Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Conversion of adult pancreatic α-cells to β-cells after extreme β-cell loss


Pancreatic insulin-producing β-cells have a long lifespan, such that in healthy conditions they replicate little during a lifetime. Nevertheless, they show increased self-duplication after increased metabolic demand or after injury (that is, β-cell loss). It is not known whether adult mammals can differentiate (regenerate) new β-cells after extreme, total β-cell loss, as in diabetes. This would indicate differentiation from precursors or another heterologous (non-β-cell) source. Here we show β-cell regeneration in a transgenic model of diphtheria-toxin-induced acute selective near-total β-cell ablation. If given insulin, the mice survived and showed β-cell mass augmentation with time. Lineage-tracing to label the glucagon-producing α-cells before β-cell ablation tracked large fractions of regenerated β-cells as deriving from α-cells, revealing a previously disregarded degree of pancreatic cell plasticity. Such inter-endocrine spontaneous adult cell conversion could be harnessed towards methods of producing β-cells for diabetes therapies, either in differentiation settings in vitro or in induced regeneration.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: β-cell ablation and regeneration.
Figure 2: Conditional β-cell lineage tracing.
Figure 3: α-to-β reprogramming.
Figure 4: β-cell marker expression.


  1. 1

    Zhou, Q. & Melton, D. A. Extreme makeover: converting one cell into another. Cell Stem Cell 3, 382–388 (2008)

    CAS  PubMed  Google Scholar 

  2. 2

    Uhlenhaut, N. H. et al. Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation. Cell 139, 1130–1142 (2009)

    CAS  PubMed  Google Scholar 

  3. 3

    Zhou, Q., Brown, J., Kanarek, A., Rajagopal, J. & Melton, D. A. In vivo reprogramming of adult pancreatic exocrine cells to β-cells. Nature 455, 627–632 (2008)

    ADS  CAS  PubMed  Google Scholar 

  4. 4

    Bonal, C. et al. Pancreatic inactivation of c-Myc decreases acinar mass and transdifferentiates acinar cells into adipocytes in mice. Gastroenterology 136, 309–319 (2009)

    CAS  PubMed  Google Scholar 

  5. 5

    Teta, M., Long, S. Y., Wartschow, L. M., Rankin, M. M. & Kushner, J. A. Very slow turnover of β-cells in aged adult mice. Diabetes 54, 2557–2567 (2005)

    CAS  PubMed  Google Scholar 

  6. 6

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

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Dor, Y., Brown, J., Martinez, O. I. & Melton, D. A. Adult pancreatic β-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429, 41–46 (2004)

    ADS  CAS  PubMed  Google Scholar 

  8. 8

    Rankin, M. M. & Kushner, J. A. Adaptive β-cell proliferation is severely restricted with advanced age. Diabetes 58, 1365–1372 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Matveyenko, A. V. & Butler, P. C. Relationship between β-cell mass and diabetes onset. Diabetes Obes. Metab. 10 (suppl. 4). 23–31 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Wang, R. N., Bouwens, L. & Kloppel, G. β-cell growth in adolescent and adult rats treated with streptozotocin during the neonatal period. Diabetologia 39, 548–557 (1996)

    CAS  PubMed  Google Scholar 

  11. 11

    Herold, K. C. et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N. Engl. J. Med. 346, 1692–1698 (2002)

    CAS  PubMed  Google Scholar 

  12. 12

    Thyssen, S., Arany, E. & Hill, D. J. Ontogeny of regeneration of beta-cells in the neonatal rat after treatment with streptozotocin. Endocrinology 147, 2346–2356 (2006)

    CAS  PubMed  Google Scholar 

  13. 13

    Bonner-Weir, S., Baxter, L. A., Schuppin, G. T. & Smith, F. E. A second pathway for regeneration of adult exocrine and endocrine pancreas. A possible recapitulation of embryonic development. Diabetes 42, 1715–1720 (1993)

    CAS  PubMed  Google Scholar 

  14. 14

    Wang, R. N., Kloppel, G. & Bouwens, L. Duct- to islet-cell differentiation and islet growth in the pancreas of duct-ligated adult rats. Diabetologia 38, 1405–1411 (1995)

    CAS  PubMed  Google Scholar 

  15. 15

    Xu, G., Stoffers, D. A., Habener, J. F. & Bonner-Weir, S. Exendin-4 stimulates both β-cell replication and neogenesis, resulting in increased β-cell mass and improved glucose tolerance in diabetic rats. Diabetes 48, 2270–2276 (1999)

    CAS  PubMed  Google Scholar 

  16. 16

    Nir, T., Melton, D. A. & Dor, Y. Recovery from diabetes in mice by beta cell regeneration. J. Clin. Invest. 117, 2553–2561 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Baeyens, L. et al. In vitro generation of insulin-producing β cells from adult exocrine pancreatic cells. Diabetologia 48, 49–57 (2005)

    CAS  PubMed  Google Scholar 

  18. 18

    Bonner-Weir, S. & Weir, G. C. New sources of pancreatic β-cells. Nature Biotechnol. 23, 857–861 (2005)

    CAS  Google Scholar 

  19. 19

    Trucco, M. Regeneration of the pancreatic β cell. J. Clin. Invest. 115, 5–12 (2005)

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Xu, X. et al. β cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell 132, 197–207 (2008)

    CAS  PubMed  Google Scholar 

  21. 21

    Herrera, P. L. Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages. Development 127, 2317–2322 (2000)

    CAS  PubMed  Google Scholar 

  22. 22

    Herrera, P. L., Nepote, V. & Delacour, A. Pancreatic cell lineage analyses in mice. Endocrine 19, 267–278 (2002)

    CAS  PubMed  Google Scholar 

  23. 23

    Herrera, P. L. et al. Ablation of islet endocrine cells by targeted expression of hormone- promoter-driven toxigenes. Proc. Natl Acad. Sci. USA 91, 12999–13003 (1994)

    ADS  CAS  PubMed  Google Scholar 

  24. 24

    Naglich, J. G., Metherall, J. E., Russell, D. W. & Eidels, L. Expression cloning of a diphtheria toxin receptor: identity with a heparin-binding EGF-like growth factor precursor. Cell 69, 1051–1061 (1992)

    CAS  PubMed  Google Scholar 

  25. 25

    Saito, M. et al. Diphtheria toxin receptor-mediated conditional and targeted cell ablation in transgenic mice. Nature Biotechnol. 19, 746–750 (2001)

    CAS  Google Scholar 

  26. 26

    Srinivas, S. et al. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol. 1, 4 (2001)

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Cano, D. A. et al. Regulated β-cell regeneration in the adult mouse pancreas. Diabetes 57, 958–966 (2008)

    CAS  PubMed  Google Scholar 

  28. 28

    Wang, Z. V. et al. PANIC-ATTAC: a mouse model for inducible and reversible β-cell ablation. Diabetes 57, 2137–2148 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Gerich, J. E., Lorenzi, M., Karam, J. H., Schneider, V. & Forsham, P. H. Abnormal pancreatic glucagon secretion and postprandial hyperglycemia in diabetes mellitus. J. Am. Med. Assoc. 234, 159–165 (1975)

    CAS  Google Scholar 

  30. 30

    Perl, A. K., Wert, S. E., Nagy, A., Lobe, C. G. & Whitsett, J. A. Early restriction of peripheral and proximal cell lineages during formation of the lung. Proc. Natl Acad. Sci. USA 99, 10482–10487 (2002)

    ADS  CAS  PubMed  Google Scholar 

  31. 31

    Quoix, N. et al. The GluCre-ROSA26EYFP mouse: a new model for easy identification of living pancreatic α-cells. FEBS Lett. 581, 4235–4240 (2007)

    CAS  PubMed  Google Scholar 

  32. 32

    Li, W. C., Horb, M. E., Tosh, D. & Slack, J. M. In vitro transdifferentiation of hepatoma cells into functional pancreatic cells. Mech. Dev. 122, 835–847 (2005)

    CAS  PubMed  Google Scholar 

  33. 33

    Fodor, A. et al. Adult rat liver cells transdifferentiated with lentiviral IPF1 vectors reverse diabetes in mice: an ex vivo gene therapy approach. Diabetologia 50, 121–130 (2007)

    CAS  PubMed  Google Scholar 

  34. 34

    Chakrabarti, S. K., James, J. C. & Mirmira, R. G. Quantitative assessment of gene targeting in vitro and in vivo by the pancreatic transcription factor, Pdx1. Importance of chromatin structure in directing promoter binding. J. Biol. Chem. 277, 13286–13293 (2002)

    CAS  PubMed  Google Scholar 

  35. 35

    Ritz-Laser, B. et al. Ectopic expression of the β-cell specific transcription factor Pdx1 inhibits glucagon gene transcription. Diabetologia 46, 810–821 (2003)

    CAS  PubMed  Google Scholar 

  36. 36

    Schisler, J. C. et al. The Nkx6.1 homeodomain transcription factor suppresses glucagon expression and regulates glucose-stimulated insulin secretion in islet β cells. Proc. Natl Acad. Sci. USA 102, 7297–7302 (2005)

    ADS  CAS  PubMed  Google Scholar 

  37. 37

    Collombat, P. et al. Opposing actions of Arx and Pax4 in endocrine pancreas development. Genes Dev. 17, 2591–2603 (2003)

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Collombat, P. et al. The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into α and subsequently β cells. Cell 138, 449–462 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Bonal, C. & Herrera, P. L. Genes controlling pancreas ontogeny. Int. J. Dev. Biol. 52, 823–835 (2008)

    CAS  PubMed  Google Scholar 

  40. 40

    Rorsman, P., Salehi, S. A., Abdulkader, F., Braun, M. & MacDonald, P. E. KATP-channels and glucose-regulated glucagon secretion. Trends Endocrinol. Metab. 19, 277–284 (2008)

    CAS  PubMed  Google Scholar 

  41. 41

    Heimberg, H., De Vos, A., Pipeleers, D., Thorens, B. & Schuit, F. Differences in glucose transporter gene expression between rat pancreatic α- and β-cells are correlated to differences in glucose transport but not in glucose utilization. J. Biol. Chem. 270, 8971–8975 (1995)

    CAS  PubMed  Google Scholar 

  42. 42

    Heimberg, H. et al. The glucose sensor protein glucokinase is expressed in glucagon-producing α-cells. Proc. Natl Acad. Sci. USA 93, 7036–7041 (1996)

    ADS  CAS  PubMed  Google Scholar 

  43. 43

    Burgoyne, R. D. & Morgan, A. Secretory granule exocytosis. Physiol. Rev. 83, 581–632 (2003)

    CAS  PubMed  Google Scholar 

  44. 44

    Fausto, N. Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. Hepatology 39, 1477–1487 (2004)

    PubMed  Google Scholar 

  45. 45

    Meier, J. J., Bhushan, A., Butler, A. E., Rizza, R. A. & Butler, P. C. Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration? Diabetologia 48, 2221–2228 (2005)

    CAS  PubMed  Google Scholar 

  46. 46

    Meier, J. J. et al. Direct evidence of attempted beta cell regeneration in an 89-year-old patient with recent-onset type 1 diabetes. Diabetologia 49, 1838–1844 (2006)

    CAS  PubMed  Google Scholar 

  47. 47

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

    CAS  PubMed  Google Scholar 

  48. 48

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

    CAS  PubMed  Google Scholar 

  49. 49

    Hogan, B., Beddington, R., Costantini, F. & Lacy, E. Manipulating the Mouse Embryo. A Laboratory Manual 2nd edn, Ch. 7 289–358 (Cold Spring Harbor Laboratory Press, 1994)

    Google Scholar 

  50. 50

    Nguyen, V. X., Nix, D. E., Gillikin, S. & Schentag, J. J. Effect of oral antacid administration on the pharmacokinetics of intravenous doxycycline. Antimicrob. Agents Chemother. 33, 434–436 (1989)

    CAS  PubMed  PubMed Central  Google Scholar 

Download references


We are grateful to P. Vassalli and C. V. E. Wright for their comments and support. We also thank R. Stein, S. Kim and A. Ruiz i Altaba for discussions, and G. Flores, C. Gysler, O. Fazio, G. Philippin and C. Vesin for their technical help. We thank D. Melton for the RIP-CreER transgenic strain, and B. Thorens and C. V. E. Wright for anti-Glut2 and anti-Pdx1 antibodies, respectively. Work was funded with grants from the NIH/NIDDK (‘Beta Cell Biology Consortium’), JDRF (Juvenile Diabetes Research Foundation), Swiss National Science Foundation (and the NCCR ‘Frontiers in Genetics’), and 6FP EU Integrated Project ‘Beta Cell Therapy for Diabetes’ to P.L.H.

Author Contributions F.T., V.N. and I.A. contributed equally to this work. F.T. and V.N. prepared constructs for generating the transgenics, wrote the manuscript and together with I.A. performed most experiments and analyses. K.K. provided one plasmid. R.D. and S.C. conducted gene expression analyses, and S.C. performed immunofluorescence microscopy. P.L.H. conceived the experiments and wrote the manuscript with contributions from F.T., V.N., I.A. and S.C.

Author information



Corresponding author

Correspondence to Pedro L. Herrera.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures S1-S12 with legends, Supplementary Methods and Supplementary References. (PDF 2623 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

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.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing