bw-723c86 and Constipation

Constipation is commonly associated with diabetes. Serotonin (5-HT), produced predominantly by enterochromaffin (EC) cells via tryptophan hydroxylase 1 (TPH1), is a key modulator of gastrointestinal (GI) motility. However, the role of serotonergic signaling in constipation associated with diabetes is unknown.. We generated EC cell reporter Tph1-tdTom, EC cell-depleted Tph1-DTA, combined Tph1-tdTom-DTA, and interstitial cell of Cajal (ICC)-specific Kit-GCaMP6 mice. Male mice and surgically ovariectomized female mice were fed a high-fat high-sucrose diet to induce diabetes. The effect of serotonergic signaling on GI motility was studied by examining 5-HT receptor expression in the colon and in vivo GI transit, colonic migrating motor complexes (CMMCs), and calcium imaging in mice treated with either a 5-HT. Colonic transit was delayed in males with diabetes, although colonic Tph1. Impaired colonic motility in mice with diabetes was improved by enhancing HTR2B signaling. The HTR2B agonist may provide therapeutic benefits for constipation associated with diabetes.

Topics: Animals; Calcium Signaling; Colon; Constipation; Diabetes Complications; Disease Models, Animal; Female; Gastrointestinal Motility; Genes, Reporter; Indoles; Interstitial Cells of Cajal; Male; Mice, Inbred C57BL; Mice, Transgenic; Myoelectric Complex, Migrating; Ovariectomy; Proto-Oncogene Proteins c-kit; Receptor, Serotonin, 5-HT2B; Serotonin; Serotonin 5-HT2 Receptor Agonists; Thiophenes; Tryptophan Hydroxylase