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, repeatab...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2021-03-01
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| Series: | BMJ Open Diabetes Research & Care |
| Online Access: | https://drc.bmj.com/content/9/1/e002083.full |
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| author | Jens Juul Holst Elin Manell Emmi Puuvuori Anna Svensson Irina Velikyan Gry Hulsart-Billström Patricia Hedenqvist Marianne Jensen Waern Olof Eriksson |
| author_facet | Jens Juul Holst Elin Manell Emmi Puuvuori Anna Svensson Irina Velikyan Gry Hulsart-Billström Patricia Hedenqvist Marianne Jensen Waern Olof Eriksson |
| author_sort | Jens Juul Holst |
| collection | DOAJ |
| description | 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 177Lu-exendin-4 in two groups of pigs, control or bottle-fed an oral glucose load. Positron emission tomography (PET) data from pigs injected with 68Ga-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 177Lu-exendin-4 was found in pancreas, and even higher uptake in areas of duodenum. Low uptake of 177Lu-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 68Ga-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. |
| format | Article |
| id | doaj-art-46fa0ed354f9436d98fc4f84ea38a91a |
| institution | DOAJ |
| issn | 2052-4897 |
| language | English |
| publishDate | 2021-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | BMJ Open Diabetes Research & Care |
| spelling | doaj-art-46fa0ed354f9436d98fc4f84ea38a91a2025-08-20T02:50:19ZengBMJ Publishing GroupBMJ Open Diabetes Research & Care2052-48972021-03-019110.1136/bmjdrc-2020-002083Exploring the GLP-1–GLP-1R axis in porcine pancreas and gastrointestinal tract in vivo by ex vivo autoradiographyJens Juul Holst0Elin Manell1Emmi Puuvuori2Anna Svensson3Irina Velikyan4Gry Hulsart-Billström5Patricia Hedenqvist6Marianne Jensen Waern7Olof Eriksson8NNF Centre for Basic Metabolic Research and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkDepartment of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, SwedenScience for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Uppsala, SwedenDepartment of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, SwedenScience for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Uppsala, SwedenScience for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Uppsala, SwedenDepartment of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, SwedenDepartment of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, SwedenScience for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Uppsala, SwedenIntroduction 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 177Lu-exendin-4 in two groups of pigs, control or bottle-fed an oral glucose load. Positron emission tomography (PET) data from pigs injected with 68Ga-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 177Lu-exendin-4 was found in pancreas, and even higher uptake in areas of duodenum. Low uptake of 177Lu-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 68Ga-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.https://drc.bmj.com/content/9/1/e002083.full |
| spellingShingle | Jens Juul Holst Elin Manell Emmi Puuvuori Anna Svensson Irina Velikyan Gry Hulsart-Billström Patricia Hedenqvist Marianne Jensen Waern Olof Eriksson Exploring the GLP-1–GLP-1R axis in porcine pancreas and gastrointestinal tract in vivo by ex vivo autoradiography BMJ Open Diabetes Research & Care |
| title | Exploring the GLP-1–GLP-1R axis in porcine pancreas and gastrointestinal tract in vivo by ex vivo autoradiography |
| title_full | Exploring the GLP-1–GLP-1R axis in porcine pancreas and gastrointestinal tract in vivo by ex vivo autoradiography |
| title_fullStr | Exploring the GLP-1–GLP-1R axis in porcine pancreas and gastrointestinal tract in vivo by ex vivo autoradiography |
| title_full_unstemmed | Exploring the GLP-1–GLP-1R axis in porcine pancreas and gastrointestinal tract in vivo by ex vivo autoradiography |
| title_short | Exploring the GLP-1–GLP-1R axis in porcine pancreas and gastrointestinal tract in vivo by ex vivo autoradiography |
| title_sort | exploring the glp 1 glp 1r axis in porcine pancreas and gastrointestinal tract in vivo by ex vivo autoradiography |
| url | https://drc.bmj.com/content/9/1/e002083.full |
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