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International Journal of Endocrinology
Volume 2014, Article ID 435481, 5 pages
Research Article

Prevention and Reversal of Diabetes by All-Trans Retinoid Acid and Exendin-4 in NOD Mice

1Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung University and Chang Gung Memorial Hospital, 5 Fu-Shin Street, Kweishan, Taoyuan 333, Taiwan
2Division of Pediatric Endocrinology, Department of Pediatrics, Chang Gung Memorial Hospital, 5 Fu-Shin Street, Kweishan, Taoyuan 333, Taiwan
3Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute of Taiwan, 195 Sec. 4, Chung Hsing Road, Chutung, Hsinchu 31040, Taiwan

Received 21 December 2013; Revised 1 May 2014; Accepted 15 May 2014; Published 3 June 2014

Academic Editor: Tien-Jyun Chang

Copyright © 2014 Jyuhn-Huarng Juang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


It has been shown that all-trans retinoid acid (ATRA) hinders the development of autoimmune diabetes by inducing immune tolerance status. Meanwhile, exendin-4 increases beta-cell function and mass. Thus, we hypothesized that ATRA and exendin-4 combination therapy would prevent and reverse autoimmune diabetes. NOD/scid mice were intravenously transferred with splenocytes isolated from 12-week-old female NOD mice. After adoptive transfer, mice were treated with vehicle, ATRA (0.5 mg/mouse intraperitoneally every other day), exendin-4 (3 μg/kg subcutaneously twice daily), or combination for 6 weeks. Compared with vehicle, ATRA ( ) and ATRA plus exendin-4 ( ) treatment delayed the onset of diabetes. The pancreatic insulin content in mice treated with ATRA ( ) and exendin-4 ( ) was significantly higher than that of control mice. All but one spontaneous diabetic NOD mouse treated with ATRA and/or exendin-4 remained persistent hyperglycemic. ATRA and/or exendin-4 treatment did not alter their blood glucose levels and survival. Our results indicate that, before the onset of autoimmune diabetes, ATRA and exendin-4 treatment alone preserves pancreatic beta cells; ATRA and ATRA plus exendin-4 treatment delays the onset of autoimmune diabetes. However, after the onset of autoimmune diabetes, ATRA and/or exendin-4 treatment is unable to reverse hyperglycemia or improve survival.