L cells to the rescue
Type 2 diabetes is a chronic disease characterized by the inability to control blood glucose levels. Therapies that prevent degradation of glucagon-like peptide-1 (GLP-1) improve insulin secretion; however, these treatments do not mimic physiological GLP-1 fluctuations and can result in hypoglycemia. Intestinal L cells are a source for secreted GLP-1; therefore, Natalia Peterson and colleagues at the Hubrecht Institute of the Royal Netherlands Academy of Arts and Sciences evaluated the use of a gamma-secretase-Notch inhibitor dibenzazepine (DBZ) to increase incretin-producing L cells as an alternative approach to enhance insulin secretion and improve glucose tolerance. In organoid cultures and mice fed a high fat diet, DBZ treatment increased expression of genes associated with L cell development, augmented intestinal L cell quantities, and led to an increase in secretory goblet cells. Furthermore, DBZ-induced L cell enrichment promoted GLP-1 production, resulting in an improved insulin response and glucose tolerance in a mouse model of type 2 diabetes. Blockade of GLP-1 with a receptor antagonist attenuated the beneficial effects of DBZ treatment. Together, these results suggest that L cell enrichment in the intestinal epithelium may be a beneficial therapeutic approach for controlling type 2 diabetes. The accompanying image of a DBZ-treated murine intestinal organoid culture from Glu-Venous mice shows a dramatic increase in L cells (green).
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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
Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)