Pancreatic GLP-1r binding potential is reduced in insulin-resistant pigs.
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2020
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Malbert, C.-H.
Chauvin, A.
Horowitz, M.
Jones, K.L.
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BMJ Open Diabetes Research & Care, 2020; 8(2):e001540-1-e001540-9
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Charles-Henri Malbert, Alain Chauvin, Michael Horowitz, Karen L. Jones
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Abstract
Introduction: The insulinotropic capacity of exogenous glucagon like peptide-1 (GLP-1) is reduced in type 2 diabetes and the insulin-resistant obese. We have tested the hypothesis that this response is the consequence of a reduced pancreatic GLP-1 receptor (GLP-1r) density in insulin-resistant obese animals. Research design and methods: GLP-1r density was measured in lean and insulin-resistant adult miniature pigs after the administration of a ⁶⁸Ga-labeled GLP-1r agonist. The effect of hyperinsulinemia on GLP-1r was assessed using sequential positron emission tomography (PET), both in the fasted state and during a clamp. The impact of tissue perfusion, which could account for changes in GLP-1r agonist uptake, was also investigated using ⁶⁸Ga-DOTA imaging. Results: GLP-1r binding potential in the obese pancreas was reduced by 75% compared with lean animals. Similar reductions were evident for fat tissue, but not for the duodenum. In the lean group, induced hyperinsulinemia reduced pancreatic GLP-1r density to a level comparable with that of the obese group. The reduction in blood to tissue transfer of the GLP-1r ligand paralleled that of tissue perfusion estimated using ⁶⁸Ga-DOTA. Conclusions: These observations establish that a reduction in abdominal tissue perfusion and a lower GLP-1r density account for the diminished insulinotropic effect of GLP-1 agonists in type 2 diabetes.
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© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.