Yang Weixia, Sheng Feifei, Sun Baolan, Fischbach Shane, Xiao Xiangwei
, Department of Pediatrics, Affiliated Hospital of Nantong University, Nantong, China.
Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
Aging (Albany NY). 2019 May 6;11(9):2787-2796. doi: 10.18632/aging.101949.
Endoplasmic reticulum (ER) stress in beta cells induces a signaling network called the unfolded protein response (UPR), which plays a dual role in diabetes. A key regulator of ER-stress and UPR, the orosomucoid 1-like protein 3 (ORMDL3), has been shown to regulate airway remodeling through a major UPR protein, activating transcription factor 6 (ATF6), but the contribution of this regulatory axis to compensatory pancreatic beta cell proliferation in diabetes has not been studied. Here, we detected significantly lower levels of ORMDL3 mRNA in leukocytes of peripheral blood specimens from type 1 diabetes (T1D) children, compared to normal children. Moreover, these ORMDL3 levels in T1D children exhibited further decreases upon follow-up. ORMDL3 levels in islets from NOD mice, a mouse model for T1D in humans, showed a mild increase before diabetes onset, but a gradual decrease subsequently. In high glucose culture, beta cell proliferation, but not apoptosis, was increased by overexpression of ORMDL3 levels, likely mediated by its downstream factor ATF6. Mechanistically, ORMDL3 transcriptionally activated ATF6, which was confirmed in a promoter reporter assay. Together, our data suggest that ORMDL3 may increase beta cell proliferation through ATF6 as an early compensatory change in response to diabetes.
β细胞内质网应激会诱导一种名为未折叠蛋白反应（UPR）的信号网络，该网络在糖尿病中发挥双重作用。内质网应激和UPR的关键调节因子，类orosomucoid 1蛋白3（ORMDL3），已被证明可通过主要的UPR蛋白激活转录因子6（ATF6）来调节气道重塑，但该调节轴对糖尿病中胰腺β细胞代偿性增殖的作用尚未得到研究。在此，我们检测到与正常儿童相比，1型糖尿病（T1D）儿童外周血标本白细胞中ORMDL3 mRNA水平显著降低。此外，T1D儿童的这些ORMDL3水平在随访中进一步下降。人类T1D小鼠模型非肥胖糖尿病（NOD）小鼠胰岛中的ORMDL3水平在糖尿病发作前略有升高，但随后逐渐下降。在高糖培养中，ORMDL3水平的过表达增加了β细胞增殖，但未增加细胞凋亡，这可能由其下游因子ATF6介导。从机制上讲，ORMDL3转录激活了ATF6，这在启动子报告基因测定中得到证实。总之，我们的数据表明，ORMDL3可能通过ATF6增加β细胞增殖，作为对糖尿病的早期代偿性变化。
