Mucosal glucagon-like peptide 1 (GLP-1) responses are mediated by calcitonin gene-related peptide (CGRP) in the mouse colon and both peptide responses are area-specific

Abstract

Background

Glucagon-like peptide (GLP)-1 is an incretin hormone and its mimetics are proven antidiabetic and antiobesity drugs. GLP-1 exerts antimotility and mucosal proliferative activities but its epithelial ion transport effects are uncharacterized and these may contribute to the gastrointestinal (GI) disturbance, i.e., diarrhea experienced with some GLP-1 mimetics. Our aim was to establish GLP-1 agonist mechanisms and identify potential mucosal mediator(s) in the colonic tissue from C57BL/6J mice.

Methods

A tissue survey of GLP-1 responses (using exendin 4, Ex4) and α-calcitonin gene-related peptide (αCGRP) was undertaken, dividing the mouse colon into eight adjacent mucosal-submucosal preparations. Each preparation was voltage-clamped and changes in short-circuit current (Isc) measured. The involvement of submucosal neurons in GLP-1 agonism was tested using Ex(9-39) and tetrodotoxin (TTX), and CGRP receptors were blocked with BIBN4094.

Key Results

Ex4 responses along the length of the colon were inhibited by the GLP-1 antagonist, Ex(9-39) or TTX, indicating neural mediation in all colonic regions. In the ascending colon, Ex4 increased Isc levels that were abolished by 10 nM BIBN4096, while in the descending colon it reduced Isc levels that were again BIBN4096-sensitive, but at 1 μM. The latter αCGRP response was dependent on epithelial Cl⁻ conductance and Na⁺/K⁺-ATPase, and was partially (~25%) peptide YY-mediated, but was not nitrergic, somatostatin sst₂, or α₂-adrenoceptor-mediated.

Conclusions and Inferences

GLP-1 modulates epithelial ion transport indirectly by activating CGRP-containing submucosal enteric neurons in the mouse colon. This GLP-1-CGRP response was area-specific and could potentially contribute to the diarrheal side effect of certain GLP-1R therapeutics.

GLP-1 responses varied along the length of the mouse colon mucosa. These epithelial effects were neuronally mediated and involved endogenous CGRP. The mucosal secretory response observed in the ascending colon may contribute to diarrhea, a transient side effect of longer acting GLP-1 mimetics.

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