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  • Review Article
  • Published:

Diabetes mellitus—advances and challenges in human β-cell proliferation

Nature Reviews Endocrinology volume 11, pages 201–212 (2015)Cite this article

Subjects

Key Points

  • As pancreatic β-cell mass is reduced in both type 1 and type 2 diabetes mellitus, β-cell regeneration and replacement represent attractive approaches for treating diabetes

  • Developing approaches for expanding adult human β cells has proven challenging as human β cells normally undergo replication only in the first few years of life

  • Gene therapy approaches that are based on cell-cycle control mechanisms can be used to induce human β cells to replicate, but these methods are not attractive therapeutically

  • Our understanding of the cell surface receptors and intracellular signalling pathways that couple extracellular events to downstream cell-cycle activation in adult human pancreatic β cells remains in its infancy

  • Epigenetic control of human pancreatic β-cell replication is an exciting and rapidly emerging field

  • Although the concept that adult human β cells can replicate and expand is new, major advances have accrued over the past 10 years and the field continues to accelerate

Abstract

The treatment of diabetes mellitus represents one of the greatest medical challenges of our era. Diabetes results from a deficiency or functional impairment of insulin-producing β cells, alone or in combination with insulin resistance. It logically follows that the replacement or regeneration of β cells should reverse the progression of diabetes and, indeed, this seems to be the case in humans and rodents. This concept has prompted attempts in many laboratories to create new human β cells using stem-cell strategies to transdifferentiate or reprogramme non-β cells into β cells or to discover small molecules or other compounds that can induce proliferation of human β cells. This latter approach has shown promise, but has also proven particularly challenging to implement. In this Review, we discuss the physiology of normal human β-cell replication, the molecular mechanisms that regulate the cell cycle in human β cells, the upstream intracellular signalling pathways that connect them to cell surface receptors on β cells, the epigenetic mechanisms that control human β-cell proliferation and unbiased approaches for discovering novel molecules that can drive human β-cell proliferation. Finally, we discuss the potential and challenges of implementing strategies that replace or regenerate β cells.

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Figure 1: Human β-cell proliferation as a function of age.
Figure 2: Discordant transcription factor expression in mouse and human pancreatic β cells.
Figure 3: Abundance and distribution of endocrine cells in mouse and human pancreatic islets.
Figure 4: Cell cycle progression at the G1/S checkpoint in human β cells.
Figure 5: Connecting cell-surface receptors to cell-cycle machinery in rodent β cells.
Figure 6: Potential impediments to adult human β-cell proliferation.

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Acknowledgements

The authors acknowledge H. Liu, K. K. Takane, A. Bender, J. C. Alvarez-Perez, H. Chen, N. G. Kondgowda, P. Zhang and A. Laxman for helpful discussions, and the NIDDK-supported Integrated Islet Distribution Program (IIDP), T. Kin (University of Alberta in Edmonton, AB, Canada), P. Witkowski (University of Chicago, IL, USA) and R. Bottino (University of Pittsburgh, PA, USA) for providing human islets. The authors acknowledge support from the NIH/NIDDK (grants R-01 DK55023, U-01 DK089538, R-01 DK067351, R-01 DK077096, R-01 DK078060 and R-01 DK072264), the JDRF (grants 17-2011-598, 1-2011-603, 47-2012-750 and 17-2012-37) and the American Diabetes Association (grants 1-14-BS-069 and 7-12-BS-046).

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  1. Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, Atran 5, Box 1152, 1 Gustave L. Levy Place, New York, 10029, NY, USA

    Peng Wang, Nathalie M. Fiaschi-Taesch, Rupangi C. Vasavada, Donald K. Scott, Adolfo García-Ocaña & Andrew F. Stewart

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All authors researched data for the article, provided substantial contributions to discussions of the content and reviewed and/or edited the manuscript before submission. P.W. and A.F.S. contributed equally to the writing of the article.

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Wang, P., Fiaschi-Taesch, N., Vasavada, R. et al. Diabetes mellitus—advances and challenges in human β-cell proliferation. Nat Rev Endocrinol 11, 201–212 (2015). https://doi.org/10.1038/nrendo.2015.9

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