The application (two years) is focused on our new findings with a clear clinical translational connection. Within the period, we expect to initiate a clinical study with anti-Gremlin treatment of obese Type 2 diabetics (T2D) in collaboration with the pharmaceutical industry. All development work has been conducted at our laboratory, including with grants from the Foundation in 2014, and we have published a first work (Diabetes 2015) - however, outside the planned IPR application. Gremlin inhibits the effects of insulin in several tissues, is highly expressed and released by adipose tissue leading to high blood levels in obesity/T2D. It is also highly expressed in human macrophages and involved in M1/M2 phenotype regulation and inflammation. We will develop new animal models and identify sequences/signaling/receptors that inhibit insulin effects and drive inflammation. We have identified blood mannose as a novel and powerful marker for the risk of developing T2D and cardiovascular disease (Cell Metab 2016). It is unknown whether mannose is just a novel biomarker or of pathogenetic importance but our studies suggest the latter. We are planning to clarify this and initiate a clinical study with mannose administration. We have found that the microvascular endothelial cells regulate the ability of adipose tissue to normally take up and store lipids via the release of endogenous PPAR-activating lipids and that GPR 40 and ATGL play a crucial role in this. We will identify the lipids, synthesize them and clarify their clinical relevance.