Glucagon like peptide-1 (GLP-1) and GLP-2 are
hormones secreted by intestinal L cells that stimulate
glucose-dependent insulin secretion and regulate intestinal growth, respectively. Mice with deletion of the
glucagon receptor (Gcgr) have high levels of circulating
GLP-1 and GLP-2. We sought to determine whether the increased level of the
glucagon-like peptides is due to L cell
hyperplasia. We found, first, that high levels of the
glucagon-like peptides increase L cell number but does not affect the number of other intestinal epithelial cell types. Second, a large proportion of ileal L cells of Gcgr(-/-) mice coexpressed
glucose-dependent insulinotropic peptide (GIP). Cells coexpressing GIP and
GLP-1 are termed LK cells. Third, the augmentation in L cell number was due to a higher rate of proliferation of L cell progenitors rather than to the entrance of mature L cells into the cell cycle. Fourth, a high concentration of the
glucagon-like peptides in the circulation augmented the
mRNA levels of
transcription factors expressed by late but not early enteroendocrine progenitors. Fifth, the administration of
exendin 9-39, a
GLP-1 receptor antagonist, resulted in a decrease in the rate of L cell precursor proliferation. Finally, we determined that L cells do not express the
GLP-1 receptor, suggesting that the effect of
GLP-1 is mediated by paracrine and/or neuronal signals. Our results suggest that
GLP-1 plays an important role in the regulation of L cell number.