Discussion
International Diabetes Federation Atlas22 revealed that approximately 425 million individuals worldwide have diabetes; among them, >90% had T2DM, a complex, multifactorial disease with genetic, epigenetic, and environmental machinery. Several studies have suggested that accelerated aging, cellular senescence, and proinflammatory mechanism are closely linked to the etiology of type 2 diabetes and insulin resistance.23 Epigenetic changes and alterations have been a major part in the inflammation regulation and cellular senescence frequently linked with type 2 diabetes.24 lncRNAs have progressively came into consideration due to increased recognition of their functional significance in health and diseases.8 lncRNAs have been also established afterward to protein-coding genes under the compact transcriptional mechanism, and expression pattern is usually associated with tissue diversity and disease severity.9 The role of lncRNAs been lately recognized in the T2DM pathogenesis and related complications, as well as its involvement in pathophysiological mechanisms linked to the genesis, advancement and the worsening of the disease.25 26
Our present study reported increased expression levels of the lncRNAs NKILA, NEAT1, MALAT1, and MIAT in patients with T2DM. Patients with T2DM showed more than threefold higher expression of the lncRNA NKILA compared with healthy controls. Higher expression levels of the lncRNA NKILA were observed in patients with T2DM with hypertension, smoking patients with T2DM, and patients with T2DM with alcoholism compared with their corresponding counterparts.
A study by Li et al in 201927 demonstrated that lncRNA NKILA was specifically upregulated in patients with T2DM who later developed diabetic-related complications such as cardiomyopathy, suggesting that overexpression of the lncRNA NKILA may contribute to cardiomyocyte apoptosis and its involvement in the progression of diabetic cardiomyopathy (DC). It was suggested that suppressing expression of the lncRNA NKILA may inhibit the development of DC.27
The apoptosis of cardiomyocytes under high-glucose conditions contributes to the pathogenesis of DC,28 overexpression, as well as knockdown of the lncRNA NKILA accelerated and inhibited apoptotic cell death, respectively.27 Compared with healthy subjects, patients with T2DM showed a more than fivefold increase in expression of the lncRNA NEAT1. Patients with T2DM with weight loss and fatigue showed higher lncRNA NEAT1 expression compared with their counterparts; patients with T2DM with wound healing showed higher expression of the lncRNA NEAT1 compared with those with slow wound healing. NEAT1 is also highly expressed due to hyperglycemia and NEAT1 with the AKT/mTOR pathway.29 Recent studies have shown that lnc-NEAT1 is aberrantly expressed in diabetic mice; moreover, some studies have shown that lnc-NEAT1 has proinflammatory influence through affecting inflammatory pathways, such as its activation of mitogen-activated protein kinase (MAPK) pathways or the toll-like receptor 3–p38 pathway in some inflammatory diseases.5 30 A study by Ma et al reported that high glucose levels are positively associated with overexpression of the lncRNA NEAT1, indicating that lnc-NEAT1 was overexpressed in the cellular model of DN.31 Overexpression of the lncRNA NEAT1 was also observed in myocardial I/R injury cells compared with normal myocardial cells.32
The lncRNA MALAT1 showed more than fourfold higher expression in patients with T2DM compared with healthy controls. Among patients with T2DM, higher expression of the lncRNA MALAT1 was linked with weight loss, blurred vision, smoking, and alcoholism compared with the corresponding counterparts without these parameters.
MALAT1 is a highly conserved lncRNA that has been related to multiple pathological conditions, including diabetes-related complications.33 Current studies have shown that MALAT1 could play significant roles in the pathophysiological condition, tissue inflammation, and progression of diabetes by modulating gene transcription.34 MALAT1 expression was elevated by high glucose in diabetic cataract tissue cells, provoking apoptosis and oxidative stress.34
Yan et al reported that MALAT1 was considerably upregulated in diabetic mouse retinas, which contributed to the occurrence of diabetic retinopathy in an in vitro animal study, and MALAT1 was also upregulated in clinical samples.35 MALAT1 overexpression serves as essential pathogenic machinery for diabetes-related dysfunction and endothelial cell proliferation through p38MAPK signaling. MALAT1 reticence may become a potent antiangiogenic therapy for diabetic microvascular difficulties.36
Zhang et al explored the relationship among the lncRNAs MALAT1, p21, and H19 and gestational diabetes mellitus (GDM) and reported the lncRNA MALAT1 expression level was significantly higher in the GDM group compared with its counterpart. Moreover, the lncRNA MALAT1 is inter-related with the expression of the lncRNAs p21 and H19. MALAT1 was acknowledged as a unique serum biomarker that predicts GDM. Detection of MALAT1 expression provides a promising biomarker for future strategies to diagnose GDM, and GDM may be treatable by regulating the expression of the lncRNA MALAT1.37
MIAT was one of the most highly expressed (>6 fold) lncRNAs in patients with T2DM compared with healthy controls. Its high expression was observed in patients with T2DM with blurred vision, and MIAT may be a leading factor in diabetic-related eye disorders. High MIAT expression was also observed to be associated with smoking and alcoholism among patients with T2DM.
Researchers have shown that the unusual expression of MIAT has participated in cell death, and various diseases development, such as myocardial infarction,38 microvascular dysfunction,39 and diabetes.40 An experiment in mice by Zhang et al in 2017 suggested that streptozotocin (STZ) supplementation significantly enhances the MIAT expression level, and highglucose supplementation promoted expression of the lncRNA MIAT.41
MIAT is particularly involved in diabetic retinopathy and numerous other microvascular problems.42 A study by Toraih et al in 201943 revealed a significantly higher expression of circulating MIAT in patients with diabetes with coronary heart disease (CAD). Higher expression levels of MIAT and MALAT1 were related to hypertension and premature CAD, and both lncRNAs displayed greater relative expression in patients with a progressive history of prior cardiac ischaemic events.
Altered MALAT1 expression was reported to be closely related to diabetic complications in previous studies.44 Moreover, the greater relative expression of MALAT1 observed in diabetic and hypertensive subgroups of patients with CAD suggests a possible role by which diabetes and hypertension produce endothelial alteration and accelerate the atherosclerosis rate.45 Recent studies reported the potential contributions of MIAT and MALAT1 to endothelial dysfunction in patients with diabetes.46 This study analyzed the prognostic importance of circulating lnc NKILA, NEAT1, MALAT1, and MIAT in patients with T2DM and observed that the MALAT1 and MEAT could be used as prognostic markers for patients with T2DM with retinopathy.