title: Targeting development of incretin-producing cells increases insulin secretion.
abstract: Glucagon-like peptide-1-based (GLP-1-based) therapies improve glycemic control in patients with type 2 diabetes. While these agents augment insulin secretion, they do not mimic the physiological meal-related rise and fall of GLP-1 concentrations. Here, we tested the hypothesis that increasing the number of intestinal L cells, which produce GLP-1, is an alternative strategy to augment insulin responses and improve glucose tolerance. Blocking the NOTCH signaling pathway with the γ-secretase inhibitor dibenzazepine increased the number of L cells in intestinal organoid-based mouse and human culture systems and augmented glucose-stimulated GLP-1 secretion. In a high-fat diet-fed mouse model of impaired glucose tolerance and type 2 diabetes, dibenzazepine administration increased L cell numbers in the intestine, improved the early insulin response to glucose, and restored glucose tolerance. Dibenzazepine also increased K cell numbers, resulting in increased gastric inhibitory polypeptide (GIP) secretion. Using a GLP-1 receptor antagonist, we determined that the insulinotropic effect of dibenzazepine was mediated through an increase in GLP-1 signaling. Together, our data indicate that modulation of the development of incretin-producing cells in the intestine has potential as a therapeutic strategy to improve glycemic control.
authors.forename: Natalia
authors.initials: N
authors.lastname: Petersen
authors.forename: Frank
authors.initials: F
authors.lastname: Reimann
authors.forename: Johan H
authors.initials: JH
authors.lastname: van Es
authors.forename: Bernard M
authors.initials: BM
authors.lastname: van den Berg
authors.forename: Chantal
authors.initials: C
authors.lastname: Kroone
authors.forename: Ramona
authors.initials: R
authors.lastname: Pais
authors.forename: Erik
authors.initials: E
authors.lastname: Jansen
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Gribble
authors.forename: Eelco J P
authors.initials: EJ
authors.lastname: de Koning
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D059305:Diet, High-Fat; D019858:Enteroendocrine Cells / Q000502:physiology*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D018149:Glucose Intolerance; D006801:Humans; D007082:Ileum / Q000166:cytology; D054795:Incretins / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D008810:Mice, Inbred C57BL; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D054795:Incretins; D007328:Insulin; D051880:Receptors, Notch; D052216:Glucagon-Like Peptide 1