Exploring the GLP-1-GLP-1R axis in porcine pancreas and gastrointestinal tract in vivo by ex vivo autoradiography

Introduction Glucagon-like peptide-1 (GLP-1) increases insulin secretion from pancreatic beta-cells and GLP-1 receptor (GLP-1R) agonists are widely used as treatment for type 2 diabetes mellitus. Studying occupancy of the GLP-1R in various tissues is challenging due to lack of quantitative, repeatable assessments of GLP-1R density. The present study aimed to describe the quantitative distribution of GLP-1Rs and occupancy by endogenous GLP-1 during oral glucose tolerance test (OGTT) in pigs, a species that is used in biomedical research to model humans. Research design and methods GLP-1R distribution and occupancy were measured in pancreas and gastrointestinal tract by ex vivo autoradiography using the GLP-1R-specific radioligand Lu-177-exendin-4 in two groups of pigs, control or bottle-fed an oral glucose load. Positron emission tomography (PET) data from pigs injected with Ga-68-exendin-4 in a previous study were used to retrieve data on biodistribution of GLP-1R in the gastrointestinal tract. Results High homogenous uptake of Lu-177-exendin-4 was found in pancreas, and even higher uptake in areas of duodenum. Low uptake of Lu-177-exendin-4 was found in stomach, jejunum, ileum and colon. During OGTT, there was no increase in plasma GLP-1 concentrations and occupancy of GLP-1Rs was low. The ex vivo autoradiography results were highly consistent with to the biodistribution of Ga-68-exendin-4 in pigs scanned by PET. Conclusion We identified areas with similarities as well as important differences regarding GLP-1R distribution and occupancy in pigs compared with humans. First, there was strong ligand binding in the exocrine pancreas in islets. Second, GLP-1 secretion during OGTT is minimal and GLP-1 might not be an important incretin in pigs under physiological conditions. These findings offer new insights on the relevance of porcine diabetes models.

Automated summary

The study examined GLP-1 receptor distribution and occupancy in pigs, finding high uptake of Lu-177-exendin-4 in the pancreas and duodenum, with lower uptake in other gastrointestinal areas. During OGTT, there was no increase in plasma GLP-1 concentrations and low GLP-1R occupancy. The findings suggest differences in GLP-1R distribution and response to OGTT in pigs compared to humans, providing new insights for porcine diabetes models.