Comparative analysis of long non‑coding RNA expression profiles induced by resveratrol and metformin treatment for hepatic insulin resistance

Abstract

Resveratrol (RSV) and metformin (MET) play a role in the treatment of diabetes; however, the mechanisms through which they mediate insulin resistance by regulating long non-coding RNAs (lncRNAs) remain unknown. The present study was conducted to determine whether RSV and MET can improve insulin resistance in the livers of high-fat diet (HFD)-fed mice by regulating lncRNAs. C57BL/6J mice were fed a HFD for 8 weeks to establish a model of insulin resistance. The mice were subsequently treated with RSV or MET for 8 weeks and liver tissue samples were then collected. High-throughput sequencing was utilized to analyze mouse liver tissue samples to obtain differential lncRNA expression profiles. RSV or MET both reduced the blood glucose levels, the insulin index and the area under the curve in HFD-fed mice. Treatment also improved liver structure and decreased lipid deposition in liver tissues, as shown by H&E and Oil Red O staining. Compared with the MET group, there were 55 lncRNAs and 19 mRNAs with a differential expression. In total, eight lncRNAs were randomly selected and evaluated by reverse transcription-quantitative PCR (RT-qPCR). The results of seven lncRNAs corresponded to those of the sequencing analysis. Pathway analysis revealed that the PI3K/Akt signaling pathway had the highest enrichment score. In addition, the results of western blot analysis and RT-qPCR revealed that the expression levels of forkhead box O1, glucose-6-phosphatase catalytic subunit 1 and phosphoenolpyruvate carboxykinase 1 in the RSV and MET groups were significantly decreased compared with those in the HFD group. NONMMUT034936.2 and G6PC target genes exhibited similar expression patterns, indicating that RSV and MET may affect the PI3K/Akt signaling pathway through NONMMUT034936.2 to attenuate insulin resistance. On the whole, the present study provides novel biomarkers or contemporary perspectives for the use of RSV and MET in the treatment of insulin resistance and diabetes.

Roles of long noncoding RNAs and small extracellular vesicle‐long noncoding RNAs in type 2 diabetes

“…Studies have shown that 456 lncRNAs are upregulated and 409 lncRNAs are downregulated by cAMP stimuli, and nearly half of them are attenuated by metformin treatment 45 . Another study also showed a similar result, in which metformin and resveratrol treatment altered lncRNA profiles in the livers of obese mice, and those lncRNAs regulate insulin signaling pathways 46 . Thus, metformin treatment may exert its antidiabetic effect by altering lncRNA expression.…”

Metformin Treatment Modulates Long Non-Coding RNA Isoforms Expression in Human Cells

“…Mice lncRNAs have been previously associated with metformin treatment accessed by RT-qPCR and microarray analyses [ 74 , 75 , 76 ]. Nevertheless, these types of analyses do not allow isoform-specific evaluation due to technical limitations and also because of the less extensive ncRNA annotation of mouse if compared to human genome.…”

Disease-Associated Regulation of Non-Coding RNAs by Resveratrol: Molecular Insights and Therapeutic Applications

“…Recent studies have shown that resveratrol and metformin (MET), a first-line drug for the management of type 2 diabetes ( Giannarelli et al, 2003 ), exert glucose-lowering effects through similar mechanisms, i.e., reduced hepatic gluconeogenesis, inflammation and oxidative stress, mainly through the activation of NAD-dependent deacetylase SIRT1 and AMP-activated protein kinase (AMPK) ( Dludla et al, 2020 ). Based on this finding, a study has sought to determine whether such effects are mediated by lncRNAs, performing a comparative analysis of liver tissue lncRNAs expression profiles by high-throughput sequencing from high-fat diet (HFD)-fed mice treated with resveratrol and MET ( Shu et al, 2021 ). Both compounds attenuated liver insulin resistance by regulating lncRNAs, although MET exerted a more prominent effect.…”

“…Both compounds attenuated liver insulin resistance by regulating lncRNAs, although MET exerted a more prominent effect. Moreover, both resveratrol and MET affected the PI3K/Akt signaling pathway through the NONMMUT034936.2 and G6PC target genes ( Shu et al, 2021 ). By using the same experimental model (HFD-fed mice), another study identified mmu-miR-363-3p as the major miRNA involved in the beneficial effects of resveratrol on insulin resistance.…”

“…Moreover, resveratrol has been found to modulate several aspects of cancer biology, such as tumor cell growth, migration, invasion, and resistance/evasion to apoptosis, by controlling the expression of miRNAs and lncRNAs (Wang et al, 2019). However, the ability of resveratrol to modulate the expression profile of ncRNAs has been also reported in other pathophysiological states (Latruffe et al, 2015;Zhu et al, 2020b;Shu et al, 2021). In this review, we critically appraise the available evidence regarding the resveratrol-mediated regulation of miRNAs and lncRNAs in various pathological conditions, particularly cancer, metabolic disorders, inflammation and ischemia.…”