Altered Extracellular Vesicle Concentration, Cargo, and Function in Diabetes
Altered Extracellular Vesicle Concentration, Cargo, and Function in Diabetes
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DOI：
10.2337/db17-1308
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发表时间：
2018-11-01
期刊：
影响因子：
7.7
通讯作者：
Evans, Michele K.
中科院分区：
文献类型：
--
作者：
Freeman, David W.;Noren Hooten, Nicole;Evans, Michele K.
2型糖尿病是一种慢性与年龄相关的退行性代谢疾病，反映了相对胰岛素缺乏和抵抗。细胞外囊泡（EVs）（外泌体、微囊泡和凋亡小体）是小的（30- 400nm）脂质结合囊泡，能够作为细胞间通讯系统的一部分，关闭功能性蛋白质、核酸和脂质。最近在小鼠模型和细胞培养中的研究表明，ev可能调节胰岛素信号传导。在这里，我们设计了血糖正常的参与者和糖尿病前期或糖尿病参与者的横断面和纵向队列。糖尿病患者血液循环中的ev水平明显高于血糖控制正常的参与者。通过细胞特异性EV测定，我们发现糖尿病患者红细胞源性EV水平较高。我们发现胰岛素抵抗会增加EV的分泌。此外，胰岛素抵抗和β细胞功能障碍患者的ev中胰岛素信号蛋白水平也发生了改变。此外，来自糖尿病患者的ev优先被循环白细胞内化。与糖尿病EVs孵育的单核细胞中，培养基和EVs中的细胞因子水平较高。这些白细胞的微阵列显示了与细胞存活、氧化应激和免疫功能相关的基因表达途径的改变。总之，这些结果表明，胰岛素抵抗增加了EVs的分泌，EVs优先被白细胞内化，并改变了白细胞的功能。
Type 2 diabetes is a chronic age-associated degenerative metabolic disease that reflects relative insulin deficiency and resistance. Extracellular vesicles (EVs) (exosomes, microvesicles, and apoptotic bodies) are small (30-400 nm) lipid-bound vesicles capable of shut-tling functional proteins, nucleic acids, and lipids as part of intercellular communication systems. Recent studies in mouse models and in cell culture suggest that EVs may modulate insulin signaling. Here, we designed cross-sectional and longitudinal cohorts of euglycemic participants and participants with prediabetes or diabetes. Individuals with diabetes had significantly higher levels of EVs in their circulation than euglycemic control participants. Using a cell-specific EV assay, we identified that levels of erythrocyte-derived EVs are higher with diabetes. We found that insulin resistance increases EV secretion. Furthermore, the levels of insulin signaling proteins were altered in EVs from individuals with high levels of insulin resistance and beta-cell dysfunction. Moreover, EVs from individuals with diabetes were preferentially internalized by circulating leukocytes. Cytokine levels in the media and in EVs were higher from monocytes incubated with diabetic EVs. Microarray of these leukocytes revealed altered gene expression pathways related to cell survival, oxidative stress, and immune function. Collectively, these results suggest that insulin resistance increases the secretion of EVs, which are preferentially internalized by leukocytes, and alters leukocyte function.