Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones. Lack of GLP-1 receptor signaling has been reported to be compensated for by increased GIP secretion and action. Conversely, GLP-1 sensitivity has been reported to be increased in GIP receptor knockout (Gipr-/-) mice. This suggests a compensatory adaptation to the loss of incretin signaling via increased action/secretion of the remaining incretin hormone. We assessed glucose-stimulated GIP and GLP-1 secretion during oral glucose tolerance tests (OGTTs) and in isolated perfused intestines of GLP-1 receptor knockout (Glp-1r-/-) mice and their wild-type littermates (Glp-1r+/+) and in Gipr-/- mice and their wild-type littermates (Gipr+/+). Sensitivity to GIP and GLP-1 was assessed in isolated perfused pancreases of Glp-1r-/- and Glp-1r+/+ mice and Gipr-/- and Gipr+/+ mice, respectively. We found similar GIP responses in Glp-1r-/- and Glp-1r+/+ mice and similar GLP-1 responses in Gipr-/- and Gipr+/+ mice during the OGTTs and in the isolated perfused intestines. Insulin responses to GIP and GLP-1 were similar in Glp-1r-/- and Glp-1r+/+ mice and in Gipr-/- and Gipr+/+ mice, respectively. Our results do not support the existence of a compensatory adaptation to the loss of single incretin signaling via increased glucose-stimulated secretion of, or sensitivity to, the remaining incretin hormone.NEW & NOTEWORTHY We show that mice lacking the GLP-1 receptor do not compensate by increased glucose-stimulated GIP secretion or sensitivity, nor do mice lacking the GIP receptor compensate by increased glucose-stimulated GLP-1 secretion or sensitivity. The notion of a compensatory adaptation to the loss of single incretin signaling via increased action/secretion of the remaining incretin hormone was thus not supported using single incretin receptor knockout mice.
Keywords: glucose tolerance test; gut hormones; incretin hormones; intestine; pancreas.