Abstract
Backgroundd-chiroinositol (DCI) is a inositolphosphoglycan (IPG) involved in several cellular functions that control the glucose metabolism. DCI functions as second messenger in the insulin signaling pathway and it is considered an insulin sensitizer since deficiency in tissue availability of DCI were shown to cause insulin resistance (IR). Polycystic ovary syndrome (PCOS) is a pathological condition that is often accompanied with insulin resistance. DCI can positively affects several aspect of PCOS etiology decreasing the total and free testosterone, lowering blood pressure, improving the glucose metabolism and increasing the ovulation frequency. The purpose of this study was to evaluate the effects of DCI and insulin combined with gonadotrophins namely follicle-stimulating hormone (FSH) and luteinizing hormone (LH) on key steroidogenic enzymes genes regulation, cytochrome P450 family 19 subfamily A member 1 (CYP19A1) and cytochrome P450 side-chain cleavage (P450scc) in primary cultures of human granulosa cells (hGCs). We also investigated whether DCI, being an insulin-sensitizer would be able to counteract the expected stimulator activity of insulin on human granulosa cells (hGCs).MethodsThe study was conducted on primary cultures of hGCs. Gene expression was evaluated by RT-qPCR method. Statistical analysis was performed applying student t-test, as appropriate (P < 0.05) set for statistical significance.ResultsDCI is able to reduce the gene expression of CYP19A1, P450scc and insulin-like growth factor 1 receptor (IGF-1R) in dose–response manner. The presence of DCI impaired the increased expression of steroidogenic enzyme genes generated by the insulin treatment in gonadotrophin-stimulated hGCs.ConclusionsInsulin acts as co-gonadotrophin increasing the expression of steroidogenic enzymes genes in gonadotrophin-stimulated granulosa cells. DCI is an insulin-sensitizer that counteracts this action by reducing the expression of the genes CYP19A1, P450scc and IGF-1R. The ability of DCI to modulate in vitro ovarian activity of insulin could in part explain its beneficial effect when used as treatment for conditions associated to insulin resistance.
Highlights
The cis-1, 2, 4-trans-3, 5, 6-Cyclohexanehexol, known as d-chiroinositol (DCI), is a six-carbon polyalcohol which belongs to the family collectively referred to as inositol which is a part of the B vitamin family
To investigate a possible role of DCI as modulator of gene expression, human granulosa cells (hGCs) primary culture were treated for 24 h with increasing concentrations of DCI dissolved into starvation medium
In order to assess the cell viability at the end of the DCI treatment the Trypan Blue exclusion test was performed while the β3 integrin gene activation, expressed as ratio normalized by Ribosomal protein S7 (RpS7) reference gene on RT-qPCR assay, was studied as positive control (Fig. 1)
Summary
The cis-1, 2, 4-trans-3, 5, 6-Cyclohexanehexol, known as d-chiroinositol (DCI), is a six-carbon polyalcohol which belongs to the family collectively referred to as inositol which is a part of the B vitamin family. Epimerase enzymes convert inositols to up to nine stereoisomers including myo-inositol (MI) and DCI while the majority of the other stereoisomers generated fail to show an evident biological activity [2]. DCI is considered as an insulin sensitizer since inositolphosphoglycan (IPG) mediators are involved in several cellular functions that control the glucose metabolism [6, 7]. Impaired metabolism of IPG mediators as well as a deficiency in tissue availability of inositol were shown to cause insulin resistance [8, 9] MI and DCI are both endogenous biosynthesized and introduced from dietary sources such as buckwheat [3], Cucurbita ficifolia [4] and soy lecithin [5].
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