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 2

In vivo L cell enrichment by the 2× 10 mg/kg DBZ regimen.

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In vivo L cell enrichment by the 2× 10 mg/kg DBZ regimen. (A) L cell num...
(A) L cell numbers in lean and HFD-fed mouse ileum. L cells were identified by GLP-1 staining and counted; results are expressed as number of cells per millimeter of mucosal lining. Data are from microscopy of 6 transverse sections per series from 3 lean and 4 HFD-fed mice. (B) L cell numbers, determined by FACS analysis, in combined lean mouse jejunum and ileum. n = 3 samples each (control and DBZ); each sample was pooled from 2 mice. (A and B) ***P < 0.001, nonpaired 2-tailed Student’s t test. (C and D) Immunostaining for GLP-1 (green) in the small intestine of a lean mouse. Arrows denote L cells (also shown at higher magnification in the insets). (E and F) Periodic acid–Schiff (PAS) staining for goblet cells (arrows) in the small intestine. (G) Body weight change in control and DBZ-treated mice after overnight fasting for OGTT. Initial body weight in nonfasted mice before treatment was assigned as 0. n = 12 (control); 10 (DBZ). Nonpaired 2-tailed Student’s t test. (C–F) Images are representative of 6 transverse sections per series (vehicle and DBZ). Scale bars: 100 μm; 20 μm (insets).