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Betacellulin ameliorates hyperglycemia in obese diabetic db/db mice

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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

  • Administration of BTC to db/db mice results in amelioration of hyperglycemia.

  • BTC stimulates beta-cell proliferation in db/db mice.

  • Ca2+ signaling was involved in BTC-induced beta-cell proliferation.

  • 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).

Conflict of interest

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

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Authors and Affiliations

  1. Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 7-45 Songdo-dong, Yeonsu-ku, Incheon, Korea

    Yoon Sin Oh, Hui Ying Li, Song Mi Lee, Cheol Soo Choi & Hee-Sook Jun

  2. Gachon Medical Research Institute, Gil Hospital, Incheon, Korea

    Yoon Sin Oh, Cheol Soo Choi & Hee-Sook Jun

  3. Northwestern University, Evanston, IL, USA

    Seungjin Shin

  4. Department of Microbiology, Chosun University College of Medicine, Chonnam, Korea

    Yong Lim

  5. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea

    Hye Seung Jung

  6. College of Pharmacy, Gachon University, Incheon, Korea

    Hui Ying Li, Song Mi Lee & Hee-Sook Jun

  7. College of Pharmacy, Mokpo National University, Jeonnam, Korea

    Eun-Young Park

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  1. Yoon Sin Oh
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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

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