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

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 3

GLP-1 and insulin secretion and glucose tolerance after DBZ treatment.

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GLP-1 and insulin secretion and glucose tolerance after DBZ treatment. (...
(A–C) Plasma GLP-1 concentration during OGTT (A and B) and area under curve (AUC) for GLP-1 release (0–15 minutes; C) in lean and HFD-fed mice. n = 12 (lean control); 10 (lean DBZ); 6 (HFD control); 8 (HFD DBZ). (D) GLP-1 release, expressed as percent total GLP-1 content, in response to vehicle control (Ctrl); 10 mM glucose (Glc); 0.5% peptone (Ptn); 10 μM forskolin, 10 μM IBMX, and 10 mM glucose combined (F/I/G); or 1 μM phorbol myristate acetate (PMA) in mouse intestinal cultures. n = 2 (control); 3 (DBZ). Number of cultures is indicated for each group. (E–G) Insulin response during OGTT (E and F) and AUC (0–15 minutes; G) in lean and HFD-fed mice. n = 10 (lean control); 8 (lean DBZ); 6 (HFD control and DBZ). (H) Absolute GLP-1 secretion per well in response to various stimuli in intestinal cultures (treatments and number of cultures as in D). n = 2 (control); 3 (DBZ). (I–K) Blood glucose concentrations during OGTT (I and J) and AUC (0–120 minutes; K) in lean and HFD-fed mice. n = 11 (lean control); 13 (lean DBZ); 6 (HFD control and DBZ). (L) Basal (3 mM glucose) or stimulated (20 mM glucose; 2 phases shown) insulin release in isolated mouse islets. n = 8 islet batches per group (2 mice per treatment). *P < 0.05, **P < 0.01, ***P < 0.001, nonpaired 2-tailed Student’s t test (A–C, E–G, and I–L) or 1-way ANOVA with Bonferroni test (D and H).