雌激素促进错误折叠的胰岛素原降解以保护胰岛素产生并延缓糖尿病。
Estrogens Promote Misfolded Proinsulin Degradation to Protect Insulin Production and Delay Diabetes.
机构信息
Diabetes Discovery Research and Gender Medicine Laboratory, Department of Medicine, Section of Endocrinology and Metabolism, School of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
Diabetes Discovery Research and Gender Medicine Laboratory, Department of Medicine, Section of Endocrinology and Metabolism, School of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Healthcare System Medical Center, New Orleans, LA 70112, USA.
出版信息
Cell Rep. 2018 Jul 3;24(1):181-196. doi: 10.1016/j.celrep.2018.06.019.
Conjugated estrogens (CE) delay the onset of type 2 diabetes (T2D) in postmenopausal women, but the mechanism is unclear. In T2D, the endoplasmic reticulum (ER) fails to promote proinsulin folding and, in failing to do so, promotes ER stress and β cell dysfunction. We show that CE prevent insulin-deficient diabetes in male and in female Akita mice using a model of misfolded proinsulin. CE stabilize the ER-associated protein degradation (ERAD) system and promote misfolded proinsulin proteasomal degradation. This involves activation of nuclear and membrane estrogen receptor-α (ERα), promoting transcriptional repression and proteasomal degradation of the ubiquitin-conjugating enzyme and ERAD degrader, UBC6e. The selective ERα modulator bazedoxifene mimics CE protection of β cells in females but not in males.
结合雌激素（CE）可延迟绝经后妇女 2 型糖尿病（T2D）的发病，但具体机制尚不清楚。在 T2D 中，内质网（ER）不能促进胰岛素原的折叠，而且不能折叠会导致 ER 应激和β细胞功能障碍。我们使用折叠错误的胰岛素原模型表明，CE 可预防雄性和雌性 Akita 小鼠的胰岛素缺乏型糖尿病。CE 稳定内质网相关蛋白降解（ERAD）系统并促进折叠错误的胰岛素原蛋白酶体降解。这涉及核和膜雌激素受体-α（ERα）的激活，促进泛素连接酶和 ERAD 降解物 UBC6e 的转录抑制和蛋白酶体降解。选择性 ERα 调节剂巴多昔芬模拟 CE 对女性而非男性β细胞的保护作用。
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