Jo Seokwon, Esch Nicholas, Nguyen Anh, Wong Alicia, Mohan Ramkumar, Kim Clara, Blandino-Rosano Manuel, Bernal-Mizrachi Ernesto, Alejandro Emilyn U
Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
Department of Internal Medicine, Division of Endocrinology, Metabolism and Diabetes, Miller School of Medicine, University of Miami, Miami, Florida, USA.
JCI Insight. 2024 Dec 6;9(23):e183033. doi: 10.1172/jci.insight.183033.
Type 2 diabetes (T2D) arises when pancreatic β cells fail to produce sufficient insulin to control blood glucose appropriately. Aberrant nutrient sensing by O-GlcNAcylation and mTORC1 is linked to T2D and the failure of insulin-producing β cells. However, the nature of their crosstalk in β cells remains unexplored. Recently, O-GlcNAcylation, a posttranslation modification controlled by enzymes O-GlcNAc transferase/O-GlcNAcase (OGT/OGA), emerged as a pivotal regulator for β cell health; deficiency in either enzyme causes β cell failure. The present study investigates the previously unidentified connection between nutrient sensor OGT and mTORC1 crosstalk to regulate β cell mass and function in vivo. We show reduced OGT and mTORC1 activity in islets of a preclinical β cell dysfunction model and islets from humans with obesity. Using loss or gain of function of OGT, we identified that O-GlcNAcylation positively regulated mTORC1 signaling in β cells. O-GlcNAcylation negatively modulated autophagy, as the removal of OGT increased autophagy, while the deletion of OGA decreased it. Increasing mTORC1 signaling, via deletion of TSC2, alleviated the diabetic phenotypes by increasing β cell mass but not β cell function in OGT-deficient mice. Downstream phospho-protein signaling analyses revealed diverging effects on MKK4 and calmodulin signaling between islets with OGT, TSC2, or combined deletion. These data provide evidence of OGT's significance as an upstream regulator of mTORC1 and autophagy, crucial for the regulation of β cell function and glucose homeostasis.
当胰腺β细胞无法产生足够的胰岛素来适当控制血糖时，就会发生2型糖尿病（T2D）。O-连接N-乙酰葡糖胺化（O-GlcNAcylation）和哺乳动物雷帕霉素靶蛋白复合物1（mTORC1）对营养物质的异常感知与T2D以及产生胰岛素的β细胞功能衰竭有关。然而，它们在β细胞中的相互作用本质仍未得到探索。最近，O-GlcNAcylation这种由O-连接N-乙酰葡糖胺转移酶/ O-连接N-乙酰葡糖胺酶（OGT / OGA）控制的翻译后修饰，成为β细胞健康的关键调节因子；这两种酶中的任何一种缺乏都会导致β细胞功能衰竭。本研究调查了营养传感器OGT与mTORC1相互作用之间以前未被发现的联系，以调节体内β细胞的数量和功能。我们发现，在临床前β细胞功能障碍模型的胰岛以及肥胖人类的胰岛中，OGT和mTORC1的活性降低。通过使用OGT功能丧失或增强的方法，我们确定O-GlcNAcylation在β细胞中正向调节mTORC1信号传导。O-GlcNAcylation负向调节自噬，因为去除OGT会增加自噬，而删除OGA则会减少自噬。通过删除结节性硬化复合物2（TSC2）来增加mTORC1信号传导，可通过增加β细胞数量而非β细胞功能来减轻OGT缺陷小鼠的糖尿病表型。下游磷酸化蛋白信号分析显示了OGT、TSC2或联合缺失的胰岛之间对丝裂原活化蛋白激酶4（MKK4）和钙调蛋白信号传导的不同影响。这些数据证明了OGT作为mTORC1和自噬上游调节因子的重要性，这对β细胞功能和葡萄糖稳态的调节至关重要。
