SAT037 Glucagon-like Peptide-1 Receptor Knockout Mice Do Not Compensate For The Lack Of Incretin Action By Increasing Glucose-dependent Insulinotropic Polypeptide Secretion

Abstract

Abstract Disclosure: K.D. Galsgaard: None. H. Kissow: None. M.M. Smits: None. J.J. Juul: None. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), secreted from the intestinal L-cells and K-cells, respectively, both enhance glucose-stimulated insulin secretion. This enhancement is referred to as the incretin effect. In the pancreatic islets of GIP receptor knockout mice, GLP-1 sensitivity may be increased. Conversely, deletion of the GLP-1 receptor has been shown to be compensated for by increased GIP secretion and action. This suggests a compensatory adaptation to loss of incretin signaling, via increased action/secretion of the remaining incretin hormone. To investigate this further, we subjected GLP-1 receptor knockout (Glp-1r-/-) mice and their wild-type littermates (Glp-1r+/+ mice) to an oral glucose tolerance test (2 g/kg body weight of glucose via oral gavage; OGTT) with subsequent measurement of plasma GIP concentrations. In separate experiments we measured pancreatic insulin, glucagon, somatostatin, and total GLP-1 concentrations in Glp-1r-/- and Glp-1r+/+ mice, and total GLP-1 and GIP concentrations in the duodenum and distal ileum were also measured. During the OGTT, we found a similar GIP secretion (total area under the curve (tAUC0-30min)) in Glp-1r-/- and Glp-1r+/+ mice (15,432±2,148 vs. 13,683±1,316 pg/mL×min, P=0.5, n≥7). Blood glucose concentrations (tAUC0-30min) were increased in Glp-1r-/- mice during the OGTT (523.9±27.4 vs. 429.1±21.2 mmol/L×min, P=0.02, n≥6). Extractable pancreatic hormone concentrations were similar in Glp-1r+/+ and Glp-1r-/- mice; insulin (284.3±11.4 vs. 303.6±32.4 pmol/g tissue, P=0.6, n≥8); glucagon (203.6±24.3 vs. 270.8±36.9 pmol/g tissue, P=0.2, n≥8); somatostatin (299.9±94.97 vs. 321.4±78.79 pmol/g tissue, P=0.9, n≥9); and total GLP-1 (30.9±8.5 vs. 20.2±4.0 pmol/g tissue, P=0.2, n≤8). In the duodenum, extractable GIP (175.0±29.6 vs. 177.3±10.8 pmol/g tissue, P>0.9, n≥8) and GLP-1 (57.5±35.6 vs. 28.9±3.2 pmol/g tissue, P=0.4, n≥9). In the distal ileum, extractable GIP (2.2±0.5 vs. 2.1±0.4 pmol/g tissue, P=0.8, n≥9) and GLP-1 (266.6±57.1 vs. 236.0±43.1, P=0.7, n≥9) concentrations were also similar in Glp-1r+/+ and Glp-1r-/- mice. In conclusion, our results do not support the notion that Glp-1r-/- mice compensate for the lack of GLP-1 receptor signaling by increasing glucose stimulated GIP secretion or by increasing the intestinal GIP content. Presentation: Saturday, June 17, 2023