Nrf2/antioxidant pathway mediates β cell self-repair after damage by high-fat diet-induced oxidative stress
Nrf2/antioxidant pathway mediates β cell self-repair after damage by high-fat diet-induced oxidative stress
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DOI：
10.1172/jci.insight.92854
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发表时间：
2017-12-21
期刊：
影响因子：
8
通讯作者：
Robertson, R. Paul
中科院分区：
文献类型：
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作者：
Abebe, Tsehay;Mahadevan, Jana;Robertson, R. Paul
为了更好地理解为什么β细胞功能和结构在2型糖尿病（T2D）过程中不断恶化，已经提出了许多理论。这些理论包括炎症、细胞凋亡、复制、新生、自噬、分化、去分化和胰岛素基因调节蛋白水平降低。然而，这些都没有考虑到现有β细胞的内源性自我修复可能是一个重要因素。为了验证这一假设，我们对雌性Zucker糖尿病脂肪大鼠进行了研究，喂食高脂肪饮食（HFD） 1、2、4、7、9、18或28天，然后恢复正常饮食2-3周。修复被定义为逆转由HFD引起的血糖升高和不适当的低血胰岛素水平，以及逆转成像研究显示的结构损伤。我们观察到暴露于高脂饲料9天后β细胞功能性损伤的证据，然后在恢复正常食物2-3周后修复（血糖[BG] = 348 +/- 30 vs 126 +/- 3; mg/dl；第9天vs. 23天，P < 0.01）。暴露于HFD 18- 28天后，损伤更严重，修复不明显。暴露于HFD 9天后，胰岛素水平逐渐降低；在恢复正常饮食后，胰岛素水平反弹到正常值，但没有达到正常值。9天后β细胞质量增加了4倍，18天后增加了3倍，28天后没有增加。在9天、18天或28天的研究中，比较恢复正常饮食前后，HFD期间β细胞质量的增加并没有什么不同。细胞凋亡和细胞复制未见变化。细胞内氧化应激标志物的形成、Nrf2的核内易位以及细胞内抗氧化蛋白的形成表明HFD/氧化应激参与了Nrf2/抗氧化途径的诱导。基于流式细胞术的β细胞体积、形态和胰岛素特异性免疫反应性评估，以及透射电镜的超微结构分析显示，短期暴露于HFD会产生β细胞形态和功能的显著变化，这些变化在恢复正常饮食后是可逆的。这些结果表明，短期暴露于HFD后介导β细胞自我修复能力的可能机制是Nrf2/抗氧化途径的激活。
Many theories have been advanced to better understand why beta cell function and structure relentlessly deteriorate during the course of type 2 diabetes (T2D). These theories include inflammation, apoptosis, replication, neogenesis, autophagy, differentiation, dedifferentiation, and decreased levels of insulin gene regulatory proteins. However, none of these have considered the possibility that endogenous self-repair of existing beta cells may be an important factor. To examine this hypothesis, we conducted studies with female Zucker diabetic fatty rats fed a highfat diet (HFD) for 1, 2, 4, 7, 9, 18, or 28 days, followed by a return to regular chow for 2-3 weeks. Repair was defined as reversal of elevated blood glucose and of inappropriately low blood insulin levels caused by a HFD, as well as reversal of structural damage visualized by imaging studies. We observed evidence of functional beta cell damage after a 9-day exposure to a HFD and then repair after 2-3 weeks of being returned to normal chow (blood glucose [BG] = 348 +/- 30 vs. 126 +/- 3; mg/dl; days 9 vs. 23 day, P < 0.01). After 18-and 28-day exposure to a HFD, damage was more severe and repair was less evident. Insulin levels progressively diminished with 9-day exposure to a HFD; after returning to a regular diet, insulin levels rebounded toward, but did not reach, normal values. Increase in beta cell mass was 4-fold after 9 days and 3-fold after 18 days, and there was no increase after 28 days of a HFD. Increases in beta cell mass during a HFD were not different when comparing values before and after a return to regular diet within the 9-, 18-, or 28-day studies. No changes were observed in apoptosis or beta cell replication. Formation of intracellular markers of oxidative stress, intranuclear translocation of Nrf2, and formation of intracellular antioxidant proteins indicated the participation of HFD/oxidative stress induction of the Nrf2/antioxidant pathway. Flow cytometry-based assessment of beta cell volume, morphology, and insulin-specific immunoreactivity, as well as ultrastructural analysis by transmission electron microscopy, revealed that short-term exposure to a HFD produced significant changes in beta cell morphology and function that are reversible after returning to regular chow. These results suggest that a possible mechanism mediating the ability of beta cells to self-repair after a short-term exposure to a HFD is the activation of the Nrf2/antioxidant pathway.