Identifying the role of metaplastic GLP-1R in pancreatitis

The global rise in obesity poses a significant risk factor for a number of health conditions including cardiovascular diseases, diabetes, cancers, neurological disorders, chronic respiratory diseases, and digestive disorders. Fortunately, pharmaceutical interventions, specifically incretin mimetics that serve as agonists for glucagon-like peptide-1 receptor (GLP-1RAs), have proven to be highly efficacious for the treatment of type 2 diabetes and obesity. Currently, about 12% of the adult population of the U.S. are consuming these medications. For many, however, long-term use is required to sustain weight loss and cardiovascular benefits. Given the large number of people being treated with GLP-1RAs for long periods of time, it is critical to identify any off-target or adverse effects resulting from treatment. In its acute form, pancreatitis (AP) is a leading cause of hospitalization in the U.S. and carries a 10-30% mortality rate. Chronic pancreatitis (CP) results from long-term injury to the pancreas and is characterized by tissue loss and malnutrition; CP is associated with severe co-morbidities such as diabetes and pancreatic cancer, one of the deadliest solid tumors. Recently, we combined genetically engineered mouse models, lineage tracing, single cell RNA-sequencing, and immunostaining and found that under conditions of chronic injury, pancreatic acinar cells undergo metaplasia (ADM) and form GLP-1R+ lesions containing diverse cell types. Current literature is conflicting as to whether GLP-1RAs cause AP or CP. The function of GLP-1R in ADM is unknown as well as the downstream signaling pathways activated by GLP-1RAs. Given that GLP-1R signaling induces PKA and MAPK signaling in other cell types, we hypothesize that GLP-1R signaling in ADM is protective. Disparate effects may occur in AP vs CP as ADM is only present in CP. We will test this hypothesis in the following specific Aims: AIM 1. Identify GLP-1R downstream signaling pathways and transcriptomic changes induced by GLP-1RAs in ADM. AIM 2. Determine the role of GLP-1R in ADM formation and CP progression. The data generated by completion of this proposal will be used to assemble a collaborative R01 grant targeted to the NIH NIDDK.