Studies of the incretins, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, and their receptors

Abstract

grantor: University of TorontoGLP-1 (Glucagon-like peptide-1) and GIP (Glucose-dependent insulinotropic polypeptide) are intestinal hormones that potentiate glucose-stimulated insulin secretion from pancreatic $\beta$ cells. GLP-1, in particular, is at the forefront of diabetes research due to its antidiabetogenic actions in Type 2 diabetics. Previous studies demonstrated that GLP-1R$-$/$-$ mice exhibit mild diabetes despite upregulation of GIP secretion and insulinotropic action. GLP-1R$-$/$-$ mice were found to have diminished pancreatic insulin protein and mRNA levels, which may explain in part, the inability of GIP to fully compensate for the absence of GLP-1 activity in these mice. An evolutionary approach was used to study the functional determinants of GLP-1. The biological activities of three novel Xenopus laevis GLP-1-like peptides with $\sim$70% amino acid identity to human GLP-1 were found to be similar to that of human GLP-1. Furthermore residues at positions 12 and 23 of the Xenopus peptides, corresponding to positions 19 and 29 of mammalian GLP-1 were identified as critical to peptide activity. Study of GIP/GLP-1 receptor chimeras localized an activation domain of a GIP/GLP-1 receptor to three residues at the amino-terminus of the first transmembrane domain.M.Sc