Abstract
We found that administration of a recombinant adenovirus (rAd) expressing betacellulin (BTC) into obese diabetic db/db mice ameliorated hyperglycemia. Exogenous glucose clearance was significantly improved, and serum insulin levels were significantly higher in rAd-BTC-treated mice than rAd-β-gal-treated control mice. rAd-BTC treatment increased insulin/bromodeoxyuridine double-positive cells in the islets, and islets from rAd-BTC-treated mice exhibited a significant increase in the level of G1-S phase-related cyclins as compared with control mice. In addition, BTC treatment increased messenger RNA (mRNA) and protein levels of these cyclins and cyclin-dependent kinases in MIN-6 cells. BTC treatment induced intracellular Ca2+ levels through phospholipase C-γ1 activation, and upregulated calcineurin B (CnB1) levels as well as calcineurin activity. Upregulation of CnB1 by BTC treatment was observed in isolated islet cells from db/db mice. When treated with CnB1 small interfering RNA (siRNA) in MIN-6 cells and isolated islets, induction of cell cycle regulators by BTC treatment was blocked and consequently reduced BTC-induced cell viability. As well as BTC’s effects on cell survival and insulin secretion, our findings demonstrate a novel pathway by which BTC controls beta-cell regeneration in the obese diabetic condition by regulating G1-S phase cell cycle expression through Ca2+ signaling pathways.
Key messages
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Administration of BTC to db/db mice results in amelioration of hyperglycemia.
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BTC stimulates beta-cell proliferation in db/db mice.
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Ca2+ signaling was involved in BTC-induced beta-cell proliferation.
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BTC has an anti-apoptotic effect and potentiates glucose-stimulated insulin secretion.
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Acknowledgments
We thank Dr. Ann Kyle for editorial assistance.
Funding
This study was supported by the grants from the Innovative Research Institute for Cell Therapy (A062260), the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number : HI14C1135) and National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (NO. 2009–0079342).
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The authors declare that there is no duality of interest associated with this manuscript.
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Oh, Y.S., Shin, S., Li, H.Y. et al. Betacellulin ameliorates hyperglycemia in obese diabetic db/db mice. J Mol Med 93, 1235–1245 (2015). https://doi.org/10.1007/s00109-015-1303-1
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DOI: https://doi.org/10.1007/s00109-015-1303-1