Molecular mechanisms that regulate insulin resistance and its progression to type2 diabetes (T2D) are not understood and might reveal a therapeutic opportunity to reduce the burden of T2D. We recently identified causative loss-of-function mutations in the CELA2A gene (Esteghamat & Mani, Nat. Genet. 2019), which encodes the pancreatic elastase Chymotrypsin-like ELAstase 2A in kindreds with extreme phenotypes of metabolic syndrome, type 2 diabetes, and early-onset atherosclerosis. Interestingly, the genome-wide association studies have also shown a strong association between common variants in the CELA2A gene and blood pressure, LDL cholesterol and BMI, underscoring its role in the disease of the general population. Although only known for its function as a pancreatic exocrine enzyme, we found it to be a circulating protein that is expressed in the extrapancreatic tissues, including gut. Its plasma levels rise after each meal in parallel to plasma insulin levels in healthy humans. Our characterization of CELA2A functions revealed its ability to trigger insulin secretion and sensitivity. In contrast, the catalytically inactive mutant CELA2A proteins found in the cohort increased platelet aggregation and reduced insulin sensitivity. Mechanistically, CELA2A was found to proteolytically cleave GPCRs such as PAR2 and induce PAR2-dependent activation of AMPK, while mutant CELA2As trigger different PAR2-dependent pathways, resulting in increased ERK and reduced AMPK activation. Thus, CELA2A appears to be an endogenous ligand of PAR2, a GPCR that has been implicated in the regulation of glucose homeostasis. These functions underscore CELA2A’s role as a novel risk factor and an attractive therapeutic target for the treatment of T2D. We will investigate the physiological functions of CELA2A and explore its molecular mechanisms of action in glucose homeostasis in global, acinar cell- and gut-specific Cela2a knockout mice, with a focus PAR2-dependent pathways. Cela2a KO mice are ideal for this goal as they show impaired insulin sensitivity and increased hepatic and plasma triglycerides that match the phenotypes of humans.