title: Prevention and Reversal of Diabetes by All-Trans Retinoid Acid and Exendin-4 in NOD Mice.
abstract: 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  μ g/kg subcutaneously twice daily), or combination for 6 weeks. Compared with vehicle, ATRA (P = 0.022) and ATRA plus exendin-4 (P = 0.013) treatment delayed the onset of diabetes. The pancreatic insulin content in mice treated with ATRA (P = 0.013) and exendin-4 (P < 0.02) 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.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung University and Chang Gung Memorial Hospital, 5 Fu-Shin Street, Kweishan, Taoyuan 333, Taiwan.
authors.forename: Jyuhn-Huarng
authors.identifier: 0000-0003-1544-6059
authors.initials: JH
authors.lastname: Juang
authors.affiliation: Division of Pediatric Endocrinology, Department of Pediatrics, Chang Gung Memorial Hospital, 5 Fu-Shin Street, Kweishan, Taoyuan 333, Taiwan.
authors.forename: Yang-Hau
authors.initials: YH
authors.lastname: Van
authors.affiliation: Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute of Taiwan, 195 Sec. 4, Chung Hsing Road, Chutung, Hsinchu 31040, Taiwan.
authors.forename: Chien-Hung
authors.initials: CH
authors.lastname: Kuo
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung University and Chang Gung Memorial Hospital, 5 Fu-Shin Street, Kweishan, Taoyuan 333, Taiwan.
authors.forename: Mei-Yin
authors.initials: MY
authors.lastname: Lin
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung University and Chang Gung Memorial Hospital, 5 Fu-Shin Street, Kweishan, Taoyuan 333, Taiwan.
authors.forename: Ying-Hsiu
authors.initials: YH
authors.lastname: Liu
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung University and Chang Gung Memorial Hospital, 5 Fu-Shin Street, Kweishan, Taoyuan 333, Taiwan.
authors.forename: Han-Ying
authors.initials: HY
authors.lastname: Chang