ReviewRisk of type 2 diabetes in patients with non-alcoholic fatty liver disease: Causal association or epiphenomenon?
Introduction
Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver pathology including simple steatosis, non-alcoholic steatohepatitis (NASH) with varying amounts of fibrosis and cirrhosis [1]. NAFLD has emerged as a public health problem of epidemic proportions in many parts of the world (affecting up to 30% of the adult population in the United States and Europe) [1], [2]. The prevalence of NAFLD is much higher in patients with type 2 diabetes (ranging from approximately 50 to 75%). Notably, patients with type 2 diabetes and NAFLD are also more likely to develop the more severe forms of NAFLD, such as NASH, advanced fibrosis, cirrhosis, and in some cases hepatocellular carcinoma [1], [2].
Over the past decade, it has become increasingly clear that NAFLD is not only associated with an increased risk of liver-related morbidity or mortality, but also it is a multisystem disease that affects a variety of extra-hepatic organ systems, and interacts with the regulation of multiple metabolic pathways [3]. Strong evidence indicates that cardiovascular disease is the leading cause of mortality in patients with NAFLD [3], [4]. As detailed below, there is now also convincing evidence suggesting that NAFLD may often precede the development of type 2 diabetes. This supports the assertion that the conventional paradigm of NAFLD representing the simple āhepatic manifestationā of the metabolic syndrome is outdated, and that NAFLD might be regarded as an early predictor and determinant for the development of diabetes and other clinical traits of the metabolic syndrome [5]. This finding may have potentially relevant clinical implications for the diagnosis, prevention and treatment of type 2 diabetes.
Specifically, in this narrative review we discuss the rapidly expanding body of clinical evidence that supports a strong association between NAFLD and the risk of new-onset type 2 diabetes, and the putative biological mechanisms underlying this association. We also briefly discuss some of the treatment options for NAFLD that may influence the risk of diabetes.
To this end, although this is not a formal systematic review, we extensively searched PubMed database to identify relevant articles published up to January 2016, using the keywords ānon-alcoholic fatty liver diseaseā or āfatty liverā combined with āincident type 2 diabetesā or ādiabetes riskā.
Section snippets
Epidemiological evidence linking NAFLD to the risk of new-onset type 2 diabetes
In this review, we have not discussed the large number of prospective, population-based studies that used serum levels of liver enzymes (or other surrogate markers of NAFLD such as the fatty liver index) to diagnose NAFLD. These studies have consistently shown that mildly elevated serum liver enzymes (mainly serum gamma-glutamyltransferase) are independent, long-term predictors of new-onset type 2 diabetes in various ethnic populations (Asian, American and European people) [6], [7], [8].
Data
Putative biological mechanisms by which NAFLD contributes to diabetes development
When imbalance occurs between energy intake and energy expenditure, or when there is an intrinsic problem with storing excess energy as tri-acylglycerol in adipose tissue depots, lipid accumulates in other organs throughout the body. If lipid accumulates in tissues or organs not designed to accumulate fat, e.g., liver or omentum, the term āectopic fat accumulationā infers that lipid accumulation has occurred in a non physiological site with the potential for increasing risk of certain common
Treatment options for NAFLD that may influence risk of type 2 diabetes
The past decade has been characterized by an intensive search of effective treatments for NAFLD, fostered by the evidence of a significant burden of disease for all national healthcare systems. Behavioural changes, including dietary restriction and increased physical activity, and drug therapy are the pillars of NAFLD treatment. The assessment of their effects on the risk of disease progression has been limited by several factors:
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the lack of valid surrogate markers, making liver biopsy
Conclusions
In this updated review of the published studies, we provide further support for the strong association between NAFLD and increased risk of new-onset type 2 diabetes, though causality remains to be proven in well-controlled prospective and intervention studies. Future studies are also needed to assess the potential added value of using the presence of NAFLD to predict the risk of incident type 2 diabetes beyond that provided by common risk factors for diabetes. Finally, in the presence of NAFLD,
Author contributions
GT conceived and designed the study. GT, GM and CDB researched data and wrote the manuscript.
Disclosure of interest
The authors declare that they have no competing interest.
Acknowledgments
GT is supported in part by grants from the University School of Medicine of Verona, Verona, Italy. CDB is supported in part by the Southampton National Institute for Health Research Biomedical Research Centre.
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