Prevention and Reversal of Diabetes by All-Trans Retinoid Acid and Exendin-4 in NOD Mice
Prevention and Reversal of Diabetes by All-Trans Retinoid Acid and Exendin-4 in NOD Mice
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DOI：
10.1155/2014/435481
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发表时间：
2014-01-01
影响因子：
2.8
通讯作者：
Chang, Han-Ying
中科院分区：
文献类型：
--
作者：
Juang, Jyuhn-Huarng;Van, Yang-Hau;Chang, Han-Ying
研究表明，全反式维甲酸（ATRA）通过诱导免疫耐受状态阻碍自身免疫性糖尿病的发展。同时，扩展蛋白-4增加β细胞的功能和质量。因此，我们假设ATRA和exendin-4联合治疗可以预防和逆转自身免疫性糖尿病。将从12周龄雌性NOD小鼠中分离的脾细胞静脉转移给NOD/scid小鼠。过继移植后，小鼠分别给予载药、ATRA（每隔一天腹腔注射0.5 mg/只）、exendin-4（每天两次皮下注射3 mu g/kg）或联合用药6周。与对照组相比，ATRA组（P = 0.022）和ATRA + exendin-4组（P = 0.013）延迟了糖尿病的发生。ATRA处理小鼠胰腺胰岛素含量（P = 0.013）和exendin-4 （P < 0.02）显著高于对照组。除一只自发性糖尿病NOD小鼠外，所有小鼠均接受ATRA和/或exendin-4治疗后仍持续高血糖。ATRA和/或exendin-4治疗没有改变他们的血糖水平和生存。我们的研究结果表明，在自身免疫性糖尿病发病前，ATRA和exendin-4单独治疗可以保护胰腺细胞；ATRA和ATRA加exendin-4治疗可延缓自身免疫性糖尿病的发病。然而，在自身免疫性糖尿病发病后，ATRA和/或exendin-4治疗无法逆转高血糖或提高生存率。
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 mu 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.