Abstract
Types 1 and 2 diabetes affect some 380 million people worldwide. Both ultimately result from a deficiency of functional pancreatic insulin-producing beta cells. Beta cells proliferate in humans during a brief temporal window beginning around the time of birth, with a peak percentage (∼2%) engaged in the cell cycle in the first year of life1,2,3,4. In embryonic life and after early childhood, beta cell replication is barely detectable. Whereas beta cell expansion seems an obvious therapeutic approach to beta cell deficiency, adult human beta cells have proven recalcitrant to such efforts1,2,3,4,5,6,7,8. Hence, there remains an urgent need for antidiabetic therapeutic agents that can induce regeneration and expansion of adult human beta cells in vivo or ex vivo. Here, using a high-throughput small-molecule screen (HTS), we find that analogs of the small molecule harmine function as a new class of human beta cell mitogenic compounds. We also define dual-specificity tyrosine-regulated kinase-1a (DYRK1A) as the likely target of harmine and the nuclear factors of activated T cells (NFAT) family of transcription factors as likely mediators of human beta cell proliferation and differentiation. Using three different mouse and human islet in vivo–based models, we show that harmine is able to induce beta cell proliferation, increase islet mass and improve glycemic control. These observations suggest that harmine analogs may have unique therapeutic promise for human diabetes therapy. Enhancing the potency and beta cell specificity of these compounds are important future challenges.
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Acknowledgements
The authors wish to thank R. Vasavada, N. Fiaschi-Taesch, H. Chen, K. Takane, M. Ohlmeyer, R. DeVita, E. Schadt, C. Argmann, B. Losic, D. Lebeche, S. Kim and B. Wagner for their many helpful discussions during this study. We thank the NIDDK-supported Integrated Islet Distribution Program (IIDP), T. Kin at the University of Alberta in Edmonton and P. Witkowski at the University of Chicago for providing human islets. Ad.GFP and Ad.NFATC1 were provided by D. Lebeche (Icahn School of Medicine at Mount Sinai). This work was supported by grants from the National Institutes of Health (R-01 DK55023 (A.F.S.), U-01 DK089538 (A.F.S.), R-01 DK065149 (D.K.S.), R-01 DK067351 (A.G.-O.) and R-01 DK077096 (A.G.-O.)), the JDRF (17-2011-598 and 1-2011-603 (A.F.S.)) and the American Diabetes Association (1-14-BS-059) (A.G.-O.).
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P.W., J.-C.A.-P., D.P.F., H.L., S.S., A.B., A.K., R.S., D.K.S., A.G.-O. and A.F.S. designed and performed experiments. P.W., A.G.-O. and A.F.S. wrote the paper.
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Wang, P., Alvarez-Perez, JC., Felsenfeld, D. et al. A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication. Nat Med 21, 383–388 (2015). https://doi.org/10.1038/nm.3820
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DOI: https://doi.org/10.1038/nm.3820
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