Dietary and genetic control of glucose transporter 2 glycosylation promotes insulin secretion in suppressing diabetes
Dietary and genetic control of glucose transporter 2 glycosylation promotes insulin secretion in suppressing diabetes
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DOI：
10.1016/j.cell.2005.09.041
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发表时间：
2005-12-29
期刊：
影响因子：
64.5
通讯作者：
Marth, JD
中科院分区：
文献类型：
--
作者：
Ohtsubo, K;Takamatsu, S;Marth, JD
胰腺细胞表面葡萄糖转运蛋白2 （Glut-2）的表达对于葡萄糖刺激的胰岛素分泌至关重要，从而控制血糖稳态以应对饮食摄入。我们通过构建胰腺凝集素受体的细胞型和糖蛋白特异性n-聚糖配体，证明小鼠GlcNAcT-IVa糖基转移酶是Glut-2在细胞表面停留所必需的。GlcNAcT-IVa的缺失，或蔗糖配体模拟物的加入，会缩短Glut-2细胞表面的半衰期，引发内吞作用，并重新进入核内体和溶酶体。随后葡萄糖刺激的胰岛素分泌受损导致2型糖尿病的代谢功能障碍诊断。值得注意的是，长期摄入高脂肪饮食诱导的糖尿病与GlcNAcT-IV表达降低和glut2糖基化减弱相关，这与glut2内吞作用一致。我们推断β细胞葡萄糖转运体糖基化介导了饮食和胰岛素产生之间的联系，而胰岛素产生通常抑制2型糖尿病的发病机制。
Pancreatic beta cell-surface expression of glucose transporter 2 (Glut-2) is essential for glucose-stimulated insulin secretion, thereby controlling blood glucose homeostasis in response to dietary intake. We show that the murine GlcNAcT-IVa glycosyltransferase is required for Glut-2 residency on the 0 cell surface by constructing a cell-type and glycoprotein-specific N-glycan ligand for pancreatic lectin receptors. Loss of GlcNAcT-IVa, or the addition of glycan ligand mimetics, attenuates Glut-2 cell surface half-life, provoking endocytosis with redistribution into endosomes and lysosomes. The ensuing impairment of glucose-stimulated insulin secretion leads to metabolic dysfunction diagnostic of type 2 diabetes. Remarkably, the induction of diabetes by chronic ingestion of a high-fat diet is associated with reduced GlcNAcT-IV expression and attenuated Glut-2 glycosylation coincident with Glut-2 endocytosis. We infer that beta cell glucose-transporter glycosylation mediates a link between diet and insulin production that typically suppresses the pathogenesis of type 2 diabetes.