Targeting development of incretin-producing cells increases insulin secretion
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
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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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 5

In vitro and in vivo K cell enrichment after DBZ treatment.

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In vitro and in vivo K cell enrichment after DBZ treatment. (A and B) K ...
(A and B) K cells (green) in a representative mouse duodenal organoid before (A) and 96 hours after (B) a 3-hour pulse of 5 μM DBZ. Shown are maximum projections of a z stack through the organoid. Images are representative of 100 organoids per series from 2 platings. Scale bars: 20 μm. (C) Basal and glucose-stimulated GIP secretion in control organoids and 96 hours after a 3-hour pulse of 5 μM DBZ. n = 8 per series from 2 platings. (D) K cell numbers in the duodenum of HFD-fed mice treated with vehicle or DBZ (2× 10 mg/kg regimen). Data were obtained from microscopy of 6 transverse sections from 3 HFD-fed mice per series. (E) GIP concentrations during OGTT in control and DBZ-treated HFD-fed mice. n = 6 (control); 7 (DBZ). (F) AUC for GIP release (0–30 minutes). (C–F) *P < 0.05, **P < 0.01, ***P < 0.001, nonpaired 2-tailed Student’s t test.