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Published on: May 2, 2019
GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated
Charles Pyke1, R Scott Heller, Rikke K Kirk
1Department of Histology and Imaging (C.P., R.S.H., R.K.K.), Department of Incretin Biology (C.Ø.), Department of Diabetes Structural Biology (S.R.-R.), Department of Antibody Technology (P.K.), Department of Pharmaceutical Medicine Programme (A.H.), and Department of Diabetes and Pharmacology Management (L.B.K.), Novo Nordisk, 2880 Bagsværd, Denmark; and Department of Surgical Gastroenterology (L.B., D.C.), Rigshospitalet, 2100 Copenhagen Ø, Denmark.
Abstract:
Glucagon-like peptide 1 (GLP-1) analogs are increasingly being used in the treatment of type 2 diabetes. It is clear that these drugs lower blood glucose through an increase in insulin secretion and a lowering of glucagon secretion; in addition, they lower body weight and systolic blood pressure and increase heart rate. Using a new monoclonal antibody for immunohistochemistry, we detected GLP-1 receptor (GLP-1R) in important target organs in humans and monkeys. In the pancreas, GLP-1R was predominantly localized in β-cells with a markedly weaker expression in acinar cells. Pancreatic ductal epithelial cells did not express GLP-1R. In the kidney and lung, GLP-1R was exclusively expressed in smooth muscle cells in the walls of arteries and arterioles. In the heart, GLP-1R was localized in myocytes of the sinoatrial node. In the gastrointestinal tract, the highest GLP-1R expression was seen in the Brunner's gland in the duodenum, with lower level expression in parietal cells and smooth muscle cells in the muscularis externa in the stomach and in myenteric plexus neurons throughout the gut. No GLP-1R was seen in primate liver and thyroid. GLP-1R expression seen with immunohistochemistry was confirmed by functional expression using in situ ligand binding with (125)I-GLP-1. In conclusion, these results give important new insight into the molecular mode of action of GLP-1 analogs by identifying the exact cellular localization of GLP-1R.
