Glucagon-Like Peptide 1 Increases beta-Cell Regeneration by Promoting alpha- to beta-Cell Transdifferentiation

Abstract

Glucagon-like peptide 1 (GLP-1) can increase pancreatic -cells, and -cells could be a source for new -cell generation. We investigated whether GLP-1 increases -cells through -cell transdifferentiation. New -cells originating from non--cells were significantly increased in recombinant adenovirus expressing GLP-1 (rAd-GLP-1)-treated RIP-CreER;R26-YFP mice. Proliferating -cells were increased in islets of rAd-GLP-1-treated mice and TC1 clone 9 (TC1-9) cells treated with exendin-4, a GLP-1 receptor agonist. Insulin(+)glucagon(+) cells were significantly increased by rAd-GLP-1 or exendin-4 treatment in vivo and in vitro. Lineage tracing to label the glucagon-producing -cells showed a higher proportion of regenerated -cells from -cells in rAd-GLP-1-treated Glucagon-rtTA;Tet-O-Cre;R26-YFP mice than rAd producing -galactosidase-treated mice. In addition, exendin-4 increased the expression and secretion of fibroblast growth factor 21 (FGF21) in TC1-9 cells and -cell-ablated islets. FGF21 treatment of -cell-ablated islets increased the expression of pancreatic and duodenal homeobox-1 and neurogenin-3 and significantly increased insulin(+)glucagon(+) cells. Generation of insulin(+)glucagon(+) cells by exendin-4 was significantly reduced in islets transfected with FGF21 small interfering RNA or islets of FGF21 knockout mice. Generation of insulin(+) cells by rAd-GLP-1 treatment was significantly reduced in FGF21 knockout mice compared with wild-type mice. We suggest that GLP-1 has an important role in -cell transdifferentiation to generate new -cells, which might be mediated, in part, by FGF21 induction.