Single incretin receptor knockout mice do not compensate by increasing glucose-stimulated secretion of the remaining incretin hormone

🎖️ Top 10% JournalFeb 11, 2025American journal of physiology. Endocrinology and metabolism

Mice missing one incretin receptor do not increase secretion of the other hormone after glucose

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Abstract

Mice lacking the GLP-1 receptor do not show increased glucose-stimulated GIP secretion or sensitivity.

GLP-1 and GIP are incretin hormones that influence insulin secretion.
In GLP-1 receptor knockout mice, GIP responses during oral glucose tolerance tests were similar to those in wild-type mice.
Conversely, GLP-1 responses in GIP receptor knockout mice were also similar to wild-type mice.
Insulin responses to both GIP and GLP-1 were comparable between knockout and wild-type mice.
The findings do not support the idea that the absence of one incretin receptor leads to compensatory increases in the other incretin's action or secretion.

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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 () 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 () mice and their wild-type littermates () and inmice and their wild-type littermates (). Sensitivity to GIP and GLP-1 was assessed in isolated perfused pancreases ofandmice andandmice, respectively. We found similar GIP responses inandmice and similar GLP-1 responses inandmice during the OGTTs and in the isolated perfused intestines. Insulin responses to GIP and GLP-1 were similar inandmice and inandmice, 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.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. Gipr Glp-1r Glp-1r Gipr Gipr Glp-1r Glp-1r Gipr Gipr Glp-1r Glp-1r Gipr Gipr Glp-1r Glp-1r Gipr Gipr -/--/-+/+ -/-+/+ -/-+/+ -/-+/+ -/-+/+ -/-+/+ -/-+/+ -/-+/+ NEW & NOTEWORTHY

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