Department of Integrative Biology & Physiology, University of Minnesota Medical School, University of Minnesota, Minneapolis, Minnesota, USA.
Department of Surgery, University of Minnesota Medical School, University of Minnesota, Minneapolis, Minnesota, USA.
J Diabetes Res. 2020 Dec 16;2020:8872639. doi: 10.1155/2020/8872639. eCollection 2020.
The purpose of this review is to integrate the role of nutrient-sensing pathways into -cell organelle dysfunction prompted by nutrient excess during type 2 diabetes (T2D). T2D encompasses chronic hyperglycemia, hyperlipidemia, and inflammation, which each contribute to -cell failure. These factors can disrupt the function of critical -cell organelles, namely, the ER, mitochondria, lysosomes, and autophagosomes. Dysfunctional organelles cause defects in insulin synthesis and secretion and activate apoptotic pathways if homeostasis is not restored. In this review, we will focus on mTORC1 and OGT, two major anabolic nutrient sensors with important roles in -cell physiology. Though acute stimulation of these sensors frequently improves -cell function and promotes adaptation to cell stress, chronic and sustained activity disturbs organelle homeostasis. mTORC1 and OGT regulate organelle function by influencing the expression and activities of key proteins, enzymes, and transcription factors, as well as by modulating autophagy to influence clearance of defective organelles. In addition, mTORC1 and OGT activity influence islet inflammation during T2D, which can further disrupt organelle and -cell function. Therapies for T2D that fine-tune the activity of these nutrient sensors have yet to be developed, but the important role of mTORC1 and OGT in organelle homeostasis makes them promising targets to improve -cell function and survival.
这篇综述的目的是整合营养感应途径在 2 型糖尿病（T2D）期间营养过剩引起的 -细胞细胞器功能障碍中的作用。T2D 包括慢性高血糖、高血脂和炎症，这些都促成了 -细胞衰竭。这些因素会破坏关键的 -细胞细胞器的功能，即内质网、线粒体、溶酶体和自噬体。如果不能恢复体内平衡，功能失调的细胞器会导致胰岛素合成和分泌缺陷，并激活凋亡途径。在这篇综述中，我们将重点讨论 mTORC1 和 OGT，这两种主要的合成代谢营养传感器在 -细胞生理学中具有重要作用。尽管这些传感器的急性刺激经常改善 -细胞功能并促进对细胞应激的适应，但慢性和持续的活动会扰乱细胞器的体内平衡。mTORC1 和 OGT 通过影响关键蛋白质、酶和转录因子的表达和活性，以及通过调节自噬来影响有缺陷的细胞器的清除，来调节细胞器功能。此外，mTORC1 和 OGT 的活性会影响 T2D 期间胰岛的炎症，这会进一步破坏细胞器和 -细胞功能。尚未开发出微调这些营养传感器活性的 T2D 疗法，但 mTORC1 和 OGT 在细胞器体内平衡中的重要作用使它们成为改善 -细胞功能和生存的有前途的靶点。
