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Glucagon‐like peptide‐1 treatment stimulates Neurogenin3 expression and pancreatic beta‐cell neogenesis in adult mice
Author(s) -
Dadheech Nidheesh,
Buteau Jean
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.883.14
Subject(s) - neogenesis , endocrinology , medicine , glucagon , pancreas , biology , beta cell , cellular differentiation , streptozotocin , progenitor cell , microbiology and biotechnology , stem cell , insulin , islet , diabetes mellitus , gene , biochemistry
Glucagon‐Like Peptide 1 (GLP‐1) is an intestinal hormone secreted after a meal. GLP‐1 is considered a key molecule in diabetes treatment because (a) it acts as a growth factor to promote beta‐cell mass expansion and (b) increases insulin secretion. Whereas GLP‐1 action on beta‐cell proliferation and survival has been extensively studied, its potential action on beta‐cell differentiation remains elusive. We herein performed lineage tracing experiments in genetically engineered mice to test the hypothesis that GLP‐1 stimulates the formation of new mature beta‐cells (neogenesis) in the adult pancreas. We used mice expressing a tamoxifen‐inducible Cre‐recombinase under the Neurog3 promoter to permanently label differentiating beta‐cells with a ZsGreen marker. This is because Neurog3 is transiently expressed in progenitor cells undergoing differentiation and is otherwise absent in the adult pancreas. Neurog3‐CreER/Rosa26‐LSL‐ZsGreen mice were injected with a moderate dose of streptozotocin to induce low levels of beta‐cell damage and regeneration. Then, mice were treated daily with tamoxifen alone or in combination with the long‐acting GLP‐1 analog Exendin4 (Ex‐4). Pancreata were harvested after 2 or 7 days of treatment. Control pancreata were devoid of ZsGreen staining, consistent with the fact that beta‐cell differentiation does not occur spontaneously in adult mice. Animals treated with Ex‐4, showed high frequency of ZsGreen+ cells in pancreatic islets and ducts, indicating that Ex‐4 induces Neurog3 expression in the adult pancreas. Mice treated with Ex‐4 for 2 days displayed small clusters of ZsGreen+ cells that were polyhormonal, a feature of immature/differentiating pancreatic endocrine cells. After 7 days of treatment, we detected a high number of insulin/ZsGreen dual positive cells, demonstrating that Ex‐4 stimulates the formation of new mature beta‐cells. We characterized the lineage of ZsGreen+ cells by studying the expression of various progenitor cell markers. Finally, we sorted ZsGreen+ cells to define their expression profile and confirm that newly‐differentiated beta‐cells could secrete insulin in response to physiological concentrations of glucose. Our study shows that GLP‐1, a naturally occurring hormone and an important anti‐diabetes therapeutic target, stimulates beta‐cell neogenesis. We thereby unveiled a new mode of action for the incretin hormone.