Betacellulin ameliorates hyperglycemia in obese diabetic db/db mice.

Abstract

UNLABELLED:

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.

KEY MESSAGES:

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: Yoon Sin Oh, Seungjin Shin, Hui Ying Li, Eun-Young Park, Song Mi Lee, Cheol Soo Choi, Yong Lim, Hye Seung Jung, Hee-Sook Jun
• Journal: Journal of molecular medicine (Berlin, Germany) (J Mol Med (Berl)) Vol. 93 Issue 11 Pg. 1235-45 (Nov 2015) ISSN: 1432-1440 [Electronic] Germany
• PMID: 26070436 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Betacellulin
• Hypoglycemic Agents
• Insulin
• MicroRNAs
• Recombinant Proteins

Topics

• Adenoviridae (genetics)
• Animals
• Apoptosis
• Betacellulin (administration & dosage, genetics)
• Calcium Signaling
• Cell Cycle
• Hyperglycemia (drug therapy)
• Hypoglycemic Agents (administration & dosage)
• Insulin (blood, metabolism)
• Insulin-Secreting Cells (cytology, drug effects)
• Mice
• Mice, Obese
• MicroRNAs (pharmacology, therapeutic use)
• Recombinant Proteins (administration & dosage)