Journal
DIABETOLOGIA
Volume 58, Issue 11, Pages 2582-2591Publisher
SPRINGER
DOI: 10.1007/s00125-015-3728-z
Keywords
Beta cell neogenesis; Gastrin; GLP-1; GLP-1 receptor
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Funding
- JDRF Advanced Postdoctoral Fellowship [10-2010-561]
- JSPS KAKENHI [25461348]
- Takeda Science Foundation
- Suzuken Memorial Foundation
- Lilly Incretin Basic Research Aid Program
- National Institutes of Health [R01 DK021344, P30 DK63720]
- Nora Eccles Treadwell Foundation
- Grants-in-Aid for Scientific Research [25461348] Funding Source: KAKEN
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Aims/hypothesis Lineage conversion of non-beta cells into insulin-producing cells has been proposed as a therapy for the cure of diabetes. Glucagon-like peptide-1 (GLP-1) and its derivatives can induce beta cell neogenesis in vitro and beta cell mass expansion in vivo, but GLP-1 signalling has not been shown to regulate cell fate decisions in vivo. We therefore tested the impact of GLP-1 receptor (GLP1R) expression on beta cell differentiation in vivo. Methods Mice overexpressing GLP1R in pancreatic exocrine cells were generated by Cre-mediated recombination in sex-determining region Y-box 9 (SOX9)-expressing cells and then treated with exendin-4 and/or gastrin. Histological analysis was performed to detect cellular reprogramming from the exocrine lineage into insulin-producing cells. Results Whereas no newly generated beta cells were detected in the mice treated with exendin-4 alone, treatment with gastrin only induced the conversion of exocrine cells into insulin-producing cells. Furthermore, the overexpression of GLP1R, together with gastrin and exendin-4, synergistically promoted beta cell neogenesis accompanied by the formation of islet-like clusters. These newly generated beta cells expressed beta cell specific transcription factors, such as pancreatic and duodenal homeobox 1 (PDX1), NK6 homeobox 1 (NKX6.1) and musculoaponeurotic fibrosarcoma oncogene family A (MafA). These mice showed no histological evidence of pancreatitis or pancreatic dysplasia in their acini and had normal plasma amylase levels. Conclusions/interpretation Activation of GLP-1 and gastrin signalling induces beta cell neogenesis in the exocrine lineage without any deleterious pancreatic changes, which may lead to a potential therapy to cure diabetes by generating surrogate beta cells.
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