Letter | Published:

Diabetes recovery by age-dependent conversion of pancreatic δ-cells into insulin producers

Nature volume 514, pages 503507 (23 October 2014) | Download Citation


Total or near-total loss of insulin-producing β-cells occurs in type 1 diabetes1,2. Restoration of insulin production in type 1 diabetes is thus a major medical challenge. We previously observed in mice in which β-cells are completely ablated that the pancreas reconstitutes new insulin-producing cells in the absence of autoimmunity3. The process involves the contribution of islet non-β-cells; specifically, glucagon-producing α-cells begin producing insulin by a process of reprogramming (transdifferentiation) without proliferation3. Here we show the influence of age on β-cell reconstitution from heterologous islet cells after near-total β-cell loss in mice. We found that senescence does not alter α-cell plasticity: α-cells can reprogram to produce insulin from puberty through to adulthood, and also in aged individuals, even a long time after β-cell loss. In contrast, before puberty there is no detectable α-cell conversion, although β-cell reconstitution after injury is more efficient, always leading to diabetes recovery. This process occurs through a newly discovered mechanism: the spontaneous en masse reprogramming of somatostatin-producing δ-cells. The juveniles display ‘somatostatin-to-insulin’ δ-cell conversion, involving dedifferentiation, proliferation and re-expression of islet developmental regulators. This juvenile adaptability relies, at least in part, upon the combined action of FoxO1 and downstream effectors. Restoration of insulin producing-cells from non-β-cell origins is thus enabled throughout life via δ- or α-cell spontaneous reprogramming. A landscape with multiple intra-islet cell interconversion events is emerging, offering new perspectives for therapy.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    & Relationship between β-cell mass and diabetes onset. Diabetes Obes. Metab. 10 (suppl. 4). 23–31 (2008)

  2. 2.

    The pathogenesis and natural history of type 1 diabetes. Cold Spring Harb. Perspect. Med. (2012)

  3. 3.

    et al. Conversion of adult pancreatic α-cells to β-cells after extreme β-cell loss. Nature 464, 1149–1154 (2010)

  4. 4.

    & Pancreatic neurogenin 3-expressing cells are unipotent islet precursors. Development 136, 3567–3574 (2009)

  5. 5.

    et al. Effect of forkhead box O1 (FOXO1) on β cell development in the human fetal pancreas. Diabetologia 53, 699–711 (2010)

  6. 6.

    , , , & Generation of functional insulin-producing cells in the gut by Foxo1 ablation. Nature Genet. 44, 406–412 (2012)

  7. 7.

    et al. Programmed cell senescence during mammalian embryonic development. Cell 155, 1104–1118 (2013)

  8. 8.

    , , , & Integration of Smad and Forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell 117, 211–223 (2004)

  9. 9.

    et al. Immunological mechanisms associated with long-term remission of human type 1 diabetes. Diabetes Metab. Res. Rev. 22, 184–189 (2006)

  10. 10.

    Id and development. Oncogene 20, 8290–8298 (2001)

  11. 11.

    , & Id family of helix-loop-helix proteins in cancer. Nature Rev. Cancer 5, 603–614 (2005)

  12. 12.

    & FOXO-binding partners: it takes two to tango. Oncogene 27, 2289–2299 (2008)

  13. 13.

    , , , & Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell 150, 1223–1234 (2012)

  14. 14.

    et al. Discovery of novel forkhead box O1 inhibitors for treating type 2 diabetes: improvement of fasting glycemia in diabetic db/db mice. Mol. Pharmacol. 78, 961–970 (2010)

  15. 15.

    et al. Effects of the novel Foxo1 inhibitor AS1708727 on plasma glucose and triglyceride levels in diabetic db/db mice. Eur. J. Pharmacol. 645, 185–191 (2010)

  16. 16.

    Regeneration and liability to injury. Science 14, 235–248 (1901)

  17. 17.

    et al. PDGF signalling controls age-dependent proliferation in pancreatic β-cells. Nature 478, 349–355 (2011)

  18. 18.

    et al. Complete long-term recovery of β-cell function in autoimmune type 1 diabetes after insulin treatment. Diabetes Care 27, 1207–1208 (2004)

  19. 19.

    , & β-Cell regeneration: the pancreatic intrinsic faculty. Trends Endocrinol. Metab. 22, 34–43 (2011)

  20. 20.

    et al. Epigenomic plasticity enables human pancreatic alpha to beta cell reprogramming. J. Clin. Invest. 123, 1275–1284 (2013)

  21. 21.

    et al. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes 62, 2595–2604 (2013)

  22. 22.

    et al. Predominance of β-cell neogenesis rather than replication in humans with an impaired glucose tolerance and newly diagnosed diabetes. J. Clin. Endocrinol. Metab. 98, 2053–2061 (2013)

  23. 23.

    et al. Normal glucagon signaling and β-cell function after near-total α-cell ablation in adult mice. Diabetes 60, 2872–2882 (2011)

Download references


We are grateful to D. Belin, P. Vassalli, R. Stein, A. Cookson, A. Ruiz i Altaba, M. González Gaitán, B. Galliot and I. Rodríguez for comments, support and discussions, and to G. Gallardo, O. Fazio, K. Hammad and B. Polat for technical help. We thank G. Gradwohl for the Ngn3-YFP mice. F.M.G. and F.R. were funded by Wellcome Trust grants WT088357/Z/09/Z and WT084210/Z/07/Z, respectively. This work was funded with grants from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (Beta Cell Biology Consortium), the Juvenile Diabetes Research Foundation and the Swiss National Science Foundation (NRP63) to P.L.H.

Author information


  1. Department of Genetic Medicine & Development, Faculty of Medicine, University of Geneva, 1 rue Michel-Servet, 1211 Geneva-4, Switzerland

    • Simona Chera
    • , Delphine Baronnier
    • , Luiza Ghila
    • , Valentina Cigliola
    • , Kenichiro Furuyama
    • , Fabrizio Thorel
    •  & Pedro L. Herrera
  2. Novo Nordisk A/S, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark

    • Jan N. Jensen
  3. Cell and Developmental Biology, Vanderbilt University Medical Center, 465 21st Av. South, Nashville, Tennessee 37232, USA

    • Guoqiang Gu
  4. Cambridge Institute for Medical Research, Hills Road, Cambridge CB2 0XY, UK

    • Fiona M. Gribble
    •  & Frank Reimann


  1. Search for Simona Chera in:

  2. Search for Delphine Baronnier in:

  3. Search for Luiza Ghila in:

  4. Search for Valentina Cigliola in:

  5. Search for Jan N. Jensen in:

  6. Search for Guoqiang Gu in:

  7. Search for Kenichiro Furuyama in:

  8. Search for Fabrizio Thorel in:

  9. Search for Fiona M. Gribble in:

  10. Search for Frank Reimann in:

  11. Search for Pedro L. Herrera in:


S.C. conceived and performed the experiments and analyses, and wrote the manuscript. F.M.G. and F.R. generated the Sst-Cre line, and G.G. and J.N.J. generated the Ngn3-CreERT, Ngn3-tTA and TRE-Ngn3 lines. D.B. characterized the pancreatic expression of the Sst-Cre line and performed the adult analysis. L.G. performed experiments and analyses. V.C. profiled sorted fluorescent adult islet cells. K.F. and F.T. performed immunofluorescence microscopy. P.L.H. conceived the experiments and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Pedro L. Herrera.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Methods and Data, Supplementary References and Supplementary Tables 1-39.

About this article

Publication history






Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.