Pharmacological Inhibition of Inositol-Requiring Enzyme 1α RNase Activity Protects Pancreatic Beta Cell and Improves Diabetic Condition in Insulin Mutation-Induced Diabetes.
Pharmacological Inhibition of Inositol-Requiring Enzyme 1α RNase Activity Protects Pancreatic Beta Cell and Improves Diabetic Condition in Insulin Mutation-Induced Diabetes.
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DOI：
10.3389/fendo.2021.749879
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发表时间：
2021
影响因子：
5.2
通讯作者：
Wang W
中科院分区：
文献类型：
--
作者：
Herlea-Pana O;Eeda V;Undi RB;Lim HY;Wang W
β细胞内质网应激在糖尿病发病过程中β细胞功能障碍和死亡中起重要作用。胰岛素原错误折叠被认为是β细胞中ER应激和未折叠蛋白反应（unfolded protein response，UPR）激活的主要起始因素之一。在这里，我们发现ER应激传感器肌醇需要酶1α（IRE1α）在秋田小鼠中被激活，秋田小鼠是突变胰岛素基因诱导的青年糖尿病（MIDY）的小鼠模型，一种单基因糖尿病。通过药理学抑制剂使IRE1α RNase高活性正常化显著改善了秋田小鼠的高血糖状况并增加了血清胰岛素水平。这些益处伴随着功能性β细胞群的伴随保护，如通过抑制β细胞凋亡、增加成熟胰岛素产生和降低胰岛素原水平所示。在分子水平上，我们观察到，在用IRE1α RNase抑制剂处理的秋田小鼠胰岛中，与β细胞身份和功能相关的基因表达显著上调，ER应激及其相关的炎症和氧化应激受到抑制。本研究提供了IRE1α RNase抑制剂在秋田小鼠体内有效性的证据，指出靶向IRE1α RNase作为糖尿病治疗方向的可能性。
β-cell ER stress plays an important role in β-cell dysfunction and death during the pathogenesis of diabetes. Proinsulin misfolding is regarded as one of the primary initiating factors of ER stress and unfolded protein response (UPR) activation in β-cells. Here, we found that the ER stress sensor inositol-requiring enzyme 1α (IRE1α) was activated in the Akita mice, a mouse model of mutant insulin gene-induced diabetes of youth (MIDY), a monogenic diabetes. Normalization of IRE1α RNase hyperactivity by pharmacological inhibitors significantly ameliorated the hyperglycemic conditions and increased serum insulin levels in Akita mice. These benefits were accompanied by a concomitant protection of functional β-cell mass, as shown by the suppression of β-cell apoptosis, increase in mature insulin production and reduction of proinsulin level. At the molecular level, we observed that the expression of genes associated with β-cell identity and function was significantly up-regulated and ER stress and its associated inflammation and oxidative stress were suppressed in islets from Akita mice treated with IRE1α RNase inhibitors. This study provides the evidence of the in vivo efficacy of IRE1α RNase inhibitors in Akita mice, pointing to the possibility of targeting IRE1α RNase as a therapeutic direction for the treatment of diabetes.
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影响因子：
16.6
作者：
Back SH;Kaufman RJ
通讯作者：
Kaufman RJ
影响因子：
16
作者：
Harding, HP;Zhang, YH;Ron, D
通讯作者：
Ron, D
DOI：
10.1073/pnas.1906999116
发表时间：
2019-08-13
影响因子：
11.1
作者：
Harnoss, Jonathan M.;Le Thomas, Adrien;Ashkenazi, Avi
通讯作者：
Ashkenazi, Avi
DOI：
10.1073/pnas.1115623109
发表时间：
2012-04-10
影响因子：
11.1
作者：
Cross, Benedict C. S.;Bond, Peter J.;Harding, Heather P.
通讯作者：
Harding, Heather P.
影响因子：
64.5
作者：
Ghosh R;Wang L;Wang ES;Perera BG;Igbaria A;Morita S;Prado K;Thamsen M;Caswell D;Macias H;Weiberth KF;Gliedt MJ;Alavi MV;Hari SB;Mitra AK;Bhhatarai B;Schürer SC;Snapp EL;Gould DB;German MS;Backes BJ;Maly DJ;Oakes SA;Papa FR
通讯作者：
Papa FR