ISSN 1662-4009 (Online)

ESPE Yearbook of Paediatric Endocrinology (2019) 16 10.19 | DOI: 10.1530/ey.16.10.19

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

Department of Genetic Medicine and Development, iGE3 and Centre Facultaire du Diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland

To read the full abstract: Nature 567, 43–48 (2019)

Cell engineering might be a way to reinstall insulin-production in the pancreas of people with autoimmune diabetes. This experimental mouse study achieved to switch human alpha cells to secrete insulin.

Cell-identity switches, in which terminally differentiated cells are converted into different cell types, 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 cells also display this plasticity, especially in diabetic conditions, was not previously shown.

This study shows 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 reversed diabetes and continued to produce insulin even after six months. Notably, insulin-producing α-cells maintained expression of α-cell markers, as seen by deep transcriptomic and proteomic characterization.

These findings provide conceptual evidence and a molecular framework for a mechanistic understanding of in situ cell plasticity as a potential future treatment for diabetes and other degenerative diseases. Applying such approaches might even bring cure for diabetes within reach. A major challenge to such therapeutic approaches is to prevent disrupted autoimmune processes in the T1D human host from attacking newly built beta-cells – this might be possible as the cells still appeared from the outside to look like α-cells.