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Pancreatic GLP-1r binding potential is reduced in insulin-resistant pigs

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 68 Ga-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 68 Ga-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 68 Ga-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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https://hal.inrae.fr/hal-03037771
Contributor : Emilie Bernard <>
Submitted on : Thursday, December 3, 2020 - 11:23:26 AM
Last modification on : Tuesday, May 11, 2021 - 3:11:04 PM

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Charles-Henri Malbert, Alain Chauvin, Michael Horowitz, Karen Jones. Pancreatic GLP-1r binding potential is reduced in insulin-resistant pigs. BMJ Open Diabetes Research & Care, BMJ Journals, 2020, 8 (2), pp.e001540. ⟨10.1136/bmjdrc-2020-001540⟩. ⟨hal-03037771⟩

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