Uncoupling Between Insulin and Release of ad-Chiro-Inositol–Containing Inositolphosphoglycan Mediator of Insulin Action in Obese Women With Polycystic Ovary Syndrome

Abstract

Background: Obese women with polycystic ovary syndrome (PCOS) manifest impaired insulin-stimulated release of a d-chiro-inositol-containing inositolphosphoglycan (DCI-IPG) insulin mediator during oral glucose tolerance testing (OGTT), which appears to be restored by the administration of metformin. This suggests that either obesity or PCOS is associated with a defect in the coupling of the stimulation of the insulin receptor by insulin to the release of the DCI-IPG mediator. The objective of this study was to compare the release of bioactive DCI-IPG between normal nonobese women and obese PCOS women during stimulation with two different concentrations of insulin when glucose levels are clamped. Methods: We performed a cross-sectional case-control study at the clinical research center of an academic medical center. A two-step euglycemic-hyperinsulinemic clamp was carried out in 8 nonobese normal and 8 obese PCOS women, during which DCI-IPG bioactivity was monitored. Results: At baseline, PCOS women were signifi cantly more obese, hyperinsulinemic, and insulin resistant than the controls. During the clamp studies, DCI-IPG bioactivity increased signifi cantly over the fi rst 45 min of the low-insulin step of the clamp in normal nonobese women (P = 0.046) and then decreased to baseline levels; DCI-IPG increased again after initiation of the high-insulin step (P = 0.029). Despite higher insulin levels during the clamp in PCOS women, DCI-IPG bioactivity remained fl at throughout both insulin steps and was thus significantly lower than in controls during the initial periods of both steps. Conclusions:The coupling between insulin action and the release of the DCI-IPG mediator is selectively impaired in obese PCOS women, which may contribute to the insulin resistance in these women.

Decreased myo-inositol to chiro-inositol (M/C) ratios and increased M/C epimerase activity in PCOS theca cells demonstrate increased insulin sensitivity compared to controls

“…Extensive examination of CYP17A1 and CYP11A1 gene expression in normal and PCOS theca cells has revealed that increased CYP17 and myo-inositol to chiro-inositol epimerase activity and a decreased myo-inositol to chiro-inositol ratio. In all previous papers, we have provided evidence for decreased epimerase activity and increased myo-inositol to chiro-inositol ratios in cases of insulin resistance [7][8][9][10][11][12][13][14][15][16]. Our experiments do not shed light on the continuing enigma of the primacy of increased testosterone versus the peripheral insulin resistance as the initiating event in PCOS.…”

“…In addition, deficiency of chiro-inositol in urine of Japanese subjects has been demonstrated to be linearly related to insulin resistance in type 2 diabetics, subjects with impaired glucose tolerance and normal subjects [10]. Further, lack of appearance of chiro-inositol glycan bioactivity (measured as PDH phosphatase (PDHP) activity) in blood of type 2 diabetic subjects during a glucose tolerance test, lack of chiro-inositol glycan bioactivity in women with PCOS during an insulin clamp, and lack of appearance of chiro-inositol glycan bioactivity release from placental membranes with insulin administration in vitro in women with preeclampsia have also been shown [11][12][13]. One glycan isolated from beef liver, named INS-2, has been identified, structure determined and chemically synthesized.…”

Pioglitazone Therapy Increases Insulin-Stimulated Release of d-Chiro-Inositol-Containing Inositolphosphoglycan Mediator in Women with Polycystic Ovary Syndrome

“…9 Recently, it was reported that the coupling between insulin action and the release of the DCI-IPG mediator is selectively impaired in PCOS women with obesity this suggests that insulin-stimulated release of the DCI-IPG mediator is defective in obese women with PCOS. 10 Moreover, interventional studies have reported that oral administration of DCI reduced circulating insulin, decreased serum androgens, and improved ovulatory frequency in obese women with PCOS. [11][12][13][14] We previously reported that metformin increased the release of bioactive DCI-IPG per unit of insulin released during an oral glucose challenge, 6 further supporting the contribution of DCI-IPG deficiency to the IR in these women.…”

The “Other” Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances inmyo‐Inositol Chemistry)

“…[133] In PCOS sufferers metformin increases the insulin-stimulated release of the putative D-chiroinositol-containing phosphoglycan that mediates insulin action: [134] there is a selective impairment in PCOS sufferers between insulin action and the release of the mediator. [135] PCOS has been associated with a degree of oxidative stress: the administration of D-chiroinositol to PCOS sufferers prevents the oxidation of protein thiol groups in the follicular fluid. [136] In obese hyperinsulinemic PCOS sufferers the administration of D-chiro-inositol improves insulin sensitivity and hormonal parameters.…”