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.
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| 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 |
| Journal | The Journal of clinical investigation (J Clin Invest) Vol. 125 Issue 1 Pg. 379-85 (Jan 2015) ISSN: 1558-8238 [Electronic] United States |
| PMID | 25500886 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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