Rather the available information from our and other studies suggest that the increase in circulating fetuin-A and the resulting decrease in insulin sensitivity may be a result of inflamed NAFLD. We then focused on the relationship of both circulating proteins with anthropometrics and metabolic traits in precisely phenotype subjects of TULIP. We confirmed the strong correlations of adiponecinemia with measures of body fat mass and distribution in these subjects as well as the absence of such relationships for fetuin-A levels. Based on the known properties of adiponectin and fetuin-A to regulate insulin sensitivity, we confirmed that the circulating levels of these proteins were independently of each other associated with insulin sensitivity, estimated from the OGTT or measured by a euglycemic, hyperinsulinemic clamp. In agreement with the findings from the EPIC-Potsdam study and the NHS, the relationship of circulating adiponectin, but not of fetuin-A, was considerably attenuated after accounting for measurements of body fat content and distribution. Consequently we asked the question whether circulating fetuin-A may be a better predictor of insulin sensitivity than circulating adiponectin in subjects who are non-obese and could confirm this hypothesis in our study. Having found strong independent associations of circulating adiponectin and fetuin-A, the two proteins that regulate insulin sensitivity, on the diabetes risk, we then asked whether they may differentially impact on insulin secretion, and thereby have distinct effects in the pathogenesis of type 2 diabetes. For adiponectin we have previously shown that this protein does not influence glucoseinduced insulin secretion in humans. In the present study we could show that fetuin-A levels are not associated with insulin secretion in our subjects. Based on the knowledge that subjects with IGT have an impaired beta cell function, we then tested the hypothesis that fetuin-A is particularly relevant specifically in this population that is at very high risk for the disease. Indeed, when we PB 203580 p38 MAPK inhibitor separated the individuals in those with NGT and IGT, a strong negative relationship of fetuin-A with insulin secretion was found in subjects with IGT. What is the relevance of our data for clinicians and researchers? Because the relative risk of incident diabetes was much higher for the combination of a high fetuin-A- and a low adiponectin level, than for the single circulating level of each protein, it may be mportant for clinicians to measure both proteins when it comes to the prediction of the risk of future type 2 diabetes. Whether fetuinA and adiponectin improve prediction of diabetes risk beyond waist circumference and other classical risk factors remains, however, uncertain. Furthermore, fetuin-A may become an important determinant of insulin resistant states, particularly in non-obese subjects where adiponectin and hs-CRP levels lost their strong predictive power in our study.