PT  - JOURNAL ARTICLE
AU  - Charles-Henri Malbert
AU  - Alain Chauvin
AU  - Michael Horowitz
AU  - Karen L Jones
TI  - Pancreatic GLP-1r binding potential is reduced in insulin-resistant pigs
AID  - 10.1136/bmjdrc-2020-001540
DP  - 2020 Nov 01
TA  - BMJ Open Diabetes Research & Care
PG  - e001540
VI  - 8
IP  - 2
4099  - http://drc.bmj.com/content/8/2/e001540.short
4100  - http://drc.bmj.com/content/8/2/e001540.full
SO  - BMJ Open Diab Res Care2020 Nov 01; 8
AB  - 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.