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Bye-bye Chiro-inositol - Myo-inositol: True progress in the treatment of polycystic ovary syndrome and ovulation induction
Abstract
Polycystic ovary syndrome (PCOS) is a multifactorial syndrome affecting 10% of women in reproductive age. Insulin sensitizer agents are the best therapeutic option for PCOS patients; among which there is Inositol. Inositol is a polyalcohol existing as nine different stereoisomers, two of which have been shown to be insulin mediators: myo-inositol (MI) and D-chiro-inositol (DCI). So far only MI have been show to be present in the follicular fluid and in a direct comparison between MI and DCI only MI was able to improve oocyte and embryo quality. Therefore, Could we say "bye-bye D-chiro-Inositol" in the practice of clinical gynecology and reproductive medicine?
... Дослідження з вивчення дії MІ і DХI на якість ооцитів у пацієнток із СПКЯ встановило, що загальна кількість ооцитів в основній (жінки з СПКЯ, які приймали МІ) та контрольній (жінки з СПКЯ, які не приймали МІ) групах не відрізнялась, тоді як кількість зрілих ооцитів, ембріонів хорошої якості і вагітностей була істотно вищою в групі пацієнток, які отримували МІ [61]. Це, ймовірно, пояснюється тим, що на відміну від таких тканин, як м'язи і печінка, яєчники не набувають резистентності до інсуліну [22,29,63]. ...
... Застосування МІ позитивно корелює з кількістю і якістю ооцитів. Так, при прийомі МІ, розпочатому за три місяці до початку контрольованої оваріальної стимуляції, відзначені наступні ефекти: • значне покращення гормональної відповіді; • зменшення кількості рекомбінантного ФСГ (рФСГ), необхідного для оптимального розвитку фолікулів; • зниження рівня естрадіолу в день тригера овуляції, що веде до зниження ризику розвитку СГЯ і меншого числа скасованих циклів [11,22,48]. ...
... The results of a study to study the effect of MI and DCI on the quality of oocytes in patients with PCOS found that the total number of oocytes in the main (women with PCOS took MI) and control (women with PCOS did not receive MI) did not differ, while the number of mature oocytes Good quality embryos and pregnancies were significantly higher in the group of patients receiving MI [61]. This is probably due to the fact that, unlike tissues such as muscle and liver, the ovaries do not acquire insulin resistance [22,29,63]. ...
У статті поданий огляд літературних даних щодо ролі інозитолу та його похідних в організмі людини, результати використання міо-інозитолу (МІ) при гінекологічних захворюваннях, лікуванні жіночого та чоловічого безпліддя, у тому числі в циклах допоміжних репродуктивних технологій, в профілактиці гестаційних і перинатальних ускладнень. Показано, що нездатність адекватно синтезувати або метаболізувати інозитол може сприяти порушенням передачі внутрішньоклітинних сигналів, порушенню активності сигнальних каскадів інсуліну, розвитку резистентності до інсуліну та гіперінсулінемії, що викликає аномальний стероїдогенез у гонадах і метаболічні порушення.
Висвітлена концепція «парадоксу D-хіро-інозитолу», відповідно до якої для жінок із синдромом полікістозних яєчників характерна посилена епімеризація МІ в D-хіро-інозитол, виснаження запасів МІ і, як наслідок, низька якість ооцитів. Доведено, що призначення вагітним біологічно активних добавок з МІ та фолієвою кислотою знижує ймовірність загрози переривання вагітності, прееклампсії, плацентарної дисфункції, гестаційного цукрового діабету, діабетичної фетопатії, вад розвитку, а також оксидативний стрес у плода. Накопичений досвід застосування міо-інозитолу в андрології: він відіграє вирішальну роль в осморегуляції сім’яної рідини і, як наслідок, у збільшенні прогресивної рухливості і швидкості сперматозоїдів, підвищенні мітохондріального потенціалу сперматозоїдів, покращує лібідо та потенцію, сприяє підвищенню рівня ендогенного тестостерону, нормалізує гормональний фон чоловіків.
Інозитоли є синергістами фолатів та інших вітамінів групи В і значуще потенціюють їхній вплив на організм людини, що є підґрунтям переваги використання в клініці жіночої та чоловічої репродукції комбінованих біологічних добавок, таких як Міофолік® та Міофолік® MEN. Гармонійне використання всіх можливих резервів мікронутрієнтної підтримки преконцепційного та гестаційного періоду із застосуванням біологічно активних добавок МІ в комбінації з фолієвою кислотою та вітаміном В12 є перспективним профілактичним і лікувальним методом у підтримці функціонування репродуктивної системи, розвитку ембріона, нейропротекції мозку плода, забезпеченні активності сигнальних каскадів інсуліну.
... Furthermore, natural remedies have gained much attention due to their various biological activities, such as anti-inflammatory and antioxidant properties. All of these functions are related to the ability of pinitol to attenuate or suppress oxidative stress and inflammation, both in vitro and in vivo [66,67]. In a study conducted in 2005, 30 patients with T2DM were treated with hypoglycemic agents using a recommended diet and physical exercises. ...
... Correctness in the use of exercise and nutrition programs, standard medication, and the frequency of potential side effects such as hypoglycemia, abdominal pain, bloating, nausea, diarrhea, and allergic symptoms, were monitored every week by a questionnaire. Anthropometric and biochemical measurements and evaluation of food intake with the 24-h withdrawal method were performed at the beginning of the study and after treatment [66]. ...
Cyclitols play a particularly important role in cell functioning because they are involved in ion channel physiology, phosphate storage, signal transduction, cell wall formation, membrane biogenesis, osmoregulation and they have antioxidant activity. They are involved in the cell membranes as a phosphatidyl myo-inositol, an inositol triphosphate precursor, which acts as a transmitter that regulates the activity of several hormones, such as follicle-stimulating hormone, thyrotropin, and insulin. The aim of this paper is to characterize the selected cyclitols: myo-inositol, D-chiro-inositol, and D-pinitol in type-2 metabolic syndrome and diabetes treatment. Results and discussion: Cyclitols have certain clinical applications in the treatment of metabolic syndromes and are considered to be an option as a dietary supplement for the treatment or prevention of gestational diabetes mellitus and type-2 diabetes. Improved metabolic parameters observed after using cyclitols, like myo-inositol, in the treatment of polycystic ovary syndrome and type-2 diabetes suggest that they may have a protective effect on the cardiovascular system. Pinitol, together with myo-inositol,maybe responsible for improving lipid profiles by reducing serum triglyceride and total cholesterol. Pinitol is also well-researched and documented for insulin-like effects. Myo-inositol, D-chiro-inositol, and D-pinitol indicate a number of therapeutic and health-promoting properties.
... Some workers promote the virtues of dietary Ins supplements that contain DCI (6) , others are non-committal (64,65) and some cite their disadvantages (66) . Given the uncertainties about the Biology of DCIits interconvertibility (or not) with Ins, its role (or not) in insulin signalling and its value (or not) as a supplementthe remainder of this discussion will be confined to exploration of possible ways in which dietary supplements of Ins, a molecule that has many undisputed and well-understood roles in cell function, might help to alleviate the effects of metabolic and hormonal imbalances. ...
... The consequence of these adverse renal events is that any person or animal that is diabetic and/or insulin-resistant, and so is likely to be hyperglycaemic and/or to have elevated circulating insulin, will lose Ins by one or both of these routes and Men with poor sperm quality Improved sperm quality and fertility; increased sperm motilityin vitro and with vaginal pessaries N/A (158)(159)(160)(161)(162)(163)(164)(165) Women undergoing assisted reproduction to relieve fertility problems Improved quality of cultured IVF embryos; more pregnancies with fewer complications (except reference (168)) Yes (66,(166)(167)(168)(169)(170)(171) Women with PCOS and insulin resistance, including some non-obese adolescents Improved hormonal profile; more frequent ovulation and menstruation; improved fertility; improved insulin sensitivity N/A (6,64,65,(172)(173)(174)(175)(176)(177)(178)(179) Pregnant women with or at risk of GDM Decreased GDM incidence (except reference (188) Women (and a few men) with high BMI and/or at risk of MetS and/or T2D Improvement of symptoms in a significant proportion of patients Yes (189)(190)(191)(192)(193)(194)(195) Women at risk of adverse pregnancy outcomes (e.g. from diabetes) ...
This review attempts to explain why consuming extra myo inositol (Ins), an essential component of membrane phospholipids, is often beneficial for patients with conditions characterised by insulin resistance, non-alcoholic fatty liver disease and endoplasmic reticulum (ER) stress. For decades we assumed that most human diets provide an adequate Ins supply, but newer evidence suggests that increasing Ins intake ameliorates several disorders, including polycystic ovary syndrome, gestational diabetes, metabolic syndrome, poor sperm development and retinopathy of prematurity. Proposed explanations often suggest functional enhancement of minor facets of Ins Biology such as insulin signalling through putative inositol-containing ‘mediators’, but offer no explanation for this selectivity. It is more likely that eating extra Ins corrects a deficiency of an abundant Ins-containing cell constituent, probably phosphatidylinositol (PtdIns). Much of a cell’s PtdIns is in ER membranes, and an increase in ER membrane synthesis, enhancing the ER’s functional capacity, is often an important part of cell responses to ER stress. This review: (a) reinterprets historical information on Ins deficiency as describing a set of events involving a failure of cells adequately to adapt to ER stress; (b) proposes that in the conditions that respond to dietary Ins there is an overstretching of Ins reserves that limits the stressed ER’s ability to make the ‘extra’ PtdIns needed for ER membrane expansion; and (c) suggests that eating Ins supplements increases the Ins supply to Ins-deficient and ER-stressed cells, allowing them to make more PtdIns and to expand the ER membrane system and sustain ER functions.
... Other studies stated that it may − at high dosage − negatively affect oocyte quality. [57][58][59] l-Carnitine Celik et al. [60] stated that l-carnitine concentrations were significantly lower in lean patients with PCOS than in lean healthy women. They recommended that l-carnitine could be used as an adjunctive therapy in the management of IR or obesity in women who have PCOS. ...
Polycystic ovary syndrome (PCOS) is a complex syndrome showing the clinical features of an endocrine/metabolic disorder, including hyperinsulinemia and hyperandrogenism. Two phenotypes are present, either lean or obese, with different biochemical, hormonal, and metabolic profiles. Evidence suggests many treatment modalities that can be applied. However, many of these modalities were found to be not suitable for the lean phenotype of PCOS. Much contradictory research was found regarding lean patients with PCOS. The aim of this narrative review is to shed light on the debate prevailing regarding characteristics, as well as metabolic, hematological, and potential management modalities. Literature review was performed from January 1, 2000 to March 31, 2017 with specific word search such as lean PCOS, hormonal abnormalities in lean PCOS, and the management of lean PCOS. All retrieved articles were carefully assessed, and data were obtained. We could conclude that the debate is still prevailing regarding this specific lean population with PCOS, especially with regard to their characteristics and management modalities. Further studies are still required to resolve this debate on the presence of PCOS in lean women.
... [12] Systematic reviews and meta-analysis have collated data on the efficacy of MI in PCOS, and suggest the need for further studies. [13,14] Data also support the use of this molecule in gestational diabetes mellitus (GDM), [15,16] which is also a syndrome characterized by insulin resistance. ...
This review describes the rationale, biochemical, and clinical data related to the use of inositols in polycystic ovary syndrome (PCOS). It covers studies related to the mechanism of action of myo-inositol and D-chiro-inositol (MDI), with randomized controlled trials conducted in women with PCOS, and utilizes these data to suggest pragmatic indications and methods for using MDI combination in PCOS. Rationally crafted inositol combinations have a potential role to play in maintaining metabolic, endocrine, and reproductive health in women with PCOS.
... In recent years, myo-inositol, a glucose isomer of inositol, in consideration of its insulin-sensitizing properties (10), has been used either alone or in combination with drugs such as clomiphene and gonadotropins in PCOS patients for the induction of ovulation. Several clinical studies have demonstrated that myo-inositol has a positive effect both on energy metabolism and on oocyte quality of women affected by PCOS who have undergone in vitro fertilization (IVF) (11)(12)(13)(14)(15)(16). It has also been shown that α-lipoic acid (17), a potent antioxidant enzyme cofactor in the mitochondrial respiratory chain, like myo-inositol, is a substance capable of improving insulin resistance, glycemic control, and lipid profiles and reducing LDL-cholesterol and triglyceride concentrations in PCOS patients with type 2 diabetes (18)(19). ...
The aim of the present study was to evaluate the effectiveness of the combined administration of myo-inositol and α-lipoic acid in polycystic ovary syndrome (PCOS) patients with normal body mass index (BMI), who had previously undergone intracytoplasmic sperm injection (ICSI) and received myo-inositol alone. Thirty-six of 65 normal-weight patients affected by PCOS who did not achieve pregnancy and one patient who had a spontaneous abortion were re-enrolled and given a cycle of treatment with myo-inositol and α-lipoic acid. For all female partners of the treated couples, the endocrine-metabolic and ultrasound parameters, ovarian volume, oocyte and embryo quality, and pregnancy rates were assessed before and after three months of treatment and compared with those of previous in vitro fertilization (IVF) cycle(s). After supplementation of myo-inositol with α-lipoic acid, insulin levels, BMI and ovarian volume were significantly reduced compared with myo-inositol alone. No differences were found in the fertilization and cleavage rate or in the mean number of transferred embryos between the two different treatments, whereas the number of grade 1 embryos was significantly increased, with a significant reduction in the number of grade 2 embryos treated with myo-inositol plus α-lipoic acid. Clinical pregnancy was not significantly different with a trend for a higher percentage for of myo-inositol and α-lipoic acid compared to the myo-inositol alone group. Our preliminary data suggest that the supplementation of myo-inositol and α-lipoic acid in PCOS patients undergoing an IVF cycle can help to improve their reproductive outcome and also their metabolic profiles, opening potential for their use in long-term prevention of PCOS.
... İnositol, özellikle DCI, insülin sinyal transdüksiyonunda görev almaktadır. Bu nedenle insülin direnci ve diyabet gibi hiperinsülinemi durumlarında olumlu etkisi bulunmaktadır (11). MI, FSH, TSH ve insülin gibi hormonların aktivitelerini düzenleyen ikincil mesajcı olarak görev yapan inositol trifosfatın yapısına katılır (12). ...
ABSTRACT
Inositol is a vitaminoid belongs to carbohydrate family. Biologically active form of inositol is Myo-inositol (MI) and less active form is another stereoisomer D-chiro inositol (DCI) synthesized by epimerisation of MI. MI is precursor of inositol triphosphate which is second messenger regulating the hormones like follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH) and insülin. Polycistic over syndrome (PCOS) is frequently seen in women in fertility age and associated with insülin resistance, hyperandrogenism and changes in ovulation. It’s thought that inositol can be effective in the treatment of PCOS due to its positive effects on insülin resistance. It has been determined that insülin sensitivity was improved in the people with PCOS after administration of MI and/or DCI, while oocyte quality was increased in people only MI administration. MI produces second messengers for FSH and glucose uptake, while DCI provides second messengers for glucose uptake and glycogene synthesis. It has been assessed that MI/DCI ratio should be 40:1 for the optimum dosage in PCOS treatment.
Keywords: Inositol, polycystic ovary syndrome, myo-inositol, D-chiro inositol
... Isabella & Raffone 2012) while myo-inositol has been shown to restore ovulatory function in PCOSGerli et al. 2007;Venturella et al. 2012) (reviewed in(Unfer et al. 2012)) and improve oocyte qualityCarlomagno et al. 2011;Galletta et al. 2011). myo-Inositol. ...
Insulin resistance is the first step in the development of type 2 diabetes so finding insulin-sensitizing strategies is challenging for scientists. Some inositol isomers or derivatives have been reported to exert insulin-mimetic activity. myo-Inositol being the most abundant stereoisomeric form of inositol in foodstuffs, we tested its insulin-mimetic potential in the long term and as a nutritional strategy for insulin resistance prevention and/or treatment. This study demonstrates that chronic myo-inositol treatment improves insulin sensitivity, reduces white adipose tissue accretion and improves mice survival mice to paraquat challenge. The insulin-sensitizing effect seems to be related to a direct effect on insulin signaling pathway. Reduction in adipose tissue mass also probably contribute to the long term effect of myo-inositol on insulin sensitivity. Myo-Inositol supplementation also improved insulin sensitivity and reduced white adipose tissue deposition in mice fed a high fat diet, but did not prevent insulin-resistance or obesity development. On one year-old mice with established obesity and altered glycemic control, myo-inositol supplementation showed no beneficial effect. myo-Inositol apparently acts on adipose tissue through reduction of de novo lipogenesis rather than stimulation of lipolysis. This may explain the lack or loss of myo-inositol efficiency in reducing adipose tissue mass in contexts of already well-established obesity (old mice) or reduced de novo lipogenesis (high fat diet feeding). Generation of inositol glycan putative insulin second messengers is probably reduced in context of insulin resistance which may explain the reduced effect of myo-inositol in both obese mice models. Moreover, myo-Inositol did not prevent lipotoxicity and so the associated insulin-resistance in high fat diet fed mice. In conclusion, myo-inositol alone and/or in a context of overnutrition is not a suitable strategy for the prevention or treatment of insulin resistance. Combining it with other insulin sentitizing strategies may however potentiate their action and help reducing insulin-sensitizing drugs use.
Objective: To determine mean decrease in VAS pain score of intraarticular injection of methyl prednisolone acetate in patients of subacromial impingement syndrome. Methods: Its Descriptive Case Series/ Quasi experimental study. Study was conducted in department of Orthopedics Unit- I, Jinnah hospital Lahore. Study completed in Six months i.e. from June 2014 to December 2014.After taking an informed consent, 70 newly diagnosed cases of Subacromial impingement syndrome by history and examination (described by the patient as pain in subacromial space when the humerus was elevated or internally rotated and tested by having the patient place his hand on the unaffected shoulder and gradually forward flexing the shoulder (positive impingement sign)which have not received any kind of treatment were included. Results: Effectiveness of intraarticular injection of methyl prednisolone acetate was measured on visual analogue scale (VAS) from 0 to 10 by VAS score after 6 weeks. 70 patients with mean age of 36.2 ± 10.6 years were included. 61 patients (75.7%) were male, 10 patients (14.3%) had gout and 20% were diabetic. Mean pretreatment VAS score was 5.03 ± 1.58 while mean post-treatment VAS score was 3.86 ± 0.839. Mean reduction was 1.17 ± 1.57 ranged from 2 to 6. There was non-significant association of age and diabetes with mean reduction in VAS score while female gender and gout were significantly and negatively associated with treatment outcome. It is concluded that mean reduction in VAS score after 6 weeks of treatment of subacromial impingement syndrome after intra articular methylprednisolone injection is 1.17 ± 1.57 and acceptable. Conclusion: It is concluded that intraatricular injection of methyl prednisolone injection is efficacious and effective for treatment of Subacromial impingement syndrome in Pakistani population. Keyword: subacromial impingement syndrome, intra articular methylprednisolone injection, visual analogue scale, effectiveness.
Objective: To assess the efficacy of myoinositol in the management of patients with Polycystic ovarian syndrome (PCOS) Methods: It was quasi experimental study conducted inDepartment of Obstetrics and Gynecology Services institute of Medical Sciences, Services Hospital, Lahore from 30-6-2018 to 31-12-2018. 140 sub fertile patients with PCOS were selected through random sampling. Patients were given 2gram of myoinositol/day. The effect was assessed after 3 and 6 months of treatment by monthly menstrual cycle regularity and ovulation. All this information was recorded in proforma. Results: The mean age of patients was 26.90±5.52years. The mean BMI of patients was 37.38±4.08kg/m2. After 3 months of treatment, menstrual cycle become regular in 34 (24.3%) patients and ovulation occurred in 54 (38.6%) cases. After 6 months of treatment, menstrual cycle become regular in 75 (53.6%) patients and ovulation occurred in 101 (72.1%) cases. Conclusion: The myoinositol is an effective treatment in terms of regularity of menstrual cycle and ovulation induction in subfertile women with PCOS. Keywords: Myoinositol, Polycystic ovarian syndrome, Menstrual irregularity, Ovulation
OBJETIVO:
Evaluar el efecto de la combinación de mioinositol y D-chiro-inositol en el perfil metabólico y endocrino de mujeres con síndrome de ovario poliquístico.
MATERIALES Y MÉTODOS:
Estudio experimental, prospectivo y longitudinal efectuado en pacientes con diagnóstico de síndrome de ovario poliquístico (criterios de Rotterdam) sin tratamiento o intervención previa. Diariamente se administraron, por vía oral, 2000 mg de mioinositol y 400 mg de D-chiro-inositol, durante 90 días. Se evalúan y comparan el perfil clínico y metabólico de cada paciente antes y después de la intervención.
RESULTADOS:
Se estudiaron 61 pacientes con síndrome de ovario poliquístico, con una diferencia estadísticamente significativa en los valores de la escala Ferriman-Gallwey (6.06 ± 2.0 y 5.57 ± 1.1; p = 0.003 pre y postratamiento, respectivamente); volumen ovárico izquierdo (7.76 ± 3.2 y 7.18 ± 2.3; p = 0.005, pre y postratamiento, respectivamente). La cuenta de folículos antrales del ovario izquierdo fue de 10.65 ± 6.4 y 10.20 ± 5.7; p=0.029 pre y postratamiento, respectivamente. La cuenta de folículos antrales del ovario derecho fue: 12.11 ± 6.5 y 11.75 ± 6.1; p=0.048 pre y postratamiento, respectivamente. Hubo mejoría en los valores del HOMA (1.85 ± 1.0 y 1.67 ± 0.7; p=0.015 pre y postratamiento, respectivamente. En la proporción LH-FSH: 1.13 ± 0.8 y 0.99 ± 0.6; p=0.018 pre y postratamiento, respectivamente.
CONCLUSIÓN:
Los resultados del estudio muestran un efecto positivo de la administración combinada de mioinositol y D-chiro-inositol en el perfil clínico y metabólico de pacientes con síndrome de ovario poliquístico. La mejora en las concentraciones séricas de andrógenos, de la proporción LH-FSH y la regularización de los ciclos menstruales puede contribuir al aumento de la fertilidad en pacientes con síndrome de ovario poliquístico y factor ovárico.
Cell signaling via inositol phosphates, in particular via the second messenger myo-inositol 1,4,5-trisphosphate, and phosphoinositides comprises a huge field of biology. Of the nine 1,2,3,4,5,6-cyclohexanehexol isomers, myo-inositol is pre-eminent, with "other" inositols (cis-, epi-, allo-, muco-, neo-, L-chiro-, D-chiro-, and scyllo-) and derivatives rarer or thought not to exist in nature. However, neo- and D-chiro-inositol hexakisphosphates were recently revealed in both terrestrial and aquatic ecosystems, thus highlighting the paucity of knowledge of the origins and potential biological functions of such stereoisomers, a prevalent group of environmental organic phosphates, and their parent inositols. Some "other" inositols are medically relevant, for example, scyllo-inositol (neurodegenerative diseases) and D-chiro-inositol (diabetes). It is timely to consider exploration of the roles and applications of the "other" isomers and their derivatives, likely by exploiting techniques now well developed for the myo series.
Zelluläre Signalkaskaden über Inositolphosphate, insbesondere über den sekundären Botenstoff myo-Inositol-1,4,5-trisphosphat und über die Phosphoinositide, umfassen ein riesiges Gebiet der Zellbiologie. Unter den neun 1,2,3,4,5,6-Cyclohexanhexolisomeren ist myo-Inositol vorherrschend, während die “anderen” Inositole (cis-, epi-, allo-, muco-, neo-, L-chiro-, D-chiro- und scyllo-) und ihre Derivate seltener sind oder nicht in der Natur vermutet wurden. Vor kurzem wurden jedoch neo- und D-chiro-Inositolhexakisphosphate in terrestrischen und aquatischen Ökosystemen entdeckt, was zeigt, wie lückenhaft unser Wissen über die Herkunft und möglichen biologischen Funktionen solcher Stereoisomere, einer vorherrschenden Gruppe in der Natur vorkommender organischer Phosphate, und der Inositole als Ausgangsverbindungen ist. Einige “andere” Inositole sind medizinisch bedeutsam, wie scyllo-Inositol (bei neurodegenerativen Erkrankungen) und D-chiro-Inositol (bei Diabetes). Es ist an der Zeit, Funktionen und Anwendungsmöglichkeiten der “anderen” Isomere und ihrer Derivate zu erforschen, vor allem mit Methoden, die für die myo-Inositole inzwischen gut etabliert sind.
Inositol is a physiological compound belonging to the sugar family. The two inositol stereoisomers, myo-inositol and D-chiroinositol are the two main stereisomers present in our body. Myo-inositol is the precursor of inositol triphosphate, a second messenger regulating many hormones such as TSH, FSH and insulin. D-chiroinositol is synthetized by an insulin dependent epimerase that converts myo-inositol into D-chiro-inositol. Polycistic Ovary Syndrome (PCOS) is a metabolic and hormonal disorder and a common cause of infertility. Insulin resistance and the consequent hyperinsulinaemia contribute to hyperandrogenism development, typical marker of PCOS. In these patients myo and/or D-chiro-inositol administration improves insulin sensivity while only myo-inositol is a quality marker for oocytes evaluation. Myo-inositol produces second messengers for FSH and glucose uptake, while D-chiroinositol provides second messengers promoting glucose uptake and glycogen synthesis. The physiological ratio of these two isomers is 40:1 (MI/DCI) and seems to be an optimal approach for the treatment of PCOS disorders.
Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies in reproductive-age women. It often presents during late adolescence but in some cases certain features are evident even before menarche. PCOS is a spectrum of disorders with any combination of oligo/anovulation, clinical and/or biochemical evidence of androgen excess, obesity, insulin resistance and polycystic ovaries on ultrasound. The pathogenesis is unknown; however, it is a complex multigenetic disorder where disordered gonadotropin release, dysregulation of steroidogenesis, hyperinsulinism and insulin resistance play a role. The diagnosis is based on a typical physical exam (acne, hirsutism, obesity, and acanthosis nigricans) and laboratory evidence of hyperandrogenism, such as elevated free testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEAS), decreased sex hormone-binding globulin (SHBG) and increased luteinizing hormone (LH). An ovarian ultrasound may detect the multiple cysts. Secondary causes of PCOS need to be excluded. There are several classes of medications correcting different parameters of PCOS that can be used alone or in combination. Oral contraceptive therapy is used to reduce androgen and LH levels with resultant improvement in acne and hirsutism, and the induction of regular menses. Antiandrogens are usually required for a substantial improvement in hirsutism score. Insulin sensitizers such as metformin are a new class of drugs utilized in treatment of PCOS. By improving insulin sensitivity and decreasing insulin levels, they improve the unfavorable metabolic profile of patients with PCOS. Metformin also helps to increase SHBG, decrease androgen levels and induce ovulation. Despite all the available medications, life-style changes are the mainstay of therapy as weight loss and exercise improve all parameters of PCOS without the potential side effects of medication.
Insulin resistance and hyperinsulinaemia are well-recognized characteristics of anovulatory women with polycystic ovary syndrome (PCOS) but, paradoxically, steroidogenesis by PCOS granulosa cells remains responsive to insulin. The hypothesis to be tested in this study is that insulin resistance in the ovary is confined to the metabolic effects of insulin (i.e. glucose uptake and metabolism), whereas the steroidogenic action of insulin remains intact.
Granulosa-lutein cells were obtained during IVF cycles from seven women with normal ovaries, six ovulatory women with PCO (ovPCO) and seven anovulatory women with PCO (anovPCO). Mean body mass index was in the normal range in all three groups. Granulosa-lutein cells were cultured with insulin (1, 10, 100 and 1000 ng/ml) and LH (1, 2.5 and 5 ng/ml). Media were sampled at 24 and 48 h and analysed for glucose uptake, lactate production and (48 h only) progesterone production.
Insulin-stimulated glucose uptake by cells from anovPCO was attenuated at higher doses of insulin (100 and 1000 ng/ml) compared with that by cells from either ovPCO (P=0.02) or controls (P=0.02). Insulin and LH stimulated lactate production in a dose-dependent manner, but insulin-dependent lactate production was markedly impaired in granulosa-lutein cells from anovPCO compared with either normal (P=0.002) or ovPCO (P<0.0001). By contrast, there was no difference in insulin-stimulated progesterone production between granulosa-lutein cells from the three ovarian types.
Granulosa-lutein cells from women with anovPCOS are relatively resistant to the effects of insulin-stimulated glucose uptake and utilization compared with those from normal and ovPCO, whilst maintaining normal steroidogenic output in response to physiological doses of insulin. These studies support the probability of a post-receptor, signalling pathway-specific impairment of insulin action in PCOS.
The D-chiro-inositol-to-myo-inositol ratio is regulated by an insulin-dependent epimerase. Enzyme activity varies among tissues, likely owing to the specific needs of the two different molecules. We hypothesize that in the ovaries of polycystic ovary syndrome patients, epimerase activity is enhanced, leading to a local myo-inositol deficiency which in turn is responsible for the poor oocyte quality.
BACKGROUND and
Inositol is a major component of the intracellular mediators of insulin action. To investigate the possible role of altered inositol metabolism in non-insulin-dependent diabetes mellitus (NIDDM), we used gas chromatography and mass spectrometry to measure the myo-inositol and chiro-inositol content of urine specimens from normal subjects and patients with NIDDM: The study subjects were whites, blacks, and Pima Indians. The type of inositol and its concentration in insulin-mediator preparations from muscle-biopsy specimens from normal subjects and diabetic patients were also determined.
The urinary excretion of chiro-inositol was much lower in the patients with NIDDM (mean [+/- SE], 1.8 +/- 0.8 mumol per day) than in the normal subjects (mean, 84.9 +/- 26.9 mumol per day; P less than 0.01). In contrast, the mean urinary myo-inositol excretion was higher in the diabetic patients than in the normal subjects (444 +/- 135 vs. 176 +/- 46 mumol per day; P less than 0.05). There was no correlation between chiro-inositol excretion and the age, sex, or weight of the diabetic patients, nor was there any correlation between urinary chiro-inositol and myo-inositol excretion in either group. The results were similar in a primate model of NIDDM, and chiro-inositol excretion was decreased to a lesser extent in animals with prediabetic insulin resistance. chiro-Inositol was undetectable in insulin-mediator preparations from muscle-biopsy samples obtained from patients with NIDDM: Similar preparations from normal subjects contained substantial amounts of chiro-inositol. Furthermore, the chiro-inositol content of such preparations increased after the administration of insulin during euglycemic-hyperinsulinemic-clamp studies in normal subjects but not in patients with NIDDM:
NIDDM is associated with decreased chiro-inositol excretion and decreased chiro-inositol content in muscle. These abnormalities seem to reflect the presence of insulin resistance in NIDDM:
Women with the polycystic ovary syndrome have insulin resistance and hyperinsulinemia, possibly because of a deficiency of a D-chiro-inositol-containing phosphoglycan that mediates the action of insulin. We hypothesized that the administration of D-chiro-inositol would replenish stores of the mediator and improve insulin sensitivity.
We measured steroids in serum and performed oral glucose-tolerance tests before and after the oral administration of 1200 mg of D-chiro-inositol or placebo once daily for six to eight weeks in 44 obese women with the polycystic ovary syndrome. The serum progesterone concentration was measured weekly to monitor for ovulation.
In the 22 women given D-chiro-inositol, the mean (+/-SD) area under the plasma insulin curve after the oral administration of glucose decreased from 13,417+/-11,572 to 5158+/-6714 microU per milliliter per minute (81+/-69 to 31+/-40 nmol per liter per minute) (P=0.007; P=0.07 for the comparison of this change with the change in the placebo group); glucose tolerance did not change significantly. The serum free testosterone concentration in these 22 women decreased from 1.1+/-0.8 to 0.5+/-0.5 ng per deciliter (38+/-7 to 17+/-3 pmol per liter) (P=0.006 for the comparison with the change in the placebo group). The women's diastolic and systolic blood pressure decreased by 4 mm Hg (P<0.001 and P=0.05, respectively, for the comparisons with the changes in the placebo group), and their plasma triglyceride concentrations decreased from 184+/-88 to 110+/-61 mg per deciliter (2.1+/-0.2 to 1.2+/-0.1 mmol per liter) (P=0.002 for the comparison with the change in the placebo group). None of these variables changed appreciably in the placebo group. Nineteen of the 22 women who received D-chiro-inositol ovulated, as compared with 6 of the 22 women in the placebo group (P<0.001).
D-Chiro-inositol increases the action of insulin in patients with the polycystic ovary syndrome, thereby improving ovulatory function and decreasing serum androgen concentrations, blood pressure, and plasma triglyceride concentrations.
Some actions of insulin are mediated by putative inositolphosphoglycan mediators, and a deficiency in D-chiro-inositol-containing inositolphosphoglycan (DCI-IPG) may contribute to insulin resistance in women with polycystic ovary syndrome (PCOS). Furthermore, similar effects of DCI and metformin, an insulin-sensitizing drug, have been demonstrated in PCOS women. To determine whether metformin improves insulin actions by increasing biologically active DCI-IPG in women with PCOS, we analyzed DCI-IPG during an oral glucose tolerance test in 19 obese women with PCOS before and after 4-8 wk of metformin or placebo. After treatment, the mean (+/-SE) area under the curve (AUC) during the oral glucose tolerance test of insulin (AUC(insulin)) decreased significantly more in the metformin group, compared with the placebo group [-3574 +/- 962 vs. +1367 +/- 1021 micro IU/min.ml (-26 +/- 7 vs. +10 +/- 7 nmol/min.liter), P = 0.003], but the AUC of DCI-IPG (AUC(DCI-IPG)) decreased similarly in both groups (-1452 +/- 968 vs. -2207 +/- 1021%/min, P = 0.60). However, the ratio of AUC(DCI-IPG)/AUC(insulin) increased by 160% after metformin and decreased by 29% after placebo (P = 0.002 between groups). Moreover, metformin seemed to improve the positive correlation between AUC(DCI-IPG) and AUC(insulin) but not placebo (r = 0.32, P = 0.68 at baseline; r = 0.52, P = 0.12 after metformin; and r = -0.39, P = 0.30 after placebo). We conclude that in obese women with PCOS, metformin may improve the action of insulin in part by improving insulin-mediated release of DCI-IPG mediators, as evidenced by increased bioactive DCI-IPG released per unit of insulin.
To determine whether the administration of D-chiro-inositol, a putative insulin-sensitizing drug, would affect the concentration of circulating insulin, the levels of serum androgens, and the frequency of ovulation in lean women with the polycystic ovary syndrome.
In 20 lean women (body mass index, 20.0 to 24.4 kg/m 2) who had the polycystic ovary syndrome, treatment was initiated with either 600 mg of D-chiro-inositol or placebo orally once daily for 6 to 8 weeks. We performed oral glucose tolerance tests and measured serum sex steroids before and after therapy. To monitor for ovulation, we determined serum progesterone concentrations weekly.
In the 10 women given D-chiro-inositol, the mean (+/- standard error) area under the plasma insulin curve after oral administration of glucose decreased significantly from 8,343 +/- 1,149 mU/mL per min to 5,335 +/- 1,792 mU/mL per min in comparison with no significant change in the placebo group (P = 0.03 for difference between groups). Concomitantly, the serum free testosterone concentration decreased by 73% from 0.83 +/- 0.11 ng/dL to 0.22 +/- 0.03 ng/dL, a significant change in comparison with essentially no change in the placebo group (P = 0.01). Six of the 10 women (60%) in the D-chiro-inositol group ovulated in comparison with 2 of the 10 women (20%) in the placebo group (P = 0.17). Systolic (P = 0.002) and diastolic (P = 0.001) blood pressures, as well as plasma triglyceride concentrations (P = 0.001), decreased significantly in the D-chiro-inositol group in comparison with the placebo group, in which these variables either increased (blood pressure) or decreased minimally (triglycerides).
We conclude that, in lean women with the polycystic ovary syndrome, D-chiro-inositol reduces circulating insulin, decreases serum androgens, and ameliorates some of the metabolic abnormalities (increased blood pressure and hypertriglyceridemia) of syndrome X.
Polycystic ovary syndrome (PCOS) is often characterized by chronic oligo- or anovulation (usually manifested as oligo- or amenorrhea), and hyperandrogenism. In addition, 30-40% of PCOS women have impaired glucose tolerance, and a defect in the insulin signaling pathway (inositol-containing phosphoglycan mediators) seems to be implicated in the pathogenesis of insulin resistance. PCOS patients are subfertile as a consequence of such ovulatory disorders and often need drugs, such as clomiphene citrate or follicle-stimulating hormone, for ovulation induction, which increases the risk of multiple pregnancy and ovarian hyperstimulation syndrome. We hypothesized that the administration of an isoform of inositol (myo-inositol), belonging to the vitamin B complex, would improve the insulin-receptor activity, restoring normal ovulatory function.
Twenty-five PCOS women of childbearing age with oligo- or amenorrhea were enrolled in the study. Ovulatory disorder due to PCOS was apparently the only cause of infertility; no tubal defect or deficiency of male semen parameters was found. Myo-inositol combined with folic acid (Inofolic) 2 g twice a day was administered continuously. During an observation period of 6 months, ovulatory activity was monitored with ultrasound scan and hormonal profile, and the numbers of spontaneous menstrual cycles and eventually pregnancies were assessed.
Twenty-two out of the 25 (88%) patients restored at least one spontaneous menstrual cycle during treatment, of whom 18 (72%) maintained normal ovulatory activity during the follow-up period. A total of 10 singleton pregnancies (40% of patients) were obtained. Nine clinical pregnancies were assessed with fetal heart beat at ultrasound scan. Two pregnancies evolved in spontaneous abortion.
Myo-inositol is a simple and safe treatment that is capable of restoring spontaneous ovarian activity and consequently fertility in most patients with PCOS. This therapy did not cause multiple pregnancy.
The aim of the study was to evaluate the efficacy of a treatment with myo-inositol plus folic acid plus melatonin compared with myo-inositol plus folic acid alone on oocyte quality in women underwent in vitro fertilization (IVF) cycles.
A prospective, clinical trial.
Starting on the day of GnRH administration, 65 women undergoing IVF cycles were randomized in two groups to receive myo-inositol plus folic acid plus melatonin (32 women, group A), and myo-inositol plus folic acid (33 women, group B), administered continuously. Primary endpoints were number of morphologically mature oocytes retrieved (MII oocytes), embryo quality, and pregnancy rate. Secondary endpoints were the total number of oocytes retrieved (immature and mature oocytes), fertilization rate per number of retrieved oocytes and embryo cleavage rate.
The mean number of oocytes retrieved did not differ between the two groups (7.88 +/- 1.76 vs 7.67 +/- 1.88; P=0.65). Whereas the group cotreated with melatonin reported a significantly greater mean number of mature oocytes (6.56 +/- 1.64 vs 5.76 +/- 1.56; P=0.047) and a lower mean number of immature oocytes (1.31 +/- 0.74 vs. 1.91 +/- 0.68; P=0.001). The mean number of embyos of top-quality (class 1 and 2) resulted higher in the group A (1.69 +/- 0.64 vs 1.24 +/- 0.75; P=0.01). Fertilization rate did not differ between the two groups. A total of 22 pregnancies were obtained (13 in group A and 9 in group B; P=0.26). Clinical pregnancy rate and implantation rate were in tendency higher in the group cotreated with melatonin, although the differences did not reach statistical significance. Biochemical pregnancy rate and abortion rate were similar in both groups.
melatonin ameliorates the activity of myo-inositol and folic acid by improving oocyte quality and pregnancy outcome in women with low oocyte quality history.
The effect of follicular fluid (FF) oxidative stress (OS) on meiotic spindle (MS) formation in oocytes and subsequent outcome in women with polycystic ovarian syndrome (PCOS) are evaluated in this study.
326 oocytes from 35 PCOS women (group A) and 208 oocytes from 32 women with tubal infertility (group B) were visualized for MS using PolScope. FF was analyzed for OS markers including reactive oxygen species (ROS), lipid peroxidation and total antioxidant capacity (TAC). Group A was further classified into groups A1 and A2, and group B into groups B1 and B2 depending upon the presence or absence of MS, respectively.
MS formation was absent in a significantly higher number of oocytes in group A compared to group B (p <or= 0.05). OS markers were significantly higher in group A compared to group B (p <or= 0.05). Fertilization rate, number of good quality embryos and clinical pregnancy rates were higher in group B compared to group A, though not statistically significant. FF ROS was significantly higher and TAC significantly lower in groups A2 and B2 compared to groups A1 and B1 (p < 0.001).
The presence of MS and oocyte maturation in PCOS women showed a positive correlation with low levels of OS.
Polycystic ovary syndrome (PCOS) is the most common endocrine cause of hirsutism, acne and pattern alopecia, often characterised by ovulation disorders (usually manifested as oligo- or amenorrhea). In addition, 30-40% of women with PCOS have impaired glucose tolerance, and a defect in the insulin signalling pathway seems to be implicated in the pathogenesis of insulin resistance. For this reason, insulin-lowering medications represent novel approach in women with PCOS. The aim of this study was to evaluate the effects of myo-inositol (MYO), an isoform of inositol, belonging to the vitamin B complex, in the treatment of cutaneous disorders like hirsutism and acne.
Fifty patients with PCOS were enrolled in the study. BMI, LH, FSH, insulin, HOMA index, androstenedione, testosterone, free testosterone, hirsutism and acne were evaluated at the baseline and after receiving MYO therapy for 6 months.
After 3 months of MYO administration, plasma LH, testosterone, free testosterone, insulin and HOMA index resulted significantly reduced; no significant changes were observed in plasma FSH and androstenedione levels. Both hirsutism and acne decreased after 6 months of therapy.
MYO administration is a simple and safe treatment that ameliorates the metabolic profile of patients with PCOS, reducing hirsutism and acne.
The aim of this study was to evaluate the effects of myo-inositol treatment in hirsute women; changes in lipid pattern and insulin sensitivity were also considered. Forty-six hirsute women were enrolled at the first Institute of Obstetrics and Gynecology and evaluated at baseline and after receiving myo-inositol therapy for 6 months. Body mass index (BMI), hirsutism, serum concentrations of total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, apolipoprotein B, lipoprotein(a), serum adrenal and ovarian androgens, fasting glucose and insulin concentrations were evaluated. No changes in BMI were observed. The hirsutism decreased after therapy (P < 0.001). Total androgens, FSH and LH concentrations decreased while oestradiol concentrations increased. There was a slight non-significant decrease in total cholesterol concentrations, an increase in HDL cholesterol concentrations and a decrease in LDL cholesterol concentrations. No significant changes were observed in serum triglyceride, apolipoprotein B and lipoprotein(a) concentrations. Insulin resistance (P < 0.01), analysed by homeostasis model assessment, was reduced significantly after therapy. Administration of oral myo-inositol significantly reduced hirsutism and hyperandrogenism and ameliorated the abnormal metabolic profile of women with hirsutism.
Some actions of insulin are mediated by inositolphosphoglycan (IPG) mediators. Deficient release of a putative D-chiro-inositol-containing (DCI) IPG mediator may contribute to insulin resistance in women with polycystic ovary syndrome (PCOS). Previously, we demonstrated that oral DCI supplementation improved ovulation and metabolic parameters in women with PCOS. However, whether oral DCI mediates an increase in the release of the DCI-IPG mediator and an improvement in insulin sensitivity in women with PCOS is unknown. We conducted a randomized controlled trial of DCI supplementation vs placebo in 11 women with PCOS who were assessed at 2 time points 6 weeks apart. Plasma DCI, DCI-IPG release during oral glucose tolerance test (AUC(DCI-IPG)), and insulin sensitivity (S(i)) by frequently sampled intravenous glucose tolerance test were assessed at baseline and end of study. The study was terminated early because of a sudden unavailability of the study drug. However, in all subjects without regard to treatment assignment, there was a positive correlation between the change in AUC(DCI-IPG)/AUC(insulin) ratio and the change in S(i) during the 6-week period (r = 0.69, P = .02), which remained significant after adjustment for body mass index (P = .022) and after further adjustment for body mass index and treatment allocation (P = .0261). This suggests that, in women with PCOS, increased glucose-stimulated DCI-IPG release is significantly correlated with improved insulin sensitivity. The significant relationship between DCI-IPG release and insulin sensitivity suggests that the DCI-IPG mediator may be a target for therapeutic interventions in PCOS.
Over the last five decades, Joseph Larner has tirelessly pursued scientific studies of the mechanism of insulin action, which are now providing new insight into the cause, diagnosis, and cure of non-insulin-dependent diabetes mellitus (NIDDM). Larner demonstrated that D-chiro-inositol (D-CI) is virtually absent in the urine of patients with NIDDM. Consequently, he suggested that the insulin resistance seen in such patients is related to the absence of one of the mediators of insulin action containing D-CI. Moreover, Larner demonstrated that this D-CI deficiency and insulin resistance could be corrected by the administration of D-CI to experimental diabetic and insulin-resistant animals. From this pioneering research, the potential for therapy using D-CI in NIDDM is evident and must be evaluated expeditiously.
chiro- and myo-Inositols are major components of the two inositol phosphoglycan mediators of insulin action. Previous work in this laboratory has shown hypo-chiro-inositoluria in type II diabetic subjects and decreased chiro-inositol in mediator prepared from skeletal-muscle biopsies of Pima Indian diabetic subjects together with increased myo-inositol concentrations. Because mediator bioactivity was not previously examined, we decided to isolate the two types of insulin mediator from hemodialysate, urine, and autopsy muscle to investigate their bioactivity in control and type II diabetic subjects. Human mediator fractions were isolated at pH 2.0 and pH 1.3 from hemodialysate, urine, and autopsy muscle of type II diabetic subjects and nondiabetic control subjects. Mediators were assayed for bioactivity, and the relative chiro-inositol/myo-inositol concentration ratio was determined for the mediator pH 2.0 samples by using HPLC or GC/MS. Regardless of source, the chiro-inositol-containing mediator pH 2.0 fractions from type II diabetic subjects were markedly less active than those from controls (50% or less) (P < 0.05). In addition, the chiro-inositol/myo-inositol ratio in samples from type II subjects was significantly reduced (1/3-1/9) compared with controls (P < 0.05 for hemodialysate and P < 0.01 for muscle samples). In contrast, no difference in bioactivity was seen in myo-inositol-containing mediator pH 1.3 samples isolated from the same type II diabetic and control subjects. In type II diabetes there is a generalized deficiency of chiro-inositol mediator in the body in terms of both decreased chiro-inositol mediator (pH 2.0) bioactivity and chiro-inositol content.
Previous data from our and other labs demonstrated a decreased chiro-inositol content in urine and tissues of human subjects and animals with type 2 diabetes. In urine this decrease in chiro-inositol was accompanied by an increase in myo-inositol content. Decreased urine levels of chiro-inositol in monkeys were next correlated with the severity of underlying insulin resistance determined by five separate assays. To investigate the decreased chiro-inositol and the accompanying increased myo-inositol excretions in urine in humans and monkeys, we postulated a defect in the epimerization of myo-inositol to chiro-inositol. [(3)H]Myo-inositol was then shown to be converted to [(3)H]chiro-inositol in rats in vivo and in fibroblasts in vitro in a process stimulated by insulin. We next demonstrated that the conversion of [(3)H]myo-inositol to [(3)H]chiro-inositol in vivo was markedly decreased in GK type 2 diabetic rats compared to Wistar controls in liver, muscle, and fat, insulin sensitive tissues. Decreases of 20-25% conversion to baseline levels of under 5% conversion were observed. In the present work, we initially compared the total contents of myo-inositol and chiro-inositol in GK type 2 diabetic rat kidney, liver, and muscle compared to Wistar controls. We demonstrated a consistent decreased total chiro-inositol to myo-inositol ratio in kidney, liver, and muscle compared to controls. We next established the presence of a myo-inositol to chiro-inositol epimerase activity in rat liver cytosol. Enzyme activity was shown to be time and enzyme concentration dependent with a broad pH optimum. It required NADH and NADPH for full activity, which is compatible with its action via an oxido-reductive mechanism. Lastly, we demonstrated that the epimerase enzyme bioactivity was significantly decreased in muscle, liver, and fat cytosolic extracts of GK type 2 diabetic rats versus Wistar controls. Decreased myo-inositol to chiro-inositol epimerase activity may therefore play a role in explaining the decreased chiro-inositol to myo-inositol urine and tissue ratios observed here and in previous animal and human studies. Further it may also possibly play a role in the underlying insulin resistance.
Evidence suggests that some actions of insulin are effected by inositolphosphoglycan (IPG) mediators. We hypothesize that a deficiency in D-chiro-inositol (DCI) and/or a DCI-containing IPG (DCI-IPG) may contribute to insulin resistance in humans.
To assess this possibility in polycystic ovary syndrome (PCOS), we determined insulin sensitivity (Si by frequently sampled intravenous glucose tolerance test), plasma and urinary DCI and myo-inositol (MYO) levels (by gas chromatography/mass spectrometry), and the release of insulin and DCI-IPG during the oral glucose tolerance test (area under the curve [AUC]) in 23 women with PCOS and 26 normal women.
Women with PCOS were heavier than control subjects (P = 0.002 for BMI), but also had decreased Si (P < 0.001) and increased AUC(insulin) (P < 0.001) compared with normal women, even when corrected for BMI. The urinary clearance of DCI (uCl(DCI)) was increased almost sixfold in PCOS compared with normal women (P = 0.001), but not MYO clearance (P = 0.10). uCl(DCI) correlated inversely with Si when all women were analyzed together (n = 49, r = -0.50, P < 0.001) and was one of the three best independent parameters predicting Si. Finally, the ratio of AUC(DCI-IPG) to AUC(insulin) was decreased threefold in women with PCOS (P < 0.001).
uCl(DCI) is inversely correlated with insulin sensitivity in women and is a strong independent predictor of insulin resistance in multivariate models. PCOS, which is characterized by insulin resistance, is associated with a selective increase in uCl(DCI) and impaired DCI-IPG release in response to insulin. These findings are consistent with a defect in tissue availability or utilization of DCI in PCOS that may contribute to the insulin resistance of the syndrome.