Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
Department of Laboratory Medicine, Karolinska Institute, Huddinge, Sweden.
Diabetes. 2019 Mar;68(3):515-526. doi: 10.2337/db18-0470. Epub 2018 Dec 14.
miRNAs are noncoding RNAs representing an important class of gene expression modulators. Extracellular circulating miRNAs are both candidate biomarkers for disease pathogenesis and mediators of cell-to-cell communication. We examined the miRNA expression profile of total serum and serum-derived exosome-enriched extracellular vesicles in people with normal glucose tolerance or type 2 diabetes. In contrast to total serum miRNA, which did not reveal any differences in miRNA expression, we identified differentially abundant miRNAs in patients with type 2 diabetes using miRNA expression profiles of exosome RNA (exoRNA). To validate the role of these differentially abundant miRNAs on glucose metabolism, we transfected miR-20b-5p, a highly abundant exoRNA in patients with type 2 diabetes, into primary human skeletal muscle cells. miR-20b-5p overexpression increased basal glycogen synthesis in human skeletal muscle cells. We identified AKTIP and STAT3 as miR-20b-5p targets. miR-20b-5p overexpression reduced AKTIP abundance and insulin-stimulated glycogen accumulation. In conclusion, exosome-derived extracellular miR-20b-5p is a circulating biomarker associated with type 2 diabetes that plays an intracellular role in modulating insulin-stimulated glucose metabolism via AKT signaling.
miRNAs 是一类非编码 RNA，代表了基因表达调控的重要一类。细胞外循环 miRNA 既是疾病发病机制的候选生物标志物，也是细胞间通讯的介质。我们检查了糖耐量正常或 2 型糖尿病患者的总血清和富含血清衍生外泌体的细胞外囊泡中的 miRNA 表达谱。与总血清 miRNA 没有显示出任何 miRNA 表达差异相反，我们使用外泌体 RNA（exoRNA）的 miRNA 表达谱鉴定了 2 型糖尿病患者中差异丰富的 miRNAs。为了验证这些差异丰富的 miRNAs 在葡萄糖代谢中的作用，我们将在 2 型糖尿病患者中高度丰富的 exoRNA miR-20b-5p 转染到原代人骨骼肌细胞中。miR-20b-5p 的过表达增加了人骨骼肌细胞中的基础糖原合成。我们鉴定出 AKTIP 和 STAT3 是 miR-20b-5p 的靶标。miR-20b-5p 过表达降低了 AKTIP 的丰度和胰岛素刺激的糖原积累。总之，外泌体衍生的细胞外 miR-20b-5p 是与 2 型糖尿病相关的循环生物标志物，它通过 AKT 信号在调节胰岛素刺激的葡萄糖代谢中发挥细胞内作用。
