Advances in drug discovery for human beta cell regeneration

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


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.


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





Cyclin-dependent kinase


Cell-division cycle-like kinases


Dual-specificity tyrosine phosphorylation-regulated kinase




Glycogen synthase kinase


Nuclear factor activated in T cells


RNA sequencing



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.


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)


  1. 1.
    Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC (2003) Beta cell deficit and increased beta cell apoptosis in humans with diabetes. Diabetes 52:102–110CrossRefPubMedGoogle Scholar
  2. 2.
    Meier JJ, Bhushan A, Butler AE, Rizza RA, Butler PC (2005) Sustained beta cell apoptosis in longstanding type 1 diabetes: indirect evidence for islet regeneration? Diabetologia 48:2221–2228CrossRefPubMedGoogle Scholar
  3. 3.
    Wang P, Fiaschi-Taesch NM, Vasavada RC, Scott DK, Garcia-Ocaña A, Stewart AF (2015) Advances and challenges in human beta cell proliferation for diabetes. Nat Rev Endocrinol 11:201–212CrossRefPubMedGoogle Scholar
  4. 4.
    Campbell-Thompson M, Fu A, Kaddis JS et al (2016) Insulitis and beta cell mass in the natural history of type 1 diabetes. Diabetes 65:719–731CrossRefPubMedGoogle Scholar
  5. 5.
    Hering BJ, Clarke WR, Bridges ND et al (2016) Phase 3 trial or transplantation of human islets in type 1 diabetes complicated by severe hypoglycemia. Diabetes Care 39:1230–1240CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Van Dellen D, Worthington J, Mitu-Pretorian OM et al (2013) Mortality in diabetes: pancreas transplantation is associated with significant survival benefit. Nephrol Diab Transplant 28:1315–1322CrossRefGoogle Scholar
  7. 7.
    Millman JR, Xie C, van Dervort A, Gurtler M, Pagliucia FW, Melton DA (2016) Generation of stem cell-derived β-cells from patients with type 1 diabetes. Nat Commun 7:11463CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Zhu S, Russ HA, Wang X et al (2016) Human pancreatic beta-like cells converted form fibroblasts. Nat Commun 7:10080CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Rezania A, Bruin JE, Arora P et al (2014) Reversal of diabetes with insulin-producing cells derived from human pluripotent stem cells. Nat Biotechnol 32:1121–1133CrossRefPubMedGoogle Scholar
  10. 10.
    Thorel F, Nepote V, Avril I et al (2010) Conversion of adult alpha cells to beta cells after extreme beta cell loss. Nature 464:1149–1154CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Talchai C, Xuan S, Lin HV, Sussel L, AcciIi D (2012) Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell 150:1223–1234CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Cinti F, Bouchi R, Kim-Muller JY et al (2016) Evidence of beta cell dedifferentiation in human type 2 diabetes. J Clin Endocrinol Metab 101:1044–1054CrossRefPubMedGoogle Scholar
  13. 13.
    Rui J, Deng S, Arzai A, Perdigoto AL, Liu Z, Herold KC (2017) Beta cell that resist immunological attack develop during progression of autoimmune diabetes in NOD mice. Cell Metab 25:727–738CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Wang P, Felsenfeld DP, Liu H et al (2015) A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication. Nat Med 21:383–388CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Meier JJ, Butler AE, Saisho Y et al (2008) Beta cell replication is the primary mechanism subserving the postnatal expansion of beta cell mass in humans. Diabetes 57:1584–1594CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Kassem SA, Ariel I, Thornton PS, Scheimberg I, Glaser B (2000) Beta-cell proliferation and apoptosis in the developing normal human pancreas and in hyperinsulinism of infancy. Diabetes 49:1325–1333CrossRefPubMedGoogle Scholar
  17. 17.
    Gregg BE, Moore PC, Demozay D et al (2012) Formation of a human beta cell population within pancreatic islets is set early in life. J Clin Endocrinol Metab 97:3197–3206CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Perl S, Kushner JA, Buchholtz BA et al (2010) Significant human ß-cell turnover is limited to the first three decades of life as determined by in vivo thymidine analog incorporation and radiocarbon dating. J Clin Endocrinol Metab 95:E234–E239CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Cnop M, Hughes SJ, Igoillo-Esteve M et al (2010) The long lifespan and low turnover of human islet beta cells estimated by mathematical modeling of lipofuscin accumulation. Diabetologia 53:321–330CrossRefPubMedGoogle Scholar
  20. 20.
    Shen W, Taylor B, Jin Q et al (2015) Inhibition of DYRK1A and GSK3B induces human beta cell proliferation. Nat Commun 6:8372CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Dirice E, Walpita D, Vetere A et al (2016) Inhibition of DYRK1A stimulates human beta cell proliferation. Diabetes 65:1660–1671CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Aamodt KI, Aramandia R, Brown J et al (2016) Development of a reliable automated screening system to identify small molecules and biologics that promote human beta cell regeneration. AJP Endorinol Metab 311:E859–E868CrossRefGoogle Scholar
  23. 23.
    Wang YJ, Golson ML, Schug J et al (2016) Singe cell mass cytometry analysis of human endocrine pancreas. Cell Metab 24:616–626CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Salomon D, Maeda P (1986) Heterogeneity and contact-dependent regulation of hormone secretion by individual beta cells. Exp Cell Res 162:507–520CrossRefPubMedGoogle Scholar
  25. 25.
    Avrhami D, Klochendler A, Dor Y, Glaser B (2017) Beta cell heterogeneity: an evolving concept. Diabetologia 60:1363–1369CrossRefGoogle Scholar
  26. 26.
    Dorrell C, Schug J, Canaday PS et al (2016) Human islets contain four distinct subtypes of beta cells. Nat Commun 7:11756CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Johnston NR, Mitchell RK, Haythorne E et al (2016) Beta cell hubs dictate pancreatic islet responses to glucose. Cell Metab 24:389–401CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Enge M, Arda HE, Mignardi M et al (2017) Single cell analysis of human pancreas reveals transcriptional signatures of aging and somatic mutation patterns. Cell 171:321–330CrossRefPubMedGoogle Scholar
  29. 29.
    Vetere A, Choudhary A, Burns SM, Wagner BK (2014) Targeting the pancreatic beta cell to treat diabetes. Nat Rev Drug Discov 13:278–289CrossRefPubMedGoogle Scholar
  30. 30.
    Shirakawa J, Kulkarni RN (2016) Novel factors modulating human beta cell proliferation. Diabetes Obes Metab 18(Suppl1):71–77CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Fiaschi-Taesch NM, Kleinberger JW, Salim F et al (2013) Developing a human pancreatic beta cell G1/S molecule atlas. Diabetes 62:2450–2459CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Fiaschi-Taesch NM, Kleinberger JW, Salim F et al (2013) Cytoplasmic-nuclear trafficking of G1/S cell cycle molecules and adult human beta cell replication: a revised model of human beta cell G1/S control. Diabetes 62:2460–2470CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Kulkarni RN, Bernal-Mizrachi E, Garcia-Ocaña A, Stewart AF (2012) Human ß-cell proliferation and intracellular signaling: driving in the dark without a roadmap. Diabetes 61:2205–2213CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Bernal-Mizrachi E, Kulkarni RN, Stewart AF, Garcia-Ocaña A (2014) Human β-cell proliferation and intracellular signaling part 2: still driving in the dark without a roadmap. Diabetes 63:819–831CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Stewart AF, Hussain MA, Garcia-Ocana A et al (2015) Human beta cell proliferation and intracellular signaling: part 3. Diabetes 54:1872–1885CrossRefGoogle Scholar
  36. 36.
    Avrahami D, Li C, Zhang J et al (2015) Aging-dependent demethylation of regulatory elements correlates with chromatin state and improved beta cell function. Cell Metab 22:619–632CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Ackermann AM, Wang Z, Schug J, Naji A, Kaestner KH (2016) Integration of ATAC-seq and RNA-seq identifies human alpha and beta cell signature genes. Mol Metab 3:233–244CrossRefGoogle Scholar
  38. 38.
    Arda HE, Li L, Tsai J et al (2016) Age-dependent pancreatic gene regulation reveals mechanisms governing human beta cell function. Cell Metab 23:909–920CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Wang H, Bender A, Wang P et al (2017) Insights into beta cell regeneration for diabetes via integration of molecular landscapes in human insulinomas. Nat Commun 8:767CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Purwana I, Zheng J, Li X et al (2014) GABA promotes human beta cell proliferation and modulates glucose homeostasis. Diabetes 63:4197–4205CrossRefPubMedGoogle Scholar
  41. 41.
    Drucker DJ (2018) Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab 27:740–756CrossRefPubMedGoogle Scholar
  42. 42.
    Kondegowda NG, Fenutria R, Pollack IR et al (2015) Osteoprotegerin and denosumab stimulate human beta cell proliferation through inhibition of the receptor activator of NFkB ligand pathway. Cell Metab 22:77–85CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Dhawan S, Dirice E, Kulkarni RN, Bhushan A (2016) Inhibition of TGF-beta signaling promotes human pancreatic beta cell replication. Diabetes 65:1208–1218CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Brown ML, Schneyer AL (2010) Emerging roles for the TGFb superfamily in pancreatic beta cell homeostasis. Trends Endocrinol Metab 21:441–448CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Smart NG, Apelqvist AA, Gu X et al (2006) Conditional expression of Smad7 in pancreatic beta cells disrupts TGF-beta signaling and induces reversible diabetes mellitus. PLoS Biol 4:e39CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    El-Gohary Y, Tulachan S, Wiersch J et al (2014) A smad signaling network regulates islet proliferation. Diabetes 63:224–236CrossRefPubMedGoogle Scholar
  47. 47.
    El Ouaamari A, Dirice E, Gedeon N et al (2016) Serpin B1 promotes pancreatic beta cell proliferation. Cell Metab 23:1–12CrossRefGoogle Scholar
  48. 48.
    Stephens SB, Schisler JC, Hohmeier H et al (2012) A VGF-derived peptide attenuates development of type 2 diabetes via enhancement of islet beta cell survival and function. Cell Metab 16:33–43CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Robitaille K, Rourke JL, McBane JE et al (2016) High-throughput functional genomics identifies regulators of primary human beta cell proliferation. J Biol Chem 291:4614–4625CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Andersson O, Adams BA, Yoo D et al (2012) Adenosine signaling promotes regeneration of pancreatic beta cells in vivo. Cell Metab 15:885–894CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Annes JP, Ryu JH, Lam K et al (2012) Adenosine kinase inhibition selectively promotes rodent and porcine islet beta cell proliferation. Proc Natl Acad Sci U S A 109:3915–3920CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Wang W, Walker JR, Wang X et al (2009) Identification of small molecule inducers of pancreatic beta cell expansion. Proc Natl Acad Sci U S A 106:1427–1432CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Walpita D, Hasaka T, Spoonamore J et al (2012) A human islet cell culture system for high-throughput screening. J Biomol Screen 17:509–518CrossRefPubMedGoogle Scholar
  54. 54.
    Dai C, Hang Y, Shostak A et al (2017) Age-dependent human beta cell proliferation induced by glucagon-like peptide-1 and calcineurin signaling. J Clin Invest 127:3835–3844CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Ogawa Y, Nonaka Y, Goto T et al (2010) Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A. Nat Commun 1:86Google Scholar
  56. 56.
    Tahtouh T, Elkins JM, Filippakopoulos P et al (2012) Selectivity, co-crystal structures and neuroprotective properties of leucettines, a family of protein kinase inhibitors derived from the marine sponge alkaloid leucettamine B. J Med Chem 55:9312–9330CrossRefPubMedGoogle Scholar
  57. 57.
    Leibowitz G, Beattie GM, Kafri T et al (1999) Gene transfer to human pancreatic endocrine cells using viral vectors. Diabetes 48:1013–1019CrossRefPubMedGoogle Scholar
  58. 58.
    Brierley DI, Davidson C (2012) Developments in harmine pharmacology – implications for ayahuasca use and drug-dependence treatment. Prog Neuropsychopharmacol Biol Psychiatry 39:263–272CrossRefPubMedGoogle Scholar

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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