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Nat Med. 2015 Apr;21(4):383-8. doi: 10.1038/nm.3820. Epub 2015 Mar 9.

A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication.

Author information

1
1] Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Division of Endocrinology and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
2
1] Experimental Therapeutics Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Integrated Screening Core, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
3
Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
4
Experimental Therapeutics Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
5
1] Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Division of Endocrinology and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [3] Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

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 life. 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 efforts. 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.

PMID:
25751815
PMCID:
PMC4690535
DOI:
10.1038/nm.3820
[Indexed for MEDLINE]
Free PMC Article

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