Type-2 diabetes mellitus (T2DM) is a complex disease characterized by reduced pancreatic islets β-cell mass and impaired insulin release from these cells. Non-coding RNAs, including microRNAs (miRNA) and long non-coding RNAs (lncRNAs), play a role in the progression of T2DM. Decreased serum lncRNA GAS5 levels were reported to be associated with T2DM. However, the role of GAS5 in regulating islet cell functions remain unknown. In this study, we found that the serum levels of GAS5 were significantly lower in patients with T2DM compared with healthy control subjects, and the low serum GAS5 levels were associated with high levels of HbAlc and fasting glucose in patients with T2DM. In addition, we found that serum GAS5 levels were negatively correlated with the serum levels of miR-29a-3p, miR-96-3p, and miR-208a-3p in patients with T2DM. Consequently, using INS-1 832/13 rat β-cell line, we found that overexpression of GAS5 by lentivirus infection increased glucose-stimulated insulin secretion and insulin content compared with negative control, whereas knockdown of GAS5 expression reduced both them. Moreover, GAS5 interacted with miR-29a-3p, miR-96-3p, and miR-208a-3p in INS-1 832/13 cells, as judged by pull-down assay and dual luciferase reporter assay. GAS5 overexpression caused the decrease in expression of miR-29a-3p, miR-96-3p, and miR-208a-3p in INS-1 832/13 cells and conversely caused the increase in expression of insulin receptor, insulin receptor substrate, and phosphoinositide-3-kinase regulatory subunit 1. Thus, these results reveal a novel mechanism whereby GAS5 is involved in maintaining insulin secretion and may represent a novel therapeutic target for T2DM.

2型糖尿病（T2DM）是一种复杂的疾病，其特征在于胰岛β细胞数量减少和这些细胞的胰岛素释放受损。非编码RNA，包括microRNA（miRNA）和长非编码RNA（lncRNA），在T2DM的进程中起作用。据报道血清lncRNA GAS5水平降低与T2DM有关。然而，GAS5在调节胰岛细胞功能中的作用仍然未知。在这项研究中，我们发现与健康对照组相比，T2DM患者的GAS5血清水平显着降低，而低血清GAS5与T2DM患者的HbAlc和空腹血糖高有关。此外，我们发现T2DM患者的血清GAS5水平与miR-29a-3p，miR-96-3p和miR-208a-3p血清水平呈负相关。所以，使用INS-1 832/13大鼠β细胞系，我们发现慢病毒感染引起的GAS5过表达与阴性对照组相比增加了葡萄糖刺激的胰岛素分泌和胰岛素含量，而敲低GAS5表达则降低了两者。此外，通过下拉测定法和双重荧光素酶报告基因测定法判断，GAS5与INS-1 832/13细胞中的miR-29a-3p，miR-96-3p和miR-208a-3p相互作用。GAS5的过度表达导致INS-1 832/13细胞中miR-29a-3p，miR-96-3p和miR-208a-3p的表达降低，反之则导致胰岛素受体，胰岛素受体底物和磷酸肌醇-3-激酶调节亚基1。因此，这些结果揭示了一种新的机制，其中GAS5参与维持胰岛素的分泌，可能代表T2DM的新治疗靶点。