Diabetes relief in mice by glucose-sensing insulin-secreting human α-cells

Kenichiro Furuyama, Simona Chera, Léon van Gurp, Daniel Oropeza, Luiza Ghila, Nicolas Damond, Heidrun Vethe, Joao A. Paulo, Antoinette M. Joosten, Thierry Berney, Domenico Bosco, Craig Dorrell, Markus Grompe, Helge Ræder, Bart O. Roep, Fabrizio Thorel, Pedro L. Herrera

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Cell-identity switches, in which terminally differentiated cells are converted into different cell types when stressed, represent a widespread regenerative strategy in animals, yet they are poorly documented in mammals. In mice, some glucagon-producing pancreatic α-cells and somatostatin-producing δ-cells become insulin-expressing cells after the ablation of insulin-secreting β-cells, thus promoting diabetes recovery. Whether human islets also display this plasticity, especially in diabetic conditions, remains unknown. Here we show that islet non-β-cells, namely α-cells and pancreatic polypeptide (PPY)-producing γ-cells, obtained from deceased non-diabetic or diabetic human donors, can be lineage-traced and reprogrammed by the transcription factors PDX1 and MAFA to produce and secrete insulin in response to glucose. When transplanted into diabetic mice, converted human α-cells reverse diabetes and continue to produce insulin even after six months. Notably, insulin-producing α-cells maintain expression of α-cell markers, as seen by deep transcriptomic and proteomic characterization. These observations provide conceptual evidence and a molecular framework for a mechanistic understanding of in situ cell plasticity as a treatment for diabetes and other degenerative diseases.

Original languageEnglish (US)
Pages (from-to)43-48
Number of pages6
JournalNature
Volume567
Issue number7746
DOIs
StatePublished - Mar 7 2019

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Insulin-Secreting Cells
Glucose
Insulin
Pancreatic Polypeptide-Secreting Cells
Somatostatin-Secreting Cells
Glucagon
Islets of Langerhans
Proteomics
Mammals
Transcription Factors

ASJC Scopus subject areas

  • General

Cite this

Furuyama, K., Chera, S., van Gurp, L., Oropeza, D., Ghila, L., Damond, N., ... Herrera, P. L. (2019). Diabetes relief in mice by glucose-sensing insulin-secreting human α-cells. Nature, 567(7746), 43-48. https://doi.org/10.1038/s41586-019-0942-8

Diabetes relief in mice by glucose-sensing insulin-secreting human α-cells. / Furuyama, Kenichiro; Chera, Simona; van Gurp, Léon; Oropeza, Daniel; Ghila, Luiza; Damond, Nicolas; Vethe, Heidrun; Paulo, Joao A.; Joosten, Antoinette M.; Berney, Thierry; Bosco, Domenico; Dorrell, Craig; Grompe, Markus; Ræder, Helge; Roep, Bart O.; Thorel, Fabrizio; Herrera, Pedro L.

In: Nature, Vol. 567, No. 7746, 07.03.2019, p. 43-48.

Research output: Contribution to journalArticle

Furuyama, K, Chera, S, van Gurp, L, Oropeza, D, Ghila, L, Damond, N, Vethe, H, Paulo, JA, Joosten, AM, Berney, T, Bosco, D, Dorrell, C, Grompe, M, Ræder, H, Roep, BO, Thorel, F & Herrera, PL 2019, 'Diabetes relief in mice by glucose-sensing insulin-secreting human α-cells', Nature, vol. 567, no. 7746, pp. 43-48. https://doi.org/10.1038/s41586-019-0942-8
Furuyama K, Chera S, van Gurp L, Oropeza D, Ghila L, Damond N et al. Diabetes relief in mice by glucose-sensing insulin-secreting human α-cells. Nature. 2019 Mar 7;567(7746):43-48. https://doi.org/10.1038/s41586-019-0942-8
Furuyama, Kenichiro ; Chera, Simona ; van Gurp, Léon ; Oropeza, Daniel ; Ghila, Luiza ; Damond, Nicolas ; Vethe, Heidrun ; Paulo, Joao A. ; Joosten, Antoinette M. ; Berney, Thierry ; Bosco, Domenico ; Dorrell, Craig ; Grompe, Markus ; Ræder, Helge ; Roep, Bart O. ; Thorel, Fabrizio ; Herrera, Pedro L. / Diabetes relief in mice by glucose-sensing insulin-secreting human α-cells. In: Nature. 2019 ; Vol. 567, No. 7746. pp. 43-48.
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