Polycystic Ovary Syndrome Insulin Research Articles

Вторичные мессенджеры инсулина при синдроме поликистозных яичников и методы его патогенетической коррекции

The study of new mechanisms of insulin resistance (IR) formation is a prerequisite for the development of new pathogenetically-oriented therapies of polycystic ovary syndrome (PCOS) and the treatment of associated disorders of carbohydrate and fat metabolism. Important regulators of insulin signaling are its secondary messengers, namely myo-inositol (MI), D-chiro inositol (DCI), and α-lipoic acid (ALA), which mediate various effects of insulin. Consequently, MI induces cellular glucose uptake and enhances glycolysis, whereas DCI stimulates glycogenesis and regulates energy metabolism. The physiologic MI/DCI ratio for oocytes is crucial for oogenesis, steroidogenesis, and the regulation of the menstrual cycle. ALA provides insulinomimetic effects through the induction of glucose translocation into cells, antioxidant and anti-inflammatory effects on pancreatic cells, and the suppression of lipolysis and the reduction of triglyceride levels. A wealth of evidence from large-scale studies, meta-analyses, and systematic reviews has demonstrated the crucial role of MI, DCI, and ALA in the treatment of PCOS. A multitude of studies, including those conducted by the authors, have demonstrated that the administration of these substances results in a reduction in HOMA, levels of glucose, insulin, triglycerides, low-density lipoproteins, and body mass index. This, in turn, has been shown to restore ovulation and the menstrual cycle in women with PCOS, as well as to reduce the risk of cardiometabolic diseases, including diabetes and nonalcoholic fatty liver disease KEYWORDS: polycystic ovary syndrome, inositol, myo-inositol, D-chiro inositol, alpha-lipoic acid, insulin resistance, fat metabolism, nonalcoholic fatty liver disease FOR CITATION: Ivanov I.A., Tabeeva G.I., Smetnik A.A. Secondary messengers of insulin in polycystic ovary syndrome and its pathogenically- oriented treatment. Russian Journal of Woman and Child Health. 2024;7(2):135–143 (in Russ.). DOI: 10.32364/2618-8430-2024-7-2-8.

Insulin-like growth factor binding protein-1 and insulin in polycystic ovary syndrome: a systematic review and meta-analysis.

Insulin-like growth factor binding protein-1 (IGFBP-1) is considered a decline in polycystic ovary syndrome (PCOS), but it remains controversial that whether such reduction is attributed to obesity. This systematic review aims to explore whether IGFBP-1 is reduced in PCOS, and whether such reduction is associated with obesity. Our pooled study included 12 studies with a total of 450 participants. IGFBP-1 levels in PCOS were significantly lower than that in non-PCOS (SMD (95%CI)=-0.49(-0.89, -0.09), P=0.02). No significant difference in IGFBP-1 levels between patients with or without PCOS classified by BMI. Whilst, stratification by PCOS status revealed a significant decrease in IGFBP-1 in overweight (SMD (95%CI)=-0.92(-1.46, -0.37), P=0.001). When comparing fasting insulin in the same way, PCOS patients had significantly elevated fasting insulin level but not statistically declined IGFBP-1 after classified by BMI. This meta-analysis provides evidence that the decrease of IGFBP-1 in PCOS was more strongly influenced by comorbid obesity than by PCOS itself. Additionally, contrast to previous findings that insulin significantly suppresses IGFBP-1, our results suggested that the suppression of PCOS-related hyperinsulinemia on IGFBP-1 seemed diminished. Overall, our work may provide a novel perspective on the mechanism between insulin and IGFBP-1 underlying PCOS development.

The relevance of inositols treatment for PCOS before and during ART.

Polycystic ovary syndrome (PCOS) is an endo-crine disorder that occurs in 8-10% of women of reproduc-tive age. It is characterized by oligo or anovulation, hyperandrogenism and/or polycystic ovaries, but also by an increased insulin plasma level especially in overweight/obese women or in those with familial diabetes. In the last years, among the insulin sensitizers, the use of the two active isoforms of inositols (myo-inositol and d-chiro-inositol) has been spreading for the treatment of PCOS insulin resistance. Several studies have shown a positive role of inositols both on the metabolic profile of PCOS patients, but also on hormonal parameters. Hence, inositols can positively affect the infertility that characterizes many PCOS patients, acting both on ovarian function and spontaneous ovulation and during IVF procedures, in terms of oocyte quality and pregnancy rate.

The relationship between vitamin D3 and insulin in polycystic ovary syndrome - a critical review.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age. It is characterized by hormonal, reproductive and metabolic disturbances, including hyperandrogenism, altered gonadotropin level, ovarian cysts and ovulatory dysfunction as well as insulin resistance, hyperinsulinemia and dyslipidemia. It was shown that increased insulin concentration is a plausible factor in the pathogenesis of PCOS. Insulin leads to overstimulation of ovarian theca cells to androgen biosynthesis and contributes to insulin resistance in tissues such as muscle, liver, adipose tissue and ovary of PCOS patients. Noteworthy, recent studies suggested that supplementation with vitamin D3 may be an alternative therapy increasing insulin sensitivity and thereby improving reproductive parameters in PCOS women. Indeed, various action of vitamin D3 on the ovarian, hormonal and metabolic features observed in PCOS were presented. Many studies reported therapeutic effects of vitamin D3, but some research found a lack of influence or contradicted these findings. Therefore, the aim of this review was to summarize the available evidence about vitamin D3 and insulin interaction in PCOS, and discusses the potential usefulness of VD3 in PCOS treatment.

Source and amount of carbohydrate in the diet and inflammation in women with polycystic ovary syndrome

High carbohydrate intake and low-grade inflammation cooperate with insulin resistance and hyperandrogenism to constitute an interactive continuum acting on the pathophysiology of polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age characterised by oligo-anovulatory infertility and cardiometabolic disorders. The role of insulin in PCOS is pivotal both in regulating the activity of ovarian and liver enzymes, respectively involved in androgen production and in triggering low-grade inflammation usually reported to be associated with an insulin resistance, dyslipidaemia and cardiometabolic diseases. Although an acute hyperglycaemia induced by oral glucose loading may increase inflammation and oxidative stress by generating reactive oxygen species through different mechanisms, the postprandial glucose increment, commonly associated with the Western diet, represents the major contributor of chronic sustained hyperglycaemia and pro-inflammatory state. Together with hyperinsulinaemia, hyperandrogenism and low-grade inflammation, unhealthy diet should be viewed as a key component of the 'deadly quartet' of metabolic risk factors associated with PCOS pathophysiology. The identification of a tight diet-inflammation-health association makes the adoption of healthy nutritional approaches a primary preventive and therapeutic tool in women with PCOS, weakening insulin resistance and eventually promoting improvements of reproductive life and endocrine outcomes. The intriguing nutritional-endocrine connections operating in PCOS underline the role of expert nutritionists in the management of this syndrome. The aim of the present review is to provide an at-a-glance overview of the possible bi-directional mechanisms linking inflammation, androgen excess and carbohydrate intake in women with PCOS.

Effect of insulin on AKR1C3 expression in female adipose tissue: in-vivo and in-vitro study of adipose androgen generation in polycystic ovary syndrome

BackgroundInsulin resistance and hyperandrogenism are the cardinal features of polycystic ovary syndrome (PCOS). Women with insulin receptor (INSR) mutations develop severe hyperandrogenism secondary to hyperinsulinaemia. We hypothesised that insulin might drive adipose testosterone generation from androstenedione through aldoketoredutase type 3 (AKR1C3) in women with insulin resistance. Here we assessed the effect of insulin on AKR1C3 activity in vivo and in vitro. MethodsTen women with PCOS, ten healthy controls, and three women with INSR mutations underwent dehydroepiandrosterone (DHEA) challenge; serum androgens were measured every 30 min for 4 h after ingestion of 100 mg DHEA. Additionally, paired subcutaneous and omental fat samples were obtained during abdominal surgery from 38 women. AKR1C3 expression was measured by real-time PCR. Serum steroids and cultured cell media androgens were measured with liquid chromatography tandem mass spectrometry. FindingsWomen with PCOS had higher androstenedione concentrations than did controls and women with INSR mutations (p=0·01 and p=0·005, respectively). However, area under the curve for testosterone was higher in women with INSR mutations after DHEA than in women with PCOS and controls (874·2 [SE 242] vs 425 [136] and 375·2 [109], p<0·001 for both). AKR1C3 mRNA expression was significantly higher in subcutaneous than in omental adipose tissue (p=0·004). AKR1C3 expression correlated positively with body-mass index in subcutaneous fat (Spearman correlation=0·51, p=0·006). Insulin significantly increased AKR1C3 expression in differentiated subcutaneous adipocytes (p=0·04). Incubation with insulin significantly increased testosterone generation from androstenedione in cultured subcutaneous cell media compared with controls (p<0·001). InterpretationWe have found in-vivo and in-vitro evidence of modulation of AKR1C3 activity by insulin in PCOS and in women with INSR mutations. Insulin seems to drive adipose androgen generation by increasing AKR1C3 activity in female subcutaneous adipose tissue. Selective AKR1C3 inhibition might offer a novel therapeutic target to reduce androgen burden and improve metabolic phenotype in PCOS. FundingWellcome Trust.

Acute Hypertriglyceridemia Induces Platelet Hyperactivity That is Not Attenuated by Insulin in Polycystic Ovary Syndrome

BackgroundAtherothrombosis is associated with platelet hyperactivity. Hypertriglyceridemia and insulin resistance (IR) are features of polycystic ovary syndrome (PCOS). The effect of induced hypertriglyceridemia on IR and platelet function was examined in young women with PCOS.Methods and ResultsFollowing overnight fasting, 13 PCOS and 12 healthy women were infused with saline or 20% intralipid for 5 hours on separate days. Insulin sensitivity was measured using a hyperinsulinemic euglycaemic clamp in the final 2 hours of each infusion. Platelet responses to adenosine diphosphate (ADP) and prostacyclin (PGI2) were measured by flow cytometric analysis of platelet fibrinogen binding and P‐selectin expression using whole blood taken during each infusion (at 2 hours) and at the end of each clamp. Lipid infusion increased triglycerides and reduced insulin sensitivity in both controls (median, interquartile range ) (5.25 [3.3, 6.48] versus 2.60 [0.88, 3.88] mg kg−1 min−1, P<0.001) and PCOS (3.15 [2.94, 3.85] versus 1.06 [0.72, 1.43] mg kg−1 min−1, P<0.001). Platelet activation by ADP was enhanced and ability to suppress platelet activation by PGI2 diminished during lipid infusion in both groups when compared to saline. Importantly, insulin infusion decreased lipid‐induced platelet hyperactivity by decreasing their response to 1 μmol/L ADP (78.7% [67.9, 82.3] versus 62.8% [51.8, 73.3], P=0.02) and increasing sensitivity to 0.01 μmol/L PGI2 (67.6% [39.5, 83.8] versus 40.9% [23.8, 60.9], P=0.01) in controls, but not in PCOS.ConclusionAcute hypertriglyceridemia induced IR, and increased platelet activation in both groups that was not reversed by insulin in PCOS subjects compared to controls. This suggests that platelet hyperactivity induced by acute hypertriglyceridemia and IR could contribute athero‐thrombotic risk.Clinical Trial RegistrationURL: www.isrctn.org. Unique Identifier: ISRCTN42448814.

Insulin resistance in polycystic ovary syndrome is associated with defective regulation of ERK1/2 by insulin in skeletal muscle in vivo

Insulin resistance is a recognized feature of PCOS (polycystic ovary syndrome). However, the molecular reason(s) underlying this reduced cellular insulin sensitivity is not clear. The present study compares the major insulin signalling pathways in skeletal muscle isolated from PCOS and controls. We measured whole-body insulin sensitivity and insulin signalling in skeletal muscle biopsies taken before and after acute exposure to hyperinsulinaemia in nine women diagnosed with PCOS and seven controls. We examined the expression, basal activity and response to in vivo insulin stimulation of three signalling molecules within these human muscle samples, namely IRS-1 (insulin receptor substrate-1), PKB (protein kinase B) and ERK (extracellular-signal-regulated kinase) 1/2. There was no significant difference in the expression, basal activity or activation of IRS-1 or PKB between PCOS and control subjects. However, there was a severe attenuation of insulin stimulation of the ERK pathway in muscle from all but two of the women with PCOS (the two most obese), and an accompanying trend towards higher basal phosphorylation of ERK1/2 in PCOS. These results are striking in that the metabolic actions of insulin are widely believed to require the IRS-1/PKB pathway rather than ERK, and the former has been reported as defective in some previous PCOS studies. Most importantly, the molecular defect identified was independent of adiposity. The altered response of ERK to insulin in PCOS was the most obvious signalling defect associated with insulin resistance in muscle from these patients.

Adipocytes from women with polycystic ovary syndrome demonstrate altered phosphorylation and activity of glycogen synthase kinase 3

To test the hypothesis that an abnormality in glycogen synthase kinase-3 (GSK3) is a pathogenic factor in polycystic ovary syndrome (PCOS). Prospective experimental study (adipocytes). Tertiary-care academic medical center and teaching hospital. Twenty patients with PCOS and 21 healthy control women. Blood sampling, physical exam, biopsy of SC lower abdominal fat. Glucose transport and protein levels and phosphorylation state of glycogen synthase kinase (GSK)-3alpha and GSK3beta in adipocytes; assessment of GSK3beta activity. Basal protein levels of glycogen synthase kinase (GSK3alpha and GSK3beta) did not differ between control women and women with PCOS, nor did basal or insulin-stimulated levels of serine phosphorylated GSK3alpha. However, in adipocytes of women with PCOS, insulin stimulation was not associated with increased serine phosphorylation of GSK3beta, in contrast to the case of control women. Tyrosine phosphorylation of GSK3beta also was higher in women with PCOS, compared with in control women. Consistent with the phosphorylation data, GSK3beta activity was elevated in PCOS adipocytes. These data suggest that GSK3beta is hyperactivated and resistant to down-regulation by insulin in PCOS. By using physiologic approaches, we demonstrated that abnormal GSK3beta regulation is a potential mechanism for the insulin resistance that is seen in some women with PCOS, which may contribute to their development of the syndrome.

Women with polycystic ovary syndrome are sensitive to the TNF‐α‐lowering effect of glucose‐induced hyperinsulinaemia

Restoration of near-euglycaemia by intensive insulin therapy results in decreased serum levels of inflammatory mediators. The authors investigated whether the anti-inflammatory effect of insulin was independent of its glucose-lowering action and if this effect was intact in insulin-resistant women with the polycystic ovary syndrome (PCOS) characterized by low-grade chronic inflammation. Blood was drawn on the third and sixth days after progestin-induced withdrawal bleeding in 20 young non-diabetic women with PCOS and once between the third and sixth days of the menstrual cycle in 21 age-matched lean healthy control women during a 75-g oral glucose tolerance test (oGTT). Serum insulin, glucose and tumour necrosis factor alpha (TNF-alpha) concentrations were measured after 0, 30, 60, 90 and 120 min. The increase in insulin and glucose concentrations during the oGTT was significantly more pronounced in patients with PCOS (one patient with impaired fasting glucose, one patient with impaired glucose tolerance, three patients with both) compared with healthy controls. The TNF-alpha serum concentrations decreased in patients with PCOS (mean of both days, P = 0.004). In patients and in controls, there was an inverse correlation between the serum concentrations of insulin and of TNF-alpha during oGTT (for patients, a mean of both days, P = 0.009; for controls, P = 0.047), but not between the serum concentrations of glucose and TNF-alpha. The decrease in TNF-alpha concentrations during oGTT and the inverse correlation between endogenous hyperinsulinaemia and serum TNF-alpha concentrations suggested an anti-inflammatory effect of moderately-high insulin concentrations. This occurred despite the presence of moderate hyperglycaemia. These findings also demonstrated a preserved responsiveness of inflammatory mediators to insulin in PCOS.

Insulin stimulation of lactate accumulation in isolated human granulosa-luteal cells: a comparison between normal and polycystic ovaries.

Polycystic ovary syndrome (PCOS) is often associated with hyperinsulinaemia and peripheral insulin resistance. Whether the ovary is resistant to insulin is a matter of controversy. The aim was therefore to study the effect of insulin on lactate accumulation, an indicator of glucose metabolism, in granulosa-luteal cells from women with PCOS and from women with normal ovarian function. The cells were obtained from women undergoing clinical in-vitro fertilization-embryo transfer, either from patients with normal ovarian function and tubal or male infertility, or from women with PCOS, with or without tubal factor. The patients were down-regulated with buserelin and stimulated with urofollitrophin and human chorionic gonadotrophin (HCG). Follicle aspiration was performed under ultrasound guidance. Following oocyte recovery the granulosa-luteal cells were isolated, washed and cultured (2-3 x 10(4) viable cells/well) in serum-free Eagle's minimal essential medium for 48 h. After washing, the cells were then cultured in medium containing HCG (0.1-10 IU/ml) or insulin (0.05-0.5 microg/ml) for 24-48 h. Lactate accumulation in the media and cellular protein were analysed. Basal lactate accumulation did not differ in granulosa-luteal cells obtained from normal or PCOS ovaries, and averaged 46 and 49 nmol/g protein/24 h, respectively. A significant stimulation (40-60%) was obtained by HCG in both groups. Insulin caused a dose-dependent increase in lactate in granulosa-luteal cells obtained from normal ovaries (control: 45.5 +/- 6.3; insulin 0.5 microg/ml: 77 +/- 10 nmol/microg protein). Lactate accumulation in granulosa-luteal cells from PCOS ovaries was not altered in the presence of insulin. These results suggest that granulosa-luteal cell glucose metabolism is resistant to insulin in PCOS.