Dataset Information

Circulating long noncoding RNA GAS5 levels are correlated to prevalence of type 2 diabetes mellitus.

ABSTRACT:

Background

Diabetes mellitus (DM), a metabolic disease, is characterized by impaired fasting glucose levels. Type 2 DM is adult onset diabetes. Long non-coding RNAs (lncRNAs) regulate gene expression and multiple studies have linked lncRNAs to human diseases.

Methods

Serum samples obtained from 96 participating veterans at JAH VA were deposited in the Research Biospecimen Repository. We used a two-stage strategy to identify an lncRNA whose levels correlated with T2DM. Initially we screened five serum samples from diabetic and non-diabetic individuals using lncRNA arrays. Next, GAS5 lncRNA levels were analyzed in 96 serum samples using quantitative PCR. Receiver operating characteristic (ROC) analysis was performed to determine the optimal cutoff GAS5 for diagnosis of DM.

Results

Our results demonstrate that decreased GAS5 levels in serum were associated with diabetes in a cohort of US military veterans. The ROC analysis revealed an optimal cutoff GAS5 value of less than or equal to 10. qPCR results indicated that individuals with absolute GAS5 < 10 ng/?l have almost twelve times higher odds of having diabetes (Exact Odds Ratio [OR] = 11.79 (95% CI: 3.97, 37.26), p < 0.001). Analysis indicated area under curve (AUC) of ROC of 0.81 with 85.1% sensitivity and 67.3% specificity in distinguishing non-diabetic from diabetic subjects. The positive predictive value is 71.4%.

Conclusion

lncRNA GAS5 levels are correlated to prevalence of T2DM.

General significance

Assessment of GAS5 in serum along with other parameters offers greater accuracy in identifying individuals at-risk for diabetes.

SUBMITTER: Carter G

PROVIDER: S-EPMC4661729 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Publications

Circulating long noncoding RNA GAS5 levels are correlated to prevalence of type 2 diabetes mellitus.

Carter Gay G Miladinovic Branko B Patel Achintya A AA Deland Lauren L Mastorides Stephen S Patel Niketa A NA

BBA clinical 20150911

<h4>Background</h4>Diabetes mellitus (DM), a metabolic disease, is characterized by impaired fasting glucose levels. Type 2 DM is adult onset diabetes. Long non-coding RNAs (lncRNAs) regulate gene expression and multiple studies have linked lncRNAs to human diseases.<h4>Methods</h4>Serum samples obtained from 96 participating veterans at JAH VA were deposited in the Research Biospecimen Repository. We used a two-stage strategy to identify an lncRNA whose levels correlated with T2DM. Initially we ...[more]

PMID: 26675493

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Project description:Objective- Macrophages play key roles in inflammation and diabetic vascular complications. Emerging evidence implicates long noncoding RNAs in inflammation, but their role in macrophage dysfunction associated with inflammatory diabetic complications is unclear and was therefore investigated in this study. Approach and Results- RNA-sequencing and real-time quantitative PCR demonstrated that a long noncoding RNA Dnm3os (dynamin 3 opposite strand) is upregulated in bone marrow-derived macrophages from type 2 diabetic db/db mice, diet-induced insulin-resistant mice, and diabetic ApoE-/- mice, as well as in monocytes from type 2 diabetic patients relative to controls. Diabetic conditions (high glucose and palmitic acid) induced Dnm3os in mouse and human macrophages. Promoter reporter analysis and chromatin immunoprecipitation assays demonstrated that diabetic conditions induce Dnm3os via NF-κB activation. RNA fluorescence in situ hybridization and real-time quantitative PCRs of subcellular fractions demonstrated nuclear localization and chromatin enrichment of Dnm3os in macrophages. Stable overexpression of Dnm3os in macrophages altered global histone modifications and upregulated inflammation and immune response genes and phagocytosis. Conversely, RNAi-mediated knockdown of Dnm3os attenuated these responses. RNA pull-down assays with macrophage nuclear lysates identified nucleolin and ILF-2 (interleukin enhancer-binding factor 2) as protein binding partners of Dnm3os, which was further confirmed by RNA fluorescence in situ hybridization immunofluorescence. Furthermore, nucleolin levels were decreased in diabetic conditions, and its knockdown enhanced Dnm3os-induced inflammatory gene expression and histone H3K9-acetylation at their promoters. Conclusions- These results demonstrate novel mechanisms involving upregulation of long noncoding RNA Dnm3os, disruption of its interaction with nucleolin, and epigenetic modifications at target genes that promote macrophage inflammatory phenotype in diabetes mellitus. The data could lead to long noncoding RNA-based therapies for inflammatory diabetes mellitus complications.

Project description:BackgroundDiabetic retinopathy (DR) is a leading cause of blindness in the working-age population, which is characterized by retinal neurodegeneration and vascular dysfunction. Long non-coding RNAs (LncRNAs) have emerged as critical regulators in several biological processes and disease progression. Here we investigated the role of lncRNA AQP4-AS1 in retinal neurovascular dysfunction induced by diabetes.MethodsQuantitative RT-PCR was used to detect the AQP4-AS1 expression pattern upon diabetes mellitus-related stresses. Visual electrophysiology examination, TUNEL staining, Evans blue staining, retinal trypsin digestion and immunofluorescent staining were conducted to detect the role of AQP4-AS1 in retinal neurovascular dysfunction in vivo. MTT assays, TUNEL staining, PI/Calcein-AM staining, EdU incorporation assay transwell assay and tube formation were conducted to detect the role of AQP4-AS1 in retinal cells function in vitro. qRT-PCR, western blot and in vivo studies were conducted to reveal the mechanism of AQP4-AS1-mediated retinal neurovascular dysfunction.FindingsAQP4-AS1 was significantly increased in the clinical samples of diabetic retinopathy patients, high glucose-treated Müller cells, and diabetic retinas of a murine model. AQP4-AS1 silencing in vivo alleviated retinal neurodegeneration and vascular dysfunction as shown by improved retinal capillary degeneration, decreased reactive gliosis, and reduced RGC loss. AQP4-AS1 directly regulated Müller cell function and indirectly affected endothelial cell and RGC function in vitro. Mechanistically, AQP4-AS1 regulated retinal neurovascular dysfunction through affecting AQP4 levels.InterpretationThis study reveals AQP4-AS1 is involved in retinal neurovascular dysfunction and expected to become a promising target for the treatment of neurovascular dysfunction in DR.FundingThis work was generously supported by the grants from the National Natural Science Foundation of China (Grant No. 81800858, 82070983, 81870679 and 81970823), grants from the Medical Science and Technology Development Project Fund of Nanjing (Grant No ZKX17053 and YKK19158), grants from Innovation Team Project Fund of Jiangsu Province (No. CXTDB2017010), and the Science and Technology Development Plan Project Fund of Nanjing (Grant No 201716007, 201805007 and 201803058).

Dataset Information

Circulating long noncoding RNA GAS5 levels are correlated to prevalence of type 2 diabetes mellitus.

Background

Methods

Results

Conclusion

General significance

Publications

Circulating long noncoding RNA GAS5 levels are correlated to prevalence of type 2 diabetes mellitus.

Similar Datasets

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