Circulating LncRNAs Analysis in Patients with Type 2 Diabetes Reveals Novel Genes Influencing Glucose Metabolism and Islet β-Cell Function

Abstract

Background/Aims: The islet is an important endocrine organ to secrete insulin to regulate the metabolism of glucose and maintain the stability of blood glucose. Long noncoding RNAs (lncRNAs) are involved in a variety of biological functions and play key roles in many diseases, including type 2 diabetes (T2D). The aim of this study was to determine whether lncRNA-p3134 is associated with glucose metabolism and insulin signaling in pancreatic β cells. Methods: LncRNA microarray technology was used to identify the differentially expressed circulating lncRNAs in T2D patients. RT-PCR analyses were performed to determine the expression of lncRNA-p3134 in 30 pairs of diabetic and non-diabetic patients. The correlation of lncRNA-p3134 to clinical data from T2D patients was analyzed. LncRNA-p3134 was overexpressed in Min6 cells and db/db mice by adenovirus-mediated technology. CCK-8, TUNEL, Western blot, glucose-stimulated insulin secretion (GSIS), ELISAs and immunochemistry were performed to determine the effect of lncRNA-p3134 on proliferation, apoptosis and insulin secretion both in vitro and vivo. Results: The circulating level of lncRNA-p3134 was higher in diabetic patients than in non-diabetic controls and was correlated with fasting blood glucose and HOMA-β levels. The lncRNA-p3134 had risen by 4 times in serum exosomes but nearly unchanged in exosome-free samples. The secretion of lncRNA-p3134 was dynamically modulated by glucose in both Min6 cells and isolated mouse islet cells. LncRNA-p3134 positively regulate GSIS through promoting of key regulators (Pdx-1, MafA, GLUT2 and Tcf7l2) in β cells. In addition, the overexpression of lncRNA-p3134 resulted in a decreased apoptosis ratio and partially reversed the glucotoxicity effects on GSIS function in Min6 cells. The restoration of insulin synthesis and secretion the increase of the insulin positive cells areas by upregulation of lncRNA-p3134 in db/db mice confirmed the compensatory role of lncRNA-p3134 to preserve β-cell function. Furthermore, a protective effect of lncRNA-p3134 on GSIS by positive modulation of PI3K/Akt/mTOR signaling was also confirmed. After blocking the PI3K/AKT signals with their specific inhibitor, the effect of overexpressed lncRNA-p3134 on insulin secretion was obviously attenuated. Conclusion: Taken together, the results of this study provide new insights into lncRNA-p3134 regulation in pancreatic β cells and provide a better understanding of novel mechanism of glucose homeostasis.

Exosomal long noncoding RNAs in aging and age‐related diseases

“…LncRNA‐p3134 could be selectively secreted by β cells treated with high concentrations of glucose, which not only regulated glucose‐stimulated insulin secretion (GSIS) by promoting key regulatory factors in β cells (Pdx‐1, MafA, GLUT2, and TCF7l2) but also protected β cells from sugar toxicity and reduced cell apoptosis. Further studies found that lncRNA‐p3134 played a protective role in GSIS through the PI3K/AKT/mammalian target of rapamycin signaling pathway . These findings suggest that lncRNA‐p3134 plays a role in antagonizing the development of T2D.…”

TCONS_00230836 silencing restores stearic acid-induced β-cell dysfunction through alleviating endoplasmic reticulum stress via a PERK/eIF2α-dependent pathway rather than apoptosis

“…Although a number of studies have preliminarily explored the mechanisms underlying stearic acidinduced pancreatic β-cell damage, the exact molecular targets and associated pathways still need to be established. Recently, accumulating evidence has suggested that noncoding RNAs play an important role in the β-cell injury caused by the long-term consumption of a high-fat diet, such as microRNAs [2,5], circRNAs [22,23], and lncRNAs [17,24,25]. Nevertheless, few studies have focused on the role of lncRNAs in β-cell dysfunction upon exposure to elevated levels of SFAs, especially stearic acid, on which no related research has previously been published.…”

Epigenetic modification and therapeutic targets of diabetes mellitus

“…Its over-expression in Min6 cells showed an increase in glucose-stimulated insulin section that is consistent with the up-regulation of insulin transcription factors. Studies have revealed that the transcription factors Pdx-1 and MafA stimulate the insulin gene promoter in response to elevated blood glucose which finally leads to stimulation of insulin synthesis [ 176 ]. In high glucose conditions a lncRNAMalat1 was found to be up-regulated in retinas while Malat1 lncRNA knockdown in STZ induced rats resulted impaired retinopathy [ 177 , 186 ] suggesting that this lncRNA promotes retinopathy under diabetic condition.…”