Activation of GLP-1 and gastrin signalling induces in vivo reprogramming of pancreatic exocrine cells into beta cells in mice.
OBJECTIVE
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
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.
Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
Shugo
S
Sasaki
Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan. miyatsuka-takeshi@umin.net.|Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. miyatsuka-takeshi@umin.net.|Center for Molecular Diabetology, Juntendo University Graduate School of Medicine, Tokyo, Japan. miyatsuka-takeshi@umin.net.
Takeshi
T
Miyatsuka
Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
Taka-aki
TA
Matsuoka
Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
Mitsuyoshi
M
Takahara
Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
Yuichi
Y
Yamamoto
Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
Tetsuyuki
T
Yasuda
Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
Hideaki
H
Kaneto
Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Yoshio
Y
Fujitani
Diabetes Center, University of California San Francisco, San Francisco, CA, USA.
Michael S
MS
German
Department of Orthopedic Surgery, School of Medicine, Kyoto University, Kyoto, Japan.
Haruhiko
H
Akiyama
Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.|Center for Molecular Diabetology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Hirotaka
H
Watada
Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
Iichiro
I
Shimomura
D000818:Animals; D065150:Cellular Reprogramming / Q000187:drug effects / Q000502:physiology*; D000077270:Exenatide; D005755:Gastrins / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D046790:Pancreas, Exocrine / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014688:Venoms / Q000494:pharmacology
D005755:Gastrins; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D010455:Peptides; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide
Beta cell neogenesis; GLP-1; GLP-1 receptor; Gastrin