1–3 T2D may cause metabolic fatty liver disease (so-called NAFLD) and, like diabetes,NAFLD is now considered a manifestation of metabolic syndrome (MetS).1 Insulin resistance, the primary pathophysiological disorder leading to T2D and MetS is so often found in NAFLD that this form of liver disease may be regarded as similar to or a complication of ‘pre-diabetes’, thereby indicating the high future risk for onset of diabetes as well as cardiovascular disease.1,3 In several studies, NAFLD diagnosed by

ultrasonography together with unexplained elevation of liver enzymes predicted diabetes risk, independent of obesity signaling pathway and other components of MetS.4–11 Thus, the concept has arisen that NAFLD may signify more than just the presence of a liver disease; it may also be an early mediator of T2D and MetS. RAD001 solubility dmso Although histological examination remains the gold standard for diagnosis of NAFLD, pathological definition is often not

possible in community-based epidemiological studies. Alternatively, in subjects without substantial alcohol consumption or other causes of liver disease, persistent elevation of alanine aminotransferase (ALT) and γ-glutamyltransferase (GGT) is regarded as a surrogate marker of NAFLD.1,12 In 1998, a longitudinal study examined the association of elevated liver enzymes with incident diabetes.4 Since then, high values of ALT and GGT, even within the normal range, have been reported to predict incident diabetes and MetS; some studies demonstrated stronger association between GGT selleck compound and diabetes than ALT, while other studies reported the

opposite.4–6 In a meta-analysis of results from prospective population-based studies fully adjusted for other diabetes risk factors (albeit variably adjusted), 1 U/L increase of loge ALT was associated with 85% increase in diabetes risk, and 1 U/L increase of loge GGT with 92% increase.4 This indicates that elevations in liver enzymes attributable to NAFLD increase incident diabetes rate independently of commonly measured diabetes risk factors. Recently, Adams et al. found subjects with elevated liver enzymes attributed to NAFLD were at increased risk of developing metabolic complications at 11 years follow up; they were threefold more likely to develop diabetes and 50% more likely to develop MetS compared with the age-matched population.5 Multivariate modeling showed that the increased risk of metabolic complications could be explained by associated visceral obesity and subsequent insulin resistance, which almost invariably accompanies patients with NAFLD. In contrast to this high risk of diabetes, only a small minority of subjects with NAFLD develop cirrhosis over 10 years, with an even smaller proportion dying from liver disease during this period of follow up.