title: Betacellulin ameliorates hyperglycemia in obese diabetic db/db mice.
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 Ca(2+) 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 Ca(2+) signaling pathways.
  
  
  CONCLUSIONS
  Administration of BTC to db/db mice results in amelioration of hyperglycemia. BTC stimulates beta-cell proliferation in db/db mice. Ca(2+) signaling was involved in BTC-induced beta-cell proliferation. BTC has an anti-apoptotic effect and potentiates glucose-stimulated insulin secretion.
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 7-45 Songdo-dong, Yeonsu-ku, Incheon, Korea.|Gachon Medical Research Institute, Gil Hospital, Incheon, Korea.
authors.forename: Yoon Sin
authors.initials: YS
authors.lastname: Oh
authors.affiliation: Northwestern University, Evanston, IL, USA.
authors.forename: Seungjin
authors.initials: S
authors.lastname: Shin
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 7-45 Songdo-dong, Yeonsu-ku, Incheon, Korea.|College of Pharmacy, Gachon University, Incheon, Korea.
authors.forename: Hui Ying
authors.initials: HY
authors.lastname: Li
authors.affiliation: College of Pharmacy, Mokpo National University, Jeonnam, Korea.
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Park
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 7-45 Songdo-dong, Yeonsu-ku, Incheon, Korea.|College of Pharmacy, Gachon University, Incheon, Korea.
authors.forename: Song Mi
authors.initials: SM
authors.lastname: Lee
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 7-45 Songdo-dong, Yeonsu-ku, Incheon, Korea.|Gachon Medical Research Institute, Gil Hospital, Incheon, Korea.
authors.forename: Cheol Soo
authors.initials: CS
authors.lastname: Choi
authors.affiliation: Department of Microbiology, Chosun University College of Medicine, Chonnam, Korea.
authors.forename: Yong
authors.initials: Y
authors.lastname: Lim
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Hye Seung
authors.initials: HS
authors.lastname: Jung
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 7-45 Songdo-dong, Yeonsu-ku, Incheon, Korea. hsjun@gachon.ac.kr.|Gachon Medical Research Institute, Gil Hospital, Incheon, Korea. hsjun@gachon.ac.kr.|College of Pharmacy, Gachon University, Incheon, Korea. hsjun@gachon.ac.kr.
authors.forename: Hee-Sook
authors.initials: HS
authors.lastname: Jun
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D066259:Betacellulin / Q000008:administration & dosage* / Q000235:genetics; D020013:Calcium Signaling; D002453:Cell Cycle; D006943:Hyperglycemia / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007328:Insulin / Q000097:blood / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008820:Mice, Obese; D035683:MicroRNAs / Q000494:pharmacology* / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000008:administration & dosage
chemical_list: D066259:Betacellulin; D007004:Hypoglycemic Agents; D007328:Insulin; D035683:MicroRNAs; D011994:Recombinant Proteins
keywords: Beta cell regeneration; Betacellulin; Calcineurin B1; Cell cycle; db/db mice