Abstract
BackgroundStudying epigenetics is expected to provide precious information on how environmental factors contribute to type 2 diabetes mellitus (T2DM) at the genomic level. With the progress of the whole-genome resequencing efforts, it is now known that 75–90% of the human genome was transcribed to generate a series of long non-coding RNAs (lncRNAs). While lncRNAs are gaining widespread attention as potential and robust biomarkers in the genesis as well as progression of several disease states, their clinical relevance and regulatory mechanisms are yet to be explored in the field of metabolic disorders including diabetes. Despite the fact that Asian Indians are highly insulin resistant and more prone to develop T2DM and associated vascular complications, there is virtually lack of data on the role of lncRNAs in the clinical diabetes setting. Therefore, we sought to evaluate a panel of lncRNAs and senescence-inflammation signatures in peripheral blood mononuclear cells (PBMCs) from patients with type 2 diabetes (T2DM; n = 30) compared to individuals with normal glucose tolerance (NGT; n = 32).ResultsCompared to control subjects, expression levels of lncRNAs in PBMCs from type 2 diabetes patients showed significantly (p < 0.05) increased levels of HOTAIR, MEG3, LET, MALAT1, MIAT, CDKN2BAS1/ANRIL, XIST, PANDA, GAS5, Linc-p21, ENST00000550337.1, PLUTO, and NBR2. In contrast, lncRNA expression patterns of THRIL and SALRNA1 were significantly (p < 0.05) decreased in patients with T2DM compared to control subjects. At the transcriptional level, senescence markers (p53, p21, p16, and β-galactosidase), proinflammatory markers (TNF-α, IL6, MCP1, and IL1-β), and epigenetic signature of histone deacetylase-3 (HDAC3) were significantly (p < 0.05) elevated in patients with type 2 diabetes compared to control subjects. Interestingly, mRNA expression of Sirt1 and telomere length were significantly (p < 0.05) decreased in patients with type 2 diabetes compared to control subjects. Majority of the altered lncRNAs were positively correlated with poor glycemic control, insulin resistance, transcriptional markers of senescence, inflammation, and HDAC3 and negatively correlated with telomere length. Logistic regression analysis revealed a significant association of altered lncRNA signatures with T2DM, but this association was lost after adjusting for insulin resistance (HOMA-IR) and senescence markers.ConclusionOur study provides a clinically relevant evidence for the association of altered lncRNAs with poor glycemic control, insulin resistance, accelerated cellular senescence, and inflammation.
Highlights
According to the latest edition of International Diabetes Federation Atlas [1], around 425 million people worldwide have diabetes and India alone harbors more than 73 millions of people with diabetes
Majority of the altered long non-coding RNAs (lncRNAs) were positively correlated with poor glycemic control, insulin resistance, transcriptional markers of senescence, inflammation, and histone deacetylase-3 (HDAC3) and negatively correlated with telomere length
Logistic regression analysis Logistic regression analysis using type 2 diabetes as dependent variable revealed that altered expression levels of lncRNAs, viz., PLUTO, ENST00000550337.1, CDKN2BAS1, LincRNA-Cyclin-dependent kinase inhibitor 1A (P21), HOTAIR, GAS5, XIST, PANDA, NBR2, MIAT, MEG3, LET, MALAT1, SALRNA1, and THRIL, were associated significantly with type 2 diabetes mellitus (T2DM), and this statistical significance was persisted even after adjusting for confounding factors like age and Body mass index (BMI)
Summary
Logistic regression analysis Logistic regression analysis using type 2 diabetes as dependent variable revealed that altered expression levels of lncRNAs, viz., PLUTO, ENST00000550337.1, CDKN2BAS1, LincRNA-P21, HOTAIR, GAS5, XIST, PANDA, NBR2, MIAT, MEG3, LET, MALAT1, SALRNA1, and THRIL, were associated significantly with T2DM, and this statistical significance was persisted even after adjusting for confounding factors like age and BMI. This statistical association was lost when adjusted for HOMA-IR and senescence markers. This implies that the association between lncRNAs and T2DM could be closely linked to insulin resistance and accelerated senescence with downstream inflammatory signaling (Table 2)
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