The insulin-sensitizing mechanism of myo-inositol is associated with AMPK activation and GLUT-4 expression in human endometrial cells exposed to a PCOS environment

Abstract

Polycystic ovary syndrome (PCOS) is an endocrine-metabolic disorder characterized by hyperandrogenism and ovulatory dysfunction but also obesity and hyperinsulinemia. These characteristics induce an insulin-resistant state in tissues such as the endometrium, affecting its reproductive functions. Myo-inositol (MYO) is an insulin-sensitizing compound used in PCOS patients; however, its insulin-sensitizing mechanism is unclear. To understand the relationship of MYO with insulin action in endometrial cells, sodium/myo-inositol transporter 1 (SMIT-1) (MYO-transporter), and MYO effects on protein levels related to the insulin pathway were evaluated. SMIT-1 was assessed in endometrial tissue from women with normal weight, obesity, insulin resistance, and PCOS; additionally, using an in vitro model of human endometrial cells exposed to an environment resembling hyperinsulinemic-obese-PCOS, MYO effect was evaluated on p-AMPK and GLUT-4 levels and glucose uptake by Western blot, immunocytochemistry, and confocal microscopy, respectively. SMIT-1 was detected in endometrial tissue from all groups and decreased in PCOS and obesity ( P < 0.05 vs. normal weight ). In the in vitro model, PCOS conditions decreased p-AMPK levels, while they were restored with MYO ( P < 0.05). The diminished GLUT-4 protein levels promoted by PCOS environment were restored by MYO through SMIT-1 and p-AMPK-dependent mechanism ( P < 0.05). Also, MYO restored glucose uptake in cells under PCOS condition through a p-AMPK-dependent mechanism. Finally, these results were similar to those obtained with metformin treatment in the same in vitro conditions. Consequently, MYO could be a potential insulin sensitizer through its positive effects on insulin-resistant tissues as PCOS-endometrium, acting through SMIT-1, provoking AMPK activation and elevated GLUT-4 levels and, consequently, increase glucose uptake by human endometrial cells. Therefore, MYO may be used as an effective treatment option in insulin-resistant PCOS women.

In Search of New Therapeutics—Molecular Aspects of the PCOS Pathophysiology: Genetics, Hormones, Metabolism and Beyond

“…A possibility to enhance the effect of metformin and reduce its dosage can be provided by administration of inositols. According to the latest research, inositols are similarly effective in combating insulin resistance and the subsequent hyperinsulinemia in the treatment of PCOS [ 120 , 121 , 122 , 123 ].…”

“…The available literature indicates proteins from the GLUT type 4 family as targets for new agents combating insulin resistance in PCOS patients. Over-expressing syntaxin 4 can lead to an enhanced insulin response by enhancing the translocation of GLUT type 4 vesicles to the skeletal muscle cell membrane [ 113 , 114 , 116 , 117 , 120 ]. When looking for new therapeutic substances, one must not forget about natural substances, such as berberine modulating GLUT type 4 expression and naringenin, which increases the concentration of enzymes responsible for scavenging free oxygen radicals and lowering the levels of testosterone and estradiol [ 117 , 133 ].…”

“…Such a ratio constitutes an appropriate approach to improving insulin sensitivity and ovulatory function, along with decreasing luteinizing hormone (LH) and free testosterone levels, which subsequently reduce the observed hyperandrogenism. The results of studies with myo-inositol were comparable to those obtained with metformin treatment, which makes it an effective and safe therapeutic option in women with PCOS suffering from insulin resistance [ 120 ]. Nevertheless, there still remain some unresolved problematic issues in inositol-based treatment of PCOS [ 121 , 122 , 123 ].…”

“…Taking into account the notable role of insulin resistance in PCOS pathogenesis, the application of insulin sensitizer medicines, such as inositols, can be effective in the amelioration of PCOS symptoms [ 118 , 119 , 120 , 121 ]. Inositols are carbocyclic polyols.…”

Direct Effects of D-Chiro-Inositol on Insulin Signaling and Glucagon Secretion of Pancreatic Alpha Cells

“…Several studies reported that DCI can reduce hyperglycemia and improve insulin resistance [ 24 , 61 , 62 ]; the administration of DCI, for example, reduced hyperglycemia and hypertriglyceridemia in diabetic patients [ 63 ]. Nevertheless, the mechanism underlying the antidiabetic effects of DCI remains largely unclear; for this purpose, we studied the influence of DCI treatment on insulin signaling pathways in pancreatic α-cells.…”