of type 2 diabetes?
Growing epidemiological evidence suggests that nonalcoholic fatty liver disease (NAFLD) is an early predictor of and determinant for the development of type 2 diabetes and other features of the metabolic syndrome. This finding may have important clinical implications for the diagnosis, prevention and treatment of type 2 diabetes and its chronic complications. However, given the complex and bi-directional relationships between NAFLD, insulin resistance and chronic hyperglycaemia, it is extremely difficult to distinguish whether NAFLD is a cause or a consequence of insulin resistance and type 2 diabetes. Indeed, at the molecular level, hepatic lipogenesis and hepatic glucose production depend on differentially regulated branches of the insulin signalling pathway. Furthermore, genetic studies suggest that excess hepatic fat is associated with progressive liver disease, but does not always increase the risk of incident type 2 diabetes. Here, we will briefly review the epidemiological, pathophysiological and molecular evidence linking NAFLD to the development of type 2 diabetes. We will also discuss some recent genetic and therapeutic advances that seem to challenge a causal role of NAFLD in the pathogenesis type 2 diabetes, and propose a working hypothesis to explain this apparent conundrum. In conclusion, progressive liver disease and type 2 diabetes are divergent though inter-related consequences of insulin resistance and the metabolic syndrome.
Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy. luca.valenti@unimi.it.|Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy. luca.valenti@unimi.it.
Luca
0000-0001-8909-0345
L
Valenti
Division of Gastroenterology, Department of Medical Sciences, A.O.U. Città della Salute e della Scienza, Università di Torino, Torino, Italy.
Elisabetta
E
Bugianesi
Division of Endocrinology, Columbia University, New York, NY, USA.
Utpal
U
Pajvani
Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy.
Giovanni
G
Targher
D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D008099:Liver / Q000473:pathology; D024821:Metabolic Syndrome / Q000453:epidemiology; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications* / Q000453:epidemiology* / Q000235:genetics; D012307:Risk Factors; D015398:Signal Transduction
D007328:Insulin
genetics; insulin resistance; nonalcoholic fatty liver disease; pathophysiology; type 2 diabetes