Advances in drug discovery for human beta cell regeneration

  • Esra Karakose
  • Courtney Ackeifi
  • Peng Wang
  • Andrew F. Stewart
Review

Abstract

The numbers of insulin-secreting pancreatic beta cells are reduced in people with type 1 and type 2 diabetes. Driving beta cell regeneration in the pancreases of people with diabetes would be an attractive approach to reversing diabetes. While adult human beta cells have long been believed to be terminally differentiated and, therefore, irreversibly quiescent, it has become clear over recent years that this is not true. More specifically, both candidate and unbiased high-throughput screen approaches have revealed several classes of molecules that are clearly able to induce human beta cell proliferation. Here, we review recent approaches and accomplishments in human beta cell regenerative drug discovery. We also list the challenges that this rapidly moving field must confront to translate beta cell regenerative therapy from the laboratory to the clinic.

Keywords

Beta cell Diabetes Drug discovery High-throughput screen Human Pancreas Proliferation Regeneration Review 

Abbreviations

BrdU

Bromo-deoxyuridine

CDK

Cyclin-dependent kinase

CLK

Cell-division cycle-like kinases

DYRK

Dual-specificity tyrosine phosphorylation-regulated kinase

EdU

5-ethynyl-2′-deoxyuridine

GSK

Glycogen synthase kinase

NFaT

Nuclear factor activated in T cells

RNA-seq

RNA sequencing

Notes

Acknowledgements

We thank A. Garcia-Ocaña, D. Scott, M. Donovan, R. DeVita, R. Sanchez, C. Argmann and E. Schadt, all at the Icahn School of Medicine at Mount Sinai (New York, NY, USA), for invaluable discussions while the work described herein unfolded. We also apologise in advance to authors whose work we were unable to cite or discuss because of space limitations.

Contribution statement

All authors were responsible for drafting the article and revising it critically for important intellectual content. All authors approved the version to be published.

Funding

This work was supported by the Foundation for Diabetes Research (FDR), the Human Islet and Adenoviral Core (HIAC) of the Einstein-Sinai Diabetes Research Centre (E-S DRC), the Human Islet Research Network (HIRN) and by NIH/NIDDK grants (P-30 020541, UC-4 104211, R-01 105015, R-01 55023) and a JDRF grant (2-SRA-2015-62).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Supplementary material

125_2018_4639_MOESM1_ESM.pptx (406 kb)
ESM Downloadable slideset (PPTX 405 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Esra Karakose
    • 1
  • Courtney Ackeifi
    • 1
  • Peng Wang
    • 1
  • Andrew F. Stewart
    • 1
  1. 1.The Diabetes, Obesity and Metabolism Institute, The Icahn School of Medicine at Mount SinaiNew YorkUSA

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