Involvement of long non-coding RNAs in beta cell failure at the onset of type 1 diabetes in NOD mice

Abstract

Aims/hypothesis Exposure of pancreatic beta cells to cytokines released by islet-infiltrating immune cells induces alterations in gene expression, leading to impaired insulin secretion and apoptosis in the initial phases of type 1 diabetes. Long non-coding RNAs (lncRNAs) are a new class of transcripts participating in the development of many diseases. As little is known about their role in insulin-secreting cells, this study aimed to evaluate their contribution to beta cell dysfunction. Methods The expression of lncRNAs was determined by microarray in the MIN6 beta cell line exposed to proinflammatory cytokines. The changes induced by cytokines were further assessed by real-time PCR in islets of control and NOD mice. The involvement of selected lncRNAs modified by cytokines was assessed after their overexpression in MIN6 cells and primary islet cells. Results MIN6 cells were found to express a large number of lncRNAs, many of which were modified by cytokine treatment. The changes in the level of selected lncRNAs were confirmed in mouse islets and an increase in these lncRNAs was also seen in prediabetic NOD mice. Overexpression of these lncRNAs in MIN6 and mouse islet cells, either alone or in combination with cytokines, favoured beta cell apoptosis without affecting insulin production or secretion. Furthermore, overexpression of lncRNA-1 promoted nuclear translocation of nuclear factor of κ light polypeptide gene enhancer in B cells 1 (NF-κB).Conclusions/interpretation Our study shows that lncRNAs are modulated during the development of type 1 diabetes in NOD mice, and that their overexpression sensitises beta cells to apoptosis, probably contributing to their failure during the initial phases of the disease.

Biomarkers of β-Cell Stress and Death in Type 1 Diabetes

“…To date, however, studies are limited with respect to the expression and function of lncRNAs in the β-cell. A recent study in mouse β-cell-derived cell lines and NOD mouse islets showed that lncRNAs 1-4 are strongly upregulated in response to proinflammatory cytokines and disease progression, respectively [75]. Carter et al [76] showed that in humans, the lncRNA GAS5 was negatively correlated with the prevalence of type 2 diabetes in a Veteran’s Administration cohort.…”

Long non-coding RNA ASncmtRNA-2 is upregulated in diabetic kidneys and high glucose-treated mesangial cells

“…Although it has recently been revealed that lncRNAs are associated with the progression of DM (17), no lncRNA of mitochondrial origin has been identified that is associated with DM or its complications. It is well-documented that mitochondria maintain ROS levels; high levels of ROS induce dysfunction of mitochondria, which in turn produce ROS at a higher rate (18).…”

EVI1 promotes cell proliferation in HBx-induced hepatocarcinogenesis as a critical transcription factor regulating lncRNAs

“…A large number of experiments and studies have performed and found the dysregulated lncRNAs profiles of various diseases in mouse models [28–30]. However, an important different feature between lncRNAs and protein-coding genes are in the evolutionary conservation [10, 31].…”