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Published on: January 23, 2018
Glucocorticoid induces human beta cell dysfunction by involving riborepressor GAS5 LincRNA
Jonathan L S Esguerra1, Jones K Ofori1, Mototsugu Nagao2
1Islet Cell Exocytosis, Department of Clinical Sciences-Malmö, Lund University, Malmö, Sweden; Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden.
Objective:
A widely recognized metabolic side effect of glucocorticoid (GC) therapy is steroid-induced diabetes mellitus (DM). However, studies on the molecular basis of GC-induced pancreatic beta cell dysfunction in human beta cells are lacking. The significance of non-coding RNAs in various cellular processes is emerging. In this study, we aimed to show the direct negative impact of GC on beta cell function and elucidate the role of riborepressor GAS5 lincRNA in the GC signaling pathway in human pancreatic beta cells.
Methods:
Patients undergoing two weeks of high-dose prednisolone therapy were monitored for C-peptide levels. Human pancreatic islets and the human beta cell line EndoC-βH1 were incubated in pharmacological concentrations of dexamethasone. The GAS5 level was modulated using anti-sense LNA gapmeR or short oligonucleotides with GAS5 HREM (hormone response element motif). Immunoblotting and/or real-time PCR were used to assess changes in protein and RNA expression, respectively. Functional characterization included glucose-stimulated insulin secretion and apoptosis assays. Correlation analysis was performed on RNAseq data of human pancreatic islets.
Results:
We found reduced C-peptide levels in patients undergoing high-dose GC therapy. Human islets and the human beta cell line EndoC-βH1 exposed to GC exhibited reduced insulin secretion and increased apoptosis. Concomitantly, reduced expression of important beta cell transcription factors, PDX1 and NKX6-1, as well as exocytotic protein SYT13 were observed. The expression of the glucocorticoid receptor was decreased, while that of serum and glucocorticoid-regulated kinase 1 (SGK1) was elevated. The expression of these genes was found to significantly correlate with GAS5 in human islet transcriptomics data. Increasing GAS5 levels using GAS5 HREM alleviated the inhibitory effects of dexamethasone on insulin secretion.
Conclusions:
The direct adverse effect of glucocorticoid in human beta cell function is mediated via important beta cell proteins and components of the GC signaling pathway in an intricate interplay with GAS5 lincRNA, a potentially novel therapeutic target to counter GC-mediated beta cell dysfunction.
Insights
Glucocorticoid therapy impairs human beta cell function, reducing insulin secretion and increasing apoptosis. The long non-coding RNA GAS5 plays a key role in this process and may be a therapeutic target for steroid-induced diabetes.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- Glucocorticoid (GC) therapy is known to cause metabolic side effects like steroid-induced diabetes mellitus (DM).
- The molecular mechanisms underlying GC-induced pancreatic beta cell dysfunction in humans remain poorly understood.
- Non-coding RNAs are increasingly recognized for their roles in cellular processes.
Purpose of the Study:
- To investigate the direct impact of GCs on human beta cell function.
- To elucidate the role of the riborepressor GAS5 long intergenic non-coding RNA (lincRNA) in the GC signaling pathway within human pancreatic beta cells.
Main Methods:
- Monitoring C-peptide levels in patients on high-dose prednisolone.
- Incubating human islets and EndoC-βH1 cells with dexamethasone.
- Modulating GAS5 levels using anti-sense oligonucleotides and assessing protein/RNA expression via immunoblotting and real-time PCR.
- Evaluating glucose-stimulated insulin secretion and apoptosis.
Main Results:
- Reduced C-peptide levels observed in patients receiving high-dose GC therapy.
- GC exposure decreased insulin secretion and increased apoptosis in human islets and beta cells.
- GCs altered the expression of key beta cell factors (PDX1, NKX6-1) and signaling molecules (GR, SGK1), with significant correlation to GAS5 levels.
- Increasing GAS5 expression ameliorated the inhibitory effects of dexamethasone on insulin secretion.
Conclusions:
- Glucocorticoids directly impair human beta cell function through interactions with critical beta cell proteins and GC signaling pathway components.
- GAS5 lincRNA is intricately involved in mediating GC-induced beta cell dysfunction.
- GAS5 represents a potential novel therapeutic target for counteracting GC-mediated beta cell dysfunction and steroid-induced diabetes.
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