Betacellulin ameliorates hyperglycemia in obese diabetic db/db mice
- Authors
- Oh, Yoon Sin; Shin, Seungjin; Li, Hui Ying; Park, Eun-Young; Lee, Song Mi; Choi, Cheol Soo; Lim, Yong; Jung, Hye Seung; Jun, Hee-Sook
- Issue Date
- Nov-2015
- Publisher
- SPRINGER HEIDELBERG
- Keywords
- Betacellulin; db/db mice; Cellcycle; Calcineurin B1; Beta cell regeneration
- Citation
- JOURNAL OF MOLECULAR MEDICINE-JMM, v.93, no.11, pp.1235 - 1245
- Journal Title
- JOURNAL OF MOLECULAR MEDICINE-JMM
- Volume
- 93
- Number
- 11
- Start Page
- 1235
- End Page
- 1245
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/9963
- DOI
- 10.1007/s00109-015-1303-1
- ISSN
- 0946-2716
- 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-beta-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-gamma 1 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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