Regulation of Mouse Intestinal L Cell Progenitors Proliferation by the Glucagon Family of Peptides

Abstract

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.

Phenotype of entero‐endocrine L cells becomes restricted during development

“…The number of LK cells in ileum of embryos ( Fig. 1F-G) is threefold higher than that in adults (Mortensen et al, 2003;Grigoryan et al, 2012). In embryos, the percentage of GLP-1þGIPþ cells is similar along the crypt-villus axis.…”

“…GIP and GLP-1 are termed incretins because they stimulate insulin secretion from pancreatic beta-cells following nutrient ingestion (Baggio and Drucker, 2007). While the primary site of endogenous GIP release is the endocrine K cell of the duodenum and proximal jejunum, several reports indicate the presence of LK cells in adult mouse ileum (Mortensen et al, 2003;Fujita et al, 2008;Grigoryan et al, 2012).…”

“…Analysis of changes in L and LK cell populations along the small intestine in normal mice (Habib et al, 2012), in ileum of mutant mice lacking the glucagon receptor (GcgrÀ/À) (Grigoryan et al, 2012), and in small intestine of rats following bariatric surgery (Patriti et al, 2007;Kohli et al, 2011;Speck et al, 2011;Woods et al, 2011) suggests an important effect of nutrients and other extrinsic cues on LK, L, and K cell number. Since in embryos, the intestine is not exposed to external cues, we speculated that the proportion of these three cell types could differ from that in adult small intestine.…”

“…To ascertain whether embryonic L cells, unlike the adult counterparts (Cheng and Leblond, 1974;Grigoryan et al, 2012), are able to proliferate, we examined sections of e-17 ileum immunostained for visualization of the proliferation marker Ki67 and GLP-1. While the large majority of L cells were Ki67 negative both within and outside the TA region (Fig.…”

Mouse Insulin Cells Expressing an Inducible RIPCre Transgene Are Functionally Impaired

“…5015, Purina) containing a DPP4i (MK0626, Research Diets, New Brunswick, NJ), an analog of sitagliptin, for an additional two months while other 4 mice remained on the regular Purina diet. The dose of MK 0626 used (4 mg/kg/day) significantly reduces circulating DDP-4 levels and stabilizes postprandial levels of GLP-1 in mice (9,10). Body weight and fed blood glucose levels were determined bi-weekly.…”