miRNA-93 Inhibits GLUT4 and Is Overexpressed in Adipose Tissue of Polycystic Ovary Syndrome Patients and Women With Insulin Resistance

Abstract

Approximately 70% of women with polycystic ovary syndrome (PCOS) have intrinsic insulin resistance (IR) above and beyond that associated with body mass, including dysfunctional glucose metabolism in adipose tissue (AT). In AT, analysis of the IRS/PI3-K/AKT pathway signaling components identified only GLUT4 expression to be significantly lower in PCOS patients and in control subjects with IR. We examined the role of miRNAs, particularly in the regulation of GLUT4, the insulin-sensitive glucose transporter, in the AT of PCOS and matched control subjects. PCOS AT was determined to have a differentially expressed miRNA profile, including upregulated miR-93, -133, and -223. GLUT4 is a highly predicted target for miR-93, while miR-133 and miR-223 have been demonstrated to regulate GLUT4 expression in cardiomyocytes. Expression of miR-93 revealed a strong correlation between the homeostasis model assessment of IR in vivo values and GLUT4 and miR-93 but not miR-133 and -223 expression in human AT. Overexpression of miR-93 resulted in downregulation of GLUT4 gene expression in adipocytes through direct targeting of the GLUT4 3′UTR, while inhibition of miR-93 activity led to increased GLUT4 expression. These results point to a novel mechanism for regulating insulin-stimulated glucose uptake via miR-93 and demonstrate upregulated miR-93 expression in all PCOS, and in non-PCOS women with IR, possibly accounting for the IR of the syndrome. In contrast, miR-133 and miR-223 may have a different, although yet to be defined, role in the IR of PCOS.

Altered microRNA and gene expression in the follicular fluid of women with polycystic ovary syndrome

“…miRNAs are already being used commercially as disease biomarkers in oncology [17]. There is evidence for the use miRNAs as biomarkers in a wide range of diseases including prostate cancer [36], cardiac disease [37], acute kidney injury [38], and Alzheimer's disease [39]. If we could identify miRNAs that could be used as biomarkers for PCOS, the diagnosis and treatment of PCOS would be revolutionized.…”

Role of Serum miRNAs in the Prediction of Ovarian Hyperstimulation Syndrome in Polycystic Ovarian Syndrome Patients

“…MiR-223 has been reported to be upregulated in the adipose tissue in PCOS, and it has been found to be overexpressed only in PCOS patients with insulin resistance (IR) but not in non-PCOS women with IR [27]. Therefore, miR-223 might be specifically associated with IR in PCOS women.…”

Integrative mRNA-microRNA analyses reveal novel interactions related to insulin sensitivity in human adipose tissue

“…This has led many to study the role of microRNAs in adipogenesis (19,32), obesity, and insulin resistance (8,29,41,44). Insulin resistance is associated with altered expression of several microRNAs whose predicted target genes are involved in insulin signaling (INSR, PI3K, GLUT4) (8,44), metabolism (ADIPOR1) (29), and inflammation (ETS1) (37). However, these studies were designed to focus on obesity; obesity and insulin resistance are only moderately correlated, and thus, previous studies were not able to identify potential microRNAs that specifically regulate insulin resistance.…”