胰岛素抵抗状态下肝细胞外泌体对胰岛beta细胞的调控及其机制研究

Insulin resistance and β cell dysfunction are regarded as two key factors causing type 2 diabetes (T2D), whereas the interconnection and interdependency between these two factors is believed to ultimately determine the development of diabetes. However, the mechanism underlying such interactions remains largely unknown. Exosomes have recently been recognized as a key transporter in mediating cell-cell communications. More recently, our preliminary data shows that insulin resistant hepatocyte-derived exosomes and their content of miRNA significantly differ from those isolated from normal hepatocytes. Moreover, insulin resistant hepatocytes can promote β cell apoptosis, and the effect of hepatocytes depends on their secretion of exosomes. These primary findings allow us hypothesizing that: Hepatocytes can remotely control β cell function under insulin resistant status via hepatic exosomes and their miRNA, leading to the development of diabetes. Based on this hypothesis, the current project aims to characterize the exosome-mediated interactions of hepatocytes with β cells under insulin resistance at a molecular, cellular, animal and patient’s level, respectively. We shall also identify the role of sphingolipids in regulation of exosome formation and secretion by hepatocytes. Finally, the project will utilize the resource of an established cohort and its 5-years follow-up to evaluate whether changes in circulating exosomes and their miRNA are associated with the onset of T2D and thus predict pre-diabetes and its progression.

胰岛素抵抗和β细胞功能障碍是2型糖尿病的两大致病因素，二者的相互影响是决定糖尿病发生发展的必要条件。但对于这种关联的调控却知之甚少。最近，外泌体作为细胞间联系的重要载体广受关注。我们的前期工作显示，胰岛素抵抗状态下肝细胞分泌的外泌体及其miRNA谱发生显著变化；依赖于外泌体分泌，胰岛素抵抗肝细胞可促进β细胞凋亡。基于这开拓性的前期工作，我们推测：胰岛素抵抗状态下肝细胞可通过外泌体及其miRNA对β细胞远程调控，影响糖尿病的发生发展。为此，本申请将从分子、细胞、动物和人群等四个层面，应用先进的实验手段，阐明这一新型的细胞间与组织间的作用机制。我们还将探索鞘磷脂信号在肝细胞外泌体形成与分泌过程中的调控机理，为该领域的研究带来新的突破。最后，我们将利用“长风队列”及其5年随访资源，检测外泌体miRNA在高危人群糖尿病发生发展过程中的变化，探索其在糖尿病前期的预测价值，为临床转化提供充实的基础。

肥胖和2型糖尿病是当今严重的全球性健康问题。特别在我国，随着人们生活水平的提高和生活习惯的改变，肥胖人群日益扩大，糖尿病发病率逐年增加，严重危害人类健康。普遍认为胰岛素抵抗是引发2型糖尿病的主要原因，而胰岛β细胞的生存及其代偿能力则是决定糖尿病发生发展的关键要素。因此，在肥胖和胰岛素抵抗状态下如何有效保护β细胞、促进其代偿，是亟待解决的重要科学问题和临床问题。本项研究首次揭示了在肥胖和胰岛素抵抗状态下，肝细胞可通过外泌体释放，经由外泌体中富含的miR-126a-3p通过抑制靶基因IRS1/2的表达，介导对胰岛β细胞的功能抑制和促进细胞凋亡，形成病理性“肝-胰岛β细胞轴”。我们还首次发现miR-126a-3p拮抗剂可逆转β细胞损伤，减缓实验小鼠糖尿病的发生发展。本研究不仅为揭示肝脏与胰岛β细胞的相互作用提供了新的理论和实验证据，也为肥胖、NAFLD在促进糖尿病发生发展中的作用阐明了新的机制，更为开发新的糖尿病防治方法提供了新的策略和新的干预靶点，具有重要的潜在应用价值。