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Targeting development of incretin-producing cells increases insulin secretion
Natalia Petersen, … , Fiona M. Gribble, Eelco J.P. de Koning
Natalia Petersen, … , Fiona M. Gribble, Eelco J.P. de Koning
Published December 15, 2014
Citation Information: J Clin Invest. 2015;125(1):379-385. https://doi.org/10.1172/JCI75838.
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Research Article Endocrinology

Targeting development of incretin-producing cells increases insulin secretion

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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

Natalia Petersen, Frank Reimann, Johan H. van Es, Bernard M. van den Berg, Chantal Kroone, Ramona Pais, Erik Jansen, Hans Clevers, Fiona M. Gribble, Eelco J.P. de Koning

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Figure 1

L cell enrichment in intestinal organoids by the NOTCH inhibitor DBZ.

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L cell enrichment in intestinal organoids by the NOTCH inhibitor DBZ.
(A...
(A) L cell numbers in mouse ileum organoids after 96 hours of continuous exposure to different DBZ concentrations. (B) L cell numbers in mouse organoids 96 hours after a 3-hour DBZ pulse. (C and D) L cells (green) in a representative Glu-Venus mouse organoid before (C) and 96 hours after (D) a 3-hour pulse of 5 μM DBZ. Shown are maximum projections of a z stack through the organoid. VD, villus domain, CD, crypt domain. Arrows denote L cells. Scale bars: 20 μm. (A–D) n = 100 crypts (3 platings) per series. (E) Baseline and glucose-stimulated GLP-1 secretion in mouse ileum organoids 96 hours after a 3-hour pulse of 5 μM DBZ. n = 7 per series from 2 platings. (F) L cell numbers 96 hours after continuous treatment with SCFAs (combined 5 mM acetate, 1 mM propionate, and 1 mM butyrate), 5-μM DBZ pulse, or both. n = 100 crypts (3 platings) per series. (G) Gene expression of Ngn3, Neurod1, and Gcg in organoids at the indicated time points after a 5-μM DBZ pulse. n = 4–6 samples from 3 platings. (H) Baseline and glucose-stimulated GLP-1 secretion in human ileum organoids 96 hours after a 3-hour pulse of 5 μM DBZ. n = 6 per series from 2 platings. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control or as indicated by brackets, 1-way ANOVA with Bonferroni test (A–D and F) or nonpaired 2-tailed Student’s t test (E, G, and H).

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