AIMS/HYPOTHESIS Lipotoxicity constitutes the major driving force for type 2 diabetes. Circular RNAs (circRNAs) play important roles in regulating beta cell function and exosomes are essential mediators of intercellular communication. The role of exosomal circRNAs in type 2 diabetes remains largely unknown. We aimed to examine whether lipotoxicity induces dysregulation of circRNAs in beta cell-derived exosomes and to determine the contribution of exosomal circRNAs to the development of type 2 diabetes. METHODS Exosomes were extracted from MIN6 cells treated with palmitate or BSA, and RNA sequencing was performed. CircGlis3 (Gli-similar 3) expression level was validated by qPCR. The impact of circGlis3 on beta cell function and the deleterious effects of exosomal circGlis3 on islet endothelial cells (islet ECs) were investigated in vitro and in vivo in human and mouse models by gain or loss of function assays. The molecular mechanism of circGlis3 was explored by RNA pull-down and immunoprecipitation assays. RESULTS Beta cell-derived exosomal circGlis3 was significantly upregulated under lipotoxic conditions, and exosomal circGlis3 levels were also elevated in the serum of mouse models of diabetes and participants with type 2 diabetes. CircGlis3 participated in lipotoxicity-induced beta cell dysfunction in vitro and in vivo. Moreover, beta cell-derived exosomal circGlis3 could be transferred to islet ECs and reduce the cell viability, cell migration and angiogenesis of islet ECs. Mechanistically, circGlis3 promoted the degradation of glucocorticoid modulatory element-binding protein 1 (GMEB1) by facilitating the interaction between GMEB1 and mindbomb E3 ubiquitin protein ligase 2 (MIB2), thus suppressing the phosphorylation of heat shock protein 27 (HSP27). CONCLUSIONS/INTERPRETATION Our study points to the involvement of circGlis3 in diabetes development, and exosomal circGlis3 transfer as a communication mode between beta cells and islet ECs, suggesting that circGlis3 might be a potential biomarker and therapeutic target for type 2 diabetes. DATA AVAILABILITY The RNA-sequencing data have been deposited in the NCBI Sequence Read Archive (SRA) database, with accession number PRJNA689673. Mass spectrometry data are available via ProteomeXchange with identifier PXD024693.

中文翻译：

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脂毒性诱导的 circGlis3 损害 β 细胞功能，并通过外泌体传递以促进胰岛内皮细胞功能障碍。

目的/假设 脂毒性是 2 型糖尿病的主要驱动力。环状 RNA (circRNA) 在调节 β 细胞功能中发挥重要作用，外泌体是细胞间通讯的重要介质。外泌体 circRNA 在 2 型糖尿病中的作用仍然很大程度上未知。我们旨在检查脂毒性是否会诱导 β 细胞衍生的外泌体中 circRNA 的失调，并确定外泌体 circRNA 对 2 型糖尿病发展的贡献。方法从棕榈酸酯或BSA处理的MIN6细胞中提取外泌体，并进行RNA测序。CircGlis3 (Gli-similar 3) 表达水平通过 qPCR 验证。circGlis3 对 β 细胞功能的影响以及外泌体 circGlis3 对胰岛内皮细胞（胰岛 ECs）的有害影响在人和小鼠模型的体外和体内通过功能获得或损失测定进行了研究。circGlis3的分子机制通过RNA pull-down和免疫沉淀分析进行了探索。结果 β 细胞衍生的外泌体 circGlis3 在脂毒性条件下显着上调，并且在糖尿病小鼠模型和 2 型糖尿病参与者的血清中外泌体 circGlis3 水平也升高。CircGlis3 在体外和体内参与了脂毒性诱导的 β 细胞功能障碍。此外，β细胞衍生的外泌体circGlis3可以转移到胰岛内皮细胞，降低胰岛内皮细胞的细胞活力、细胞迁移和血管生成。机械地，circGlis3 通过促进 GMEB1 与 Mindbomb E3 泛素蛋白连接酶 2 (MIB2) 之间的相互作用促进糖皮质激素调节元件结合蛋白 1 (GMEB1) 的降解，从而抑制热休克蛋白 27 (HSP27) 的磷酸化。结论/解释 我们的研究指出 circGlis3 参与糖尿病的发展，以及外泌体 circGlis3 转移作为 β 细胞和胰岛 ECs 之间的通信模式，这表明 circGlis3 可能是 2 型糖尿病的潜在生物标志物和治疗靶点。数据可用性 RNA 测序数据已保存在 NCBI 序列读取存档 (SRA) 数据库中，登录号为 PRJNA689673。质谱数据可通过 ProteomeXchange 获得，标识符为 PXD024693。