Intestine-selective reduction of Gcg expression reveals the importance of the distal gut for GLP-1 secretion.

OBJECTIVE: Glucagon-like peptide-1 is a nutrient-sensitive hormone secreted from enteroendocrine L cells within the small and large bowel. Although GLP-1 levels rise rapidly in response to food ingestion, the greatest density of L cells is localized to the distal small bowel and colon. Here, we assessed the importance of the distal gut in the acute L cell response to diverse secretagogues.

METHODS: Circulating levels of glucose and plasma GLP-1 were measured in response to the administration of L cell secretagogues in wild-type mice and in mice with (1) genetic reduction of Gcg expression throughout the small bowel and large bowel (Gcg) and (2) selective reduction of Gcg expression in the distal gut (Gcg).

RESULTS: The acute GLP-1 response to olive oil or arginine administration was markedly diminished in Gcg but preserved in Gcg mice. In contrast, the increase in plasma GLP-1 levels following the administration of the GPR119 agonist AR231453, or the melanocortin-4 receptor (MC4R) agonist LY2112688, was markedly diminished in the Gcg mice. The GLP-1 response to LPS was also markedly attenuated in the Gcg mice and remained submaximal in the Gcg mice. Doses of metformin sufficient to lower glucose and increase GLP-1 levels in the Gcg mice retained their glucoregulatory activity, yet they failed to increase GLP-1 levels in the Gcg mice. Surprisingly, the actions of metformin to increase plasma GLP-1 levels were substantially attenuated in the Gcg mice.

CONCLUSION: These findings further establish the importance of the proximal gut for the acute response to nutrient-related GLP-1 secretagogues. In contrast, we identify essential contributions of the distal gut to (i) the rapid induction of circulating GLP-1 levels in response to pharmacological selective agonism of G-protein-coupled receptors, (ii) the increased GLP-1 levels following the activation of Toll-Like Receptors with LPS, and iii) the acute GLP-1 response to metformin. Collectively, these results reveal that distal gut Gcg + endocrine cells are rapid responders to structurally and functionally diverse GLP-1 secretagogues.