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Research article - Peer-reviewed, 2021

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

Manell, Elin; Puuvuori, Emmi; Svensson, Anna; Velikyan, Irina; Hulsart-Billstrom, Gry; Hedenqvist, Patricia; Holst, Jens Juul; Waern, Marianne Jensen; Eriksson, Olof

Abstract

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.

Keywords

incretins; glucagon-like peptide 1; receptors; gastrointestinal hormone; glucose tolerance test

Published in

BMJ Open Diabetes Research and Care
2021, volume: 9, number: 1, article number: e002083
Publisher: BMJ PUBLISHING GROUP

Authors' information

Swedish University of Agricultural Sciences, Department of Clinical Sciences
Puuvuori, Emmi
Uppsala University
Swedish University of Agricultural Sciences, Department of Clinical Sciences
Velikyan, Irina
Uppsala University
Hulsart-Billstrom, Gry
Uppsala University
Swedish University of Agricultural Sciences, Department of Clinical Sciences
Holst, Jens Juul
University of Copenhagen
Swedish University of Agricultural Sciences, Department of Clinical Sciences
Eriksson, Olof
Uppsala University

UKÄ Subject classification

Endocrinology and Diabetes

Publication Identifiers

DOI: https://doi.org/10.1136/bmjdrc-2020-002083

URI (permanent link to this page)

https://res.slu.se/id/publ/118776