Insulin resistance is considered one of the greatest challenges faced by modern medicine. Recent studies reported that miRs have profound role in several aspects like insulin resistance, obesity and T2DM [2].
In the present study, we assessed the expression levels of miR 103 and miR 107 in obese newly diagnosed diabetic patients and obese type 2 diabetic patients treated with metformin. Also, we clarify the effects of metformin on miR 103, miR 107 and DICER levels in type 2 diabetic obese patients.
Our results showed that levels of Total cholesterol, TG, LDL, and VLDL were reduced along with increased HDL after treatment with metformin in MetD group compared to ONDD and OC groups. These findings were in agreement with Sumanth et al [17] and Syed et al [18], who concluded the ability of metformin to correct dyslipidemia and lipid profiles in T2DM patients.
The present study also showed improvement in HbA1C, FBG, insulin levels and HOMA IR after treatment with metformin in MetD group compared to ONDD and OC groups. As metformin acts through improving the sensitivity of peripheral tissues to insulin, it leads to the reduction in circulating insulin levels. In addition, metformin could inhibit hepatic gluconeogenesis, increases glucose uptake by peripheral tissues and reduces fatty acid oxidation [19].
Herein, the current study showed higher expression levels of miR 103 and miR 107 in ONDD group compared to OC group. These findings were in agreement with those achieved by Mao et al [20], Maryam H et al [21] and Qian et al [6], who reported that the expression level of miR-103/107 is up-regulated in obese mice, while silencing of miR-103/107 leads to improved glucose homeostasis and insulin sensitivity.
MiR-103 and miR-107 affect insulin resistance and glucose metabolism by inhibiting the expression of caveolin-1 (CAV-1). CAV-1 is essential for insulin receptor (INSR) structure stabilization for proper insulin signaling [22, 23]. It has shown that miR-103 and miR-107 directly bind CAV-1 3UTR sequence, thus controlling its expression. Moreover, the decreased expression levels of miR-103 and miR-107 led to an improvement in glucose homeostasis and insulin sensitivity [24, 25].
The present results also showed a significant positive correlation between miR103, miR 107 and HOMA-IR. These findings were consistent with Qian et al [6], who reported that miR-103 and miR 107 may be a potential molecular markers for insulin resistance and the onset of diabetes [4].
Another role of miR-103 and miR-107 in insulin resistance and glucose metabolism is their ability to inhibit the endonuclease enzyme DICER, which belongs to endonucleases family 111 that are essential for processing miR precursors to mature miRs. This raised the possibility that some mature miRs could feed back to control DICER expression [26, 10].
Herein, the present results showed significant decrease in levels of DICER-1 in OC group and ONDD group and significant increase in MetD group. Also, our results showed a significant negative correlation between levels of miR 103 and miR 107 and DICER levels in all studied groups. These findings were in agreement with Taisuke et al [27], Li et al [28] and Graziano et al [8].
The present study also showed that metformin significantly down-regulated the expression levels of miR 103 and 107 in MetD group. These results were on the contrary with Ibrahim et al 2018 [9], who investigated the expressions of miR 103 & 107 are non-significantly down-regulated by metformin.
Herein, the present study showed that metformin significantly increased the level of DICER1 in MetD group. Our results were in accordance with Nicole et al. [11] and Giovani et al. [30], who showed the treatment with metformin affects levels of DICER both in mice and human. Moreover, previous studies showed that chronic metformin treatment in mice increased DICER levels through altering the post-transcriptional processes that would affect the stability and/or turnover of DICER1 mRNA.
Abdelmohsen et al. [28] showed that RBP AUF1 binds DICER mRNA and negatively regulates DICER-1 protein levels by lowering the stability of DICER-1 mRNA. Treatment with metformin changes subcellular localization of AUF, disrupting its interaction with DICER mRNA and causes stabilization of DICER-1 mRNA, allowing DICER to accumulate and so metformin enhances and increases the levels of DICER [11].
The current study showed AUC values of the ROC curve of both miR 103 and miR 107that they were an excellent diagnostic markers for insulin resistance. These results were in agreement with Mao et al [20], who reported the increased levels of miR 103 not only provided high sensitivity and specificity to differentiate the pre-diabetes population but also acted as biomarkers for predicting T2DM with high diagnostic value.