LncRNA-Malat1 is involved in lipotoxicity-induced β-cell dysfunction and the therapeutic effect of exendin-4 via Ptbp1

Increasing evidence indicates that long noncoding RNAs (lncRNAs) have
crucial roles in various biological processes. However, the contribution
of lncRNAs to β-cell dysfunction and their roles in diabetes therapeutics
remain poorly understood. The aim of this study was to identify the
lncRNAs dysregulated in diabetic islets and to explore the lncRNAs
involved in β-cell function as potential therapeutic targets. By using
RNA-sequencing and real-time PCR, we identified thousands of lncRNAs in
the islets of db/db mice and db/m littermate mice. Among the
differentially expressed lncRNAs, lncRNA-Malat1 (metastasis associated
lung adenocarcinoma transcript 1) was reduced in the islets of db/db mice
and palmitate-treated MIN6 cells. The results of TUNEL, western blot and
flow cytometric analyses and GSIS assays revealed that Malat1 knockdown
significantly induced β-cell apoptosis and inhibited insulin secretion.
Mechanistically, RNA-immunoprecipitation showed that Malat1 enhanced Ptbp1
(polypyrimidine tract-binding protein 1) protein stability by direct
interaction, thereby adjusting the ratio of PKM (pyruvate kinase muscle)
isoforms 1 and 2 (PKM1/PKM2). Moreover, luciferase assay and chromatin
immunoprecipitation indicated that Malat1 was transcriptionally activated
by Pdx1, through which exendin-4 alleviated lipotoxicity-induced β-cell
damage. In summary, our findings suggested the involvement of Malat1 in
β-cell dysfunction under diabetic conditions via the Malat1/Ptbp1/PKM2
pathway. In addition, exendin-4 ameliorated β-cell impairment by
Pdx1-mediated Malat1 upregulation. Hence, Malat1 may serve as a
therapeutic target for the treatment of type 2 diabetes.