Islet O-GlcNAcylation Is Required for Lipid Potentiation of Insulin Secretion through SERCA2.
Islet O-GlcNAcylation Is Required for Lipid Potentiation of Insulin Secretion through SERCA2.
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DOI：
10.1016/j.celrep.2020.107609
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发表时间：
2020-05-05
期刊：
影响因子：
8.8
通讯作者：
Alejandro EU
中科院分区：
文献类型：
--
作者：
Lockridge A;Jo S;Gustafson E;Damberg N;Mohan R;Olson M;Abrahante JE;Alejandro EU
在早期肥胖期间，胰腺β细胞通过胰岛素分泌过多的短暂阶段来补偿增加的代谢需求，从而稳定血糖并阻止糖尿病进展。我们发现的证据表明，β-细胞O-GlcNAc酰化，一种由OGT调节的营养响应性翻译后蛋白质修饰，对于在此代偿性糖尿病前期阶段将高脂血症与β-细胞功能适应偶联至关重要。在小鼠中，胰岛O-GlcNAc酰化在高脂喂养期间与分泌增强的时间时间轴同步上升和福尔斯，而β细胞特异性OGT损失的遗传模型在体内和体外消除了对脂质的高胰岛素血症反应。我们在小鼠和人类中鉴定了ER Ca 2 + ATP酶SERCA 2作为β细胞O-GlcNAc酰化蛋白，其能够通过药理学激活来拯救棕榈酸盐刺激的胰岛素分泌。这项研究揭示了β细胞O-GlcNAc化在感知和响应肥胖中的重要生理作用，对管理2型糖尿病及其最常见风险因素之间的关系具有治疗意义。
During early obesity, pancreatic β-cells compensate for increased metabolic demand through a transient phase of insulin hypersecretion that stabilizes blood glucose and forestalls diabetic progression. We found evidence that β-cell O-GlcNAcylation, a nutrient-responsive post-translational protein modification regulated by OGT, is critical for coupling hyperlipidemia to β-cell functional adaptation during this compensatory prediabetic phase. In mice, islet O-GlcNAcylation rises-and-falls in tandem with the timeline of secretory potentiation during high-fat feeding while genetic models of β-cell specific OGT loss abolish hyperinsulinemic responses to lipids, in vivo and in vitro. We identified the ER Ca2+ ATPase SERCA2 as a β-cell O-GlcNAcylated protein in mice and humans that was able to rescue palmitate-stimulated insulin secretion through pharmacological activation. This study reveals an important physiological role for β-cell O-GlcNAcylation in sensing and responding to obesity, with therapeutic implications for managing the relationship between type 2 diabetes and its most common risk factor.
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