Vitamin C supplementation reduces expression of circulating miR-451a in subjects with poorly controlled type 2 diabetes mellitus and high oxidative stress

Abstract

Background Vitamin C is an essential element required for normal metabolic function. We investigated the effect of vitamin C supplementation on circulating miRNA (miR) expression in subjects with poorly controlled type 2 diabetes mellitus (T2DM). Changes in miR expression were also correlated with clinical measures of disease. Methods Pre- and post-vitamin C supplementation samples from five participants who had increased vitamin C levels, improved oxidative status and polymorphonuclear (PMN) function after receiving 1,000 mg of vitamin C daily for six weeks were screened for miRNA expression using the NanoString miRNA assay. Differences in miRNA expression identified from the miRNA screen were validated by qRT-PCR. Results Four miRNAs showed significantly different expression post-vitamin C supplementation relative to baseline, including the down-regulation of miR-451a (−1.72 fold change (FC), p = 0.036) and up-regulation of miR-1253 (0.62 FC, p = 0.027), miR-1290 (0.53 FC, p = 0.036) and miR-644a (0.5 FC, p = 0.042). The validation study showed only miR-451a expression was significantly different from baseline with vitamin C supplementation. MiR-451a expression was negatively correlated with vitamin C levels (r = − 0.497, p = 0.049) but positively correlated with levels of malondialdehyde (MDA) (r = 0.584, p = 0.017), cholesterol (r = 0.564, p = 0.022) and low-density lipoproteins (LDL) (r = 0.522, p = 0.037). Bioinformatics analysis of the putative target genes of miR-451a indicated gene functions related to signaling pathways involved in cellular processes, such as the mammalian target of rapamycin (mTOR) signaling pathway. Conclusions Vitamin C supplementation altered circulating miR-451a expression. The results from this pilot study suggest that miRNAs could be used as biomarkers to indicate oxidative status in subjects with T2DM and with poor glycemic control and could lead to a novel molecular strategy to reduce oxidative stress in T2DM.

EndMT Regulation by Small RNAs in Diabetes-Associated Fibrotic Conditions: Potential Link With Oxidative Stress

“…The latter, previously described for its ability to induce EndMT in diabetic mouse heart ( Liang et al, 2019 ), has been recently reported to be up-regulated in diabetic subjects with high oxidative stress. The association between miR-451 and oxidative stress has been further confirmed with the use of the antioxidant Vitamin C; indeed, Vitamin C administration in diabetic subjects decreased both the expression of miR-451 and ROS levels ( Ruknarong et al, 2021 ). Finally, an interplay being the basis of mitochondrial functions in kidney ECs involves the miR-let-7 family, (FGF)/FGFR1 signaling pathway and SIRT3 ( Srivastava et al, 2020c ).…”

“…The miR-200 family, the anti-fibrotic activity of which has been described both in diabetic nephropathy and retinopathy, has also been shown to be associated with a decrease in oxidative stress in diabetes; specifically, the antioxidant effect of miR-200 is exerted by silencing the O-GlcNAc transferase, also known as OGT, whose enzymatic activity is associated with diabetic complications and endothelial inflammation ( Qadir et al, 2019 ). Another proof of the oxidative stress-small RNAs-EndMT interconnection comes from a study investigating the activity of miR-451 ( Ruknarong et al, 2021 ). The latter, previously described for its ability to induce EndMT in diabetic mouse heart ( Liang et al, 2019 ), has been recently reported to be up-regulated in diabetic subjects with high oxidative stress.…”

The Effect of β-Carotene, Tocopherols and Ascorbic Acid as Anti-Oxidant Molecules on Human and Animal In Vitro/In Vivo Studies: A Review of Research Design and Analytical Techniques Used

“…In a study consisting of 34 female participants with type 2 diabetes, the oral supplementation of α-tocopherol (800 IU/day) to 13 participants for 6 weeks resulted in the decrease in MDA erythrocyte level, if compared to a group (n = 21) without α-tocopherol administration [ 230 ]. In another study, 5 participants with diabetes mellitus type 2 who received vitamin C (1000 mg/day) for 6 weeks, showed decreased plasma levels of MDA and F 2 -isoprostanes, if compared to results before supplementation [ 231 ]. In a group of 40 participants with clinically diagnosed DMT2, hypoglycemic drug-administered diabetic (27 macrovascular, 13 microvascular) patients supplemented for 3 months with vitamin E (400 mg/day) showed decreased MDA serum concentration and increased serum SOD activity and erythrocyte GSH content, if compared to the beginning of study, or when compared with 40 DMT2 patients treated for 3 months with hypoglycemic drugs but without VitE supplementation [ 232 ].…”

“… 1 —if compared to the beginning of the study; 2 —if compared to profile without antioxidant used; C1 —if compared to control: normoglycemic profile; C2 —if compared to control: healthy subjects; I —if compared to lower intake of antioxidants; Measurement methods of oxidative stress biomarkers: MDA: TBA; LHP: FOX assay; F 2 -Isoprostanes: GC-MS [ 227 ], Radioimmunoassay [ 229 ], ELISA [ 231 ]. …”

Involvement of intestinal flora and miRNA into the mechanism of coarse grains improving type 2 diabetes: an overview

“…A 6‐month dietary vitamin E deficiency diet lowered hepatic miR‐122 and miR‐125b expression in freshly weaned rats, resulting in enhanced oxidative stress and inflammatory responses 10 . A recent human clinical study found that vitamin C supplementation given to T2D patients for 6 weeks down‐regulated circulating miR‐451a levels to reduce oxidative stress, suggesting that circulating miR‐451a levels can serve as a biomarker of oxidative stress 11 . Similarly, whole grain highland barley significantly suppressed the expression of the liver miRNA‐126a and miRNA‐29a in db/db mice, both of which are thought to target the gene expression of insulin receptor substrate 1 (IRS‐1)/PI3K 12 .…”