Pancreatic GLP-1r binding potential is reduced in insulin-resistant pigs. Issue 2 (1st November 2020)

• Record Type: Journal Article
• Authors: Malbert, Charles-Henri; Chauvin, Alain; Horowitz, Michael; Jones, Karen L
• Is Part Of: BMJ open diabetes research and care. Volume 8:Issue 2(2020)
• Publication Date: 2020-11-01
• Subjects: glucagon-like peptide 1 -- positron-emission tomography -- insulin resistance -- animal experimentation; Diabetes -- Periodicals; 616.462005
• DOI: 10.1136/bmjdrc-2020-001540
• Languages: English
• ISSNs: 2052-4897

Abstract

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.