In the present study we now asked two questions: first, to what extent are circulating levels of these proteins related to incident type 2 diabetes independently of each other? Second, because the circulating levels of these two proteins strongly reflect the dysregulation of their source tissues, adipose tissue and liver, can they be used to estimate the contribution of expanded and inflamed adipose tissue and NAFLD to the pathogenesis of insulin resistance and impaired beta cell function? For this we investigated associations of circulating adiponectin and fetuin-A with incident type 2 diabetes by applying a head to head comparison of these proteins in two large cohort studies, the European Prospective Investigation into Cancer and Nutrition -Potsdam study and the Nurses’ Health Study. In addition, we studied the independent relationships of the circulating levels of these proteins with precisely measured body fat mass and distribution, liver fat content, insulin sensitivity and insulin secretion in subjects of the Tu¨bingen Lifestyle Intervention Program. During the last decade much effort has been made to identify important pathways involved in the natural history of type 2 diabetes. Thereby, several candidates were described, predominantly based on animal and on in-vitro studies. However, often it was not possible to prove these pathways to be of high relevance for human metabolism. In human studies, on the other hand, several blood, genetic or phenotypic markers were found to predict incident type 2 diabetes. Nevertheless, no precise mechanisms of action for several of these parameters are known and/or their predictive effect on the development of type 2 diabetes was either small or absent, which so far limits their potential in the prevention and the treatment of the disease. Because these limitations largely do not apply to the adipokine adiponectin and the hepatokine fetuin-A, we here investigated to what extent circulating adiponectin and fetuin-A determine incident type 2 diabetes, independently of each other. Towards this aim, we first chose an epidemiological approach and investigated the associations of circulating adiponectin and fetuin-A with incident type 2 diabetes by applying a head to head comparison of these proteins in two large cohort studies, the EPIC-Potsdam study and the NHS. In both studies we found that circulating adiponectin and fetuin-A were associated with risk of incident diabetes, independently of several confounders, and of each other. The consistency of the association suggests that it might be generalizable to healthy populations, at least to those with Caucasian origin. Because the strength of association of adiponectinemia, but not of circulating fetuin-A, was considerably attenuated after accounting for estimates of PI-103 citations overall and visceral obesity, our data support that the adiponectin levels confer at least in part the effect of obesity on the type 2 diabetes risk.