Long-Term GABA Administration Induces Alpha Cell-Mediated Beta-like Cell Neogenesis

Nouha Ben-Othman; Andhira Vieira; Monica Courtney; Fabien Record; Elisabet Gjernes; Fabio Avolio; Biljana Hadzic; Noémie Druelle; Tiziana Napolitano; Sergi Navarro-Sanz; Serena Silvano; Keith Al-Hasani; Anja Pfeifer; Sandra Lacas-Gervais; Gunter Leuckx; Laura Marroquí; Julien Thévenet; Ole Dragsbaek Madsen; Decio Laks Eizirik; Harry Heimberg; Julie Kerr-Conte; François Pattou; Ahmed Mansouri; Patrick Collombat

doi:10.1016/j.cell.2016.11.002

Long-Term GABA Administration Induces Alpha Cell-Mediated Beta-like Cell Neogenesis

Nouha Ben-Othman, Andhira Vieira, Monica Courtney, Fabien Record, Elisabet Gjernes, Fabio Avolio, Biljana Hadzic, Noémie Druelle, Tiziana Napolitano, Sergi Navarro-Sanz, Serena Silvano, Keith Al-Hasani, Anja Pfeifer, Sandra Lacas-Gervais, Gunter Leuckx, Laura Marroquí, Julien Thévenet, Ole Dragsbaek Madsen, Decio Laks Eizirik, Harry HeimbergJulie Kerr-Conte, François Pattou, Ahmed Mansouri, Patrick Collombat

The Danish Stem Cell Center

140 Citations (Scopus)

Abstract

The recent discovery that genetically modified α cells can regenerate and convert into β-like cells in vivo holds great promise for diabetes research. However, to eventually translate these findings to human, it is crucial to discover compounds with similar activities. Herein, we report the identification of GABA as an inducer of α-to-β-like cell conversion in vivo. This conversion induces α cell replacement mechanisms through the mobilization of duct-lining precursor cells that adopt an α cell identity prior to being converted into β-like cells, solely upon sustained GABA exposure. Importantly, these neo-generated β-like cells are functional and can repeatedly reverse chemically induced diabetes in vivo. Similarly, the treatment of transplanted human islets with GABA results in a loss of α cells and a concomitant increase in β-like cell counts, suggestive of α-to-β-like cell conversion processes also in humans. This newly discovered GABA-induced α cell-mediated β-like cell neogenesis could therefore represent an unprecedented hope toward improved therapies for diabetes.

Original language	English
Journal	Cell
Volume	168
Issue number	1-2
Pages (from-to)	73-85, e1-e11
Number of pages	24
ISSN	0092-8674
DOIs	https://doi.org/10.1016/j.cell.2016.11.002
Publication status	Published - 12 Jan 2017

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Ben-Othman, N., Vieira, A., Courtney, M., Record, F., Gjernes, E., Avolio, F., Hadzic, B., Druelle, N., Napolitano, T., Navarro-Sanz, S., Silvano, S., Al-Hasani, K., Pfeifer, A., Lacas-Gervais, S., Leuckx, G., Marroquí, L., Thévenet, J., Madsen, O. D., Eizirik, D. L., ... Collombat, P. (2017). Long-Term GABA Administration Induces Alpha Cell-Mediated Beta-like Cell Neogenesis. Cell, 168(1-2), 73-85, e1-e11. https://doi.org/10.1016/j.cell.2016.11.002

Ben-Othman, N, Vieira, A, Courtney, M, Record, F, Gjernes, E, Avolio, F, Hadzic, B, Druelle, N, Napolitano, T, Navarro-Sanz, S, Silvano, S, Al-Hasani, K, Pfeifer, A, Lacas-Gervais, S, Leuckx, G, Marroquí, L, Thévenet, J, Madsen, OD, Eizirik, DL, Heimberg, H, Kerr-Conte, J, Pattou, F, Mansouri, A & Collombat, P 2017, 'Long-Term GABA Administration Induces Alpha Cell-Mediated Beta-like Cell Neogenesis', Cell, vol. 168, no. 1-2, pp. 73-85, e1-e11. https://doi.org/10.1016/j.cell.2016.11.002

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title = "Long-Term GABA Administration Induces Alpha Cell-Mediated Beta-like Cell Neogenesis",

abstract = "The recent discovery that genetically modified α cells can regenerate and convert into β-like cells in vivo holds great promise for diabetes research. However, to eventually translate these findings to human, it is crucial to discover compounds with similar activities. Herein, we report the identification of GABA as an inducer of α-to-β-like cell conversion in vivo. This conversion induces α cell replacement mechanisms through the mobilization of duct-lining precursor cells that adopt an α cell identity prior to being converted into β-like cells, solely upon sustained GABA exposure. Importantly, these neo-generated β-like cells are functional and can repeatedly reverse chemically induced diabetes in vivo. Similarly, the treatment of transplanted human islets with GABA results in a loss of α cells and a concomitant increase in β-like cell counts, suggestive of α-to-β-like cell conversion processes also in humans. This newly discovered GABA-induced α cell-mediated β-like cell neogenesis could therefore represent an unprecedented hope toward improved therapies for diabetes.",

author = "Nouha Ben-Othman and Andhira Vieira and Monica Courtney and Fabien Record and Elisabet Gjernes and Fabio Avolio and Biljana Hadzic and No{\'e}mie Druelle and Tiziana Napolitano and Sergi Navarro-Sanz and Serena Silvano and Keith Al-Hasani and Anja Pfeifer and Sandra Lacas-Gervais and Gunter Leuckx and Laura Marroqu{\'i} and Julien Th{\'e}venet and Madsen, {Ole Dragsbaek} and Eizirik, {Decio Laks} and Harry Heimberg and Julie Kerr-Conte and Fran{\c c}ois Pattou and Ahmed Mansouri and Patrick Collombat",

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AU - Ben-Othman, Nouha

AU - Vieira, Andhira

AU - Courtney, Monica

AU - Record, Fabien

AU - Gjernes, Elisabet

AU - Avolio, Fabio

AU - Hadzic, Biljana

AU - Druelle, Noémie

AU - Napolitano, Tiziana

AU - Navarro-Sanz, Sergi

AU - Silvano, Serena

AU - Al-Hasani, Keith

AU - Pfeifer, Anja

AU - Lacas-Gervais, Sandra

AU - Leuckx, Gunter

AU - Marroquí, Laura

AU - Thévenet, Julien

AU - Madsen, Ole Dragsbaek

AU - Eizirik, Decio Laks

AU - Heimberg, Harry

AU - Kerr-Conte, Julie

AU - Pattou, François

AU - Mansouri, Ahmed

AU - Collombat, Patrick

PY - 2017/1/12

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N2 - The recent discovery that genetically modified α cells can regenerate and convert into β-like cells in vivo holds great promise for diabetes research. However, to eventually translate these findings to human, it is crucial to discover compounds with similar activities. Herein, we report the identification of GABA as an inducer of α-to-β-like cell conversion in vivo. This conversion induces α cell replacement mechanisms through the mobilization of duct-lining precursor cells that adopt an α cell identity prior to being converted into β-like cells, solely upon sustained GABA exposure. Importantly, these neo-generated β-like cells are functional and can repeatedly reverse chemically induced diabetes in vivo. Similarly, the treatment of transplanted human islets with GABA results in a loss of α cells and a concomitant increase in β-like cell counts, suggestive of α-to-β-like cell conversion processes also in humans. This newly discovered GABA-induced α cell-mediated β-like cell neogenesis could therefore represent an unprecedented hope toward improved therapies for diabetes.

AB - The recent discovery that genetically modified α cells can regenerate and convert into β-like cells in vivo holds great promise for diabetes research. However, to eventually translate these findings to human, it is crucial to discover compounds with similar activities. Herein, we report the identification of GABA as an inducer of α-to-β-like cell conversion in vivo. This conversion induces α cell replacement mechanisms through the mobilization of duct-lining precursor cells that adopt an α cell identity prior to being converted into β-like cells, solely upon sustained GABA exposure. Importantly, these neo-generated β-like cells are functional and can repeatedly reverse chemically induced diabetes in vivo. Similarly, the treatment of transplanted human islets with GABA results in a loss of α cells and a concomitant increase in β-like cell counts, suggestive of α-to-β-like cell conversion processes also in humans. This newly discovered GABA-induced α cell-mediated β-like cell neogenesis could therefore represent an unprecedented hope toward improved therapies for diabetes.

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DO - 10.1016/j.cell.2016.11.002

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Long-Term GABA Administration Induces Alpha Cell-Mediated Beta-like Cell Neogenesis

Abstract

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