Lund Institute of Advanced Neutron and X-ray Science (LINXS), Lund, Sweden.
Department of Clinical Sciences, Lund University, Malmö, Sweden.
Biochim Biophys Acta Mol Basis Dis. 2020 Mar 1;1866(3):165613. doi: 10.1016/j.bbadis.2019.165613. Epub 2019 Nov 22.
The increase of plasma levels of high-density lipoproteins and Apolipoprotein A-I (ApoA-I), its main protein component, has been shown to have a positive action on glucose disposal in type 2 diabetic patients. The current study investigates the unexplored function of ApoA-I to prime beta cells for improved insulin secretion. INS-1E rat clonal beta cells as well as isolated murine islets were used to study the effect of ApoA-I on responsiveness of the beta cells to high glucose challenge. Confocal and transmission electron microscopy were used to dissect ApoA-I mechanisms of action. Chemical endocytosis blockers were used to understand the role of ApoA-I internalization in mediating its positive effect. Pre-incubation of beta cells and isolated murine islets with ApoA-I augmented glucose stimulated insulin secretion. This effect appeared to be due to an increased reservoir of insulin granules at the cell membrane, as confirmed by confocal and transmission electron microscopy. Moreover, ApoA-I induced pancreatic and duodenal homeobox 1 (PDX1) shuttling from the cytoplasm to the nucleus, with the subsequent increase in the proinsulin processing enzyme protein convertase 1 (PC1/3). Finally, the blockade of ApoA-I endocytosis in beta cells resulted in a loss of ApoA-I positive action on insulin secretion. The proposed mechanisms of the phenomenon here described include ApoA-I internalization into beta cells, PDX1 nuclear translocation, and increased levels of proinsulin processing enzymes. Altogether, these events lead to an increased number of insulin granules.
高密度脂蛋白（HDL）和载脂蛋白 A-I（ApoA-I）的血浆水平升高已被证明对 2 型糖尿病患者的葡萄糖处置具有积极作用。本研究探讨了 ApoA-I 的一个尚未被探索的功能，即促使β细胞为改善胰岛素分泌做好准备。我们使用 INS-1E 大鼠克隆β细胞和分离的小鼠胰岛来研究 ApoA-I 对β细胞对高葡萄糖挑战的反应性的影响。共聚焦和透射电子显微镜用于剖析 ApoA-I 的作用机制。使用化学内吞作用阻滞剂来了解 ApoA-I 内化在介导其积极作用中的作用。β细胞和分离的小鼠胰岛预先用 ApoA-I 孵育可增强葡萄糖刺激的胰岛素分泌。该作用似乎是由于细胞膜上胰岛素颗粒的储备增加所致，共聚焦和透射电子显微镜证实了这一点。此外，ApoA-I 诱导胰腺十二指肠同源盒 1（PDX1）从细胞质向细胞核易位，随后增加胰岛素原加工酶蛋白转化酶 1（PC1/3）的水平。最后，β细胞中 ApoA-I 内吞作用的阻断导致 ApoA-I 对胰岛素分泌的积极作用丧失。此处描述的现象的提出的机制包括 ApoA-I 进入β细胞的内吞作用、PDX1 核易位以及胰岛素原加工酶水平的升高。总之，这些事件导致胰岛素颗粒数量增加。
