Insulin resistance and PCOS -
Several PCOS genetic susceptibility loci have been mapped and replicated. Some of the same susceptibility genes contribute to disease risk in Chinese and European PCOS populations, suggesting that PCOS is an ancient trait.
Background and Historical Perspective. Experiments of nature—rare syndromes of extreme insulin resistance and hyperandrogenism. The pathways linking reproductive function with metabolic cues are evolutionarily conserved traits that are present in Caenorhabditis elegans and Drosophila 1 , 2.
The reproductive features of polycystic ovary syndrome PCOS were noted by Hippocrates in the fifth century B. The observation that signs of androgen excess were coupled with metabolic abnormalities, such as increased visceral fat, dates back to at least the 18th century.
In , Morgagni 4 reported detailed anatomic investigations in various conditions. He described a yr-old woman with severe obesity and android aspect valde obesa et virili aspectu.
Elegant studies by Kissebah et al. These women also had increased androgen production rates 8. In the s, several rare syndromes of extreme insulin resistance, acanthosis nigricans, and hyperandrogenism were described 9. The molecular mechanisms of insulin resistance in these syndromes involved reduced insulin binding to its receptor or defective receptor autophosphorylation due to insulin receptor mutations Type A syndrome, Rabson-Mendenhall syndrome, Donohue syndrome, or leprechaunism or insulin receptor autoantibodies type B syndrome 10 — The phenotypically distinct disorders of familial lipodystrophy and extreme insulin resistance were also noted to be associated with signs and symptoms of hyperandrogenism 12 — The common feature of these syndromes was profound hyperinsulinemia, which suggested for the first time that insulin might directly stimulate testosterone T production 9 , The original description of enlarged, smooth polycystic ovaries PCO is credited to Chereau in In the 19th century, ovarian wedge resection became a recommended therapy 17 , although Stein and Leventhal 18 first reported that the clinical features of menstrual regularity and infertility could be improved by removal of portions of both ovaries.
As a result, the constellation of enlarged, sclerocystic ovaries frequently associated with hirsutism, menstrual irregularity, obesity, and infertility became known as the Stein-Leventhal syndrome 17 , In recent decades, PCOS has become the preferred terminology 17 , Until the s, PCOS remained a poorly understood reproductive disorder 17 , In , Burghen et al.
Furthermore, women with typical PCOS had acanthosis nigricans, raising the possibility that they were insulin resistant, similar to women with the rare syndromes of extreme insulin resistance 22 , These observations launched a new field of study on the mechanisms for the association between insulin resistance and PCOS Fig.
A new field—PCOS and insulin resistance. The first article reporting an association between PCOS and hyperinsulinemia was published in There are approximately , citations in a Web of Science Thomson Reuters, New York, NY Citation Report for — on the topics of PCOS or hyperandrogenism and hyperinsulinemia, insulin resistance, glucose intolerance, or diabetes mellitus.
The annual citations have increased steadily from 1 in to approximately 12, in This figure was created from the Web of Science Citation Report.
Pathophysiology of the PCOS reproductive phenotype. There is increased frequency of pulsatile GnRH release that selectively increases LH secretion.
LH stimulates ovarian theca cell T production. T is incompletely aromatized by the adjacent granulosa cells because of relative FSH deficiency. There are also constitutive increases in the activity of multiple steroidogenic enzymes in polycystic ovaries contributing to increased androgen production.
Increased adrenal androgen production may also be present in PCOS. T acts in the periphery to produce signs of androgen excess, such as hirsutism, acne, and alopecia. T and androstenedione can also be aromatized extragonadally to estradiol and estrone, respectively, resulting in unopposed estrogen action on the endometrium.
T feeds back on the hypothalamus to decrease the sensitivity to the normal feedback effects of estradiol and progesterone to slow GnRH pulse frequency. This figure is used with the permission of Andrea Dunaif. Acne and androgenic alopecia are other clinical signs of hyperandrogenemia 25 — Acanthosis nigricans is a skin lesion characterized clinically by velvety, papillomatous, brownish-black, hyperkeratotic plaques, typically on the intertriginous surfaces and neck.
However, acanthosis nigricans is diagnosed definitively by histological examination of the skin showing hyperkeratosis and papillomatosis, frequently with hyperpigmentation It is evident on clinical examination in a substantial percentage of obese women with PCOS as well as in some lean affected women.
However, it is present in the majority of obese women with PCOS and in obese control women by histological examination Many lean women with PCOS also show histological evidence of acanthosis nigricans Its severity is directly correlated with the degree of insulin resistance 33 , Oligomenorrhea is defined as menstrual cycles that are longer than 35 d usually fewer than eight cycles per year and is a sign of anovulatory cycles However, regular menstrual cycles do not exclude chronic anovulation, especially in women with clinical signs of androgen excess Therefore, ovulation should be assessed by measuring serum progesterone concentration during the luteal phase of the menstrual cycle in women with regular menses and androgenic signs or symptoms Hyperandrogenemia is the biochemical hallmark of PCOS Elevated levels of free T account for the vast majority of abnormal findings in the laboratory examination 24 , This finding reflects the fact that SHBG levels are typically decreased in PCOS due to the effects of T 38 and insulin 39 to decrease hepatic production of SHBG.
The measurement of total and free T levels is constrained by the available assay methods. Assays for total T lack precision and sensitivity in the female T range, including T levels typical of PCOS 40 , The accurate measurement of free T by equilibrium dialysis is technically challenging and costly, whereas direct measurement of free T is inaccurate 41 , Measurements of total T by RIA or liquid chromatography-mass spectrometry in a specialized endocrine laboratory are currently the best available methodologies Free and biologically available T can be calculated from the concentrations of total T, SHBG, and albumin by using the affinity constants of T for these molecules In practice, albumin is often not measured, and an assumed normal value is used in the calculation.
Whether the concurrent measurement of androstenedione increases the diagnosis of hyperandrogenemia is unclear 24 , Although the ovaries are the main source of increased androgens in PCOS 44 , adrenal androgen excess is a common feature of the syndrome 24 , Women with PCOS demonstrate increased secretion of adrenocortical precursor steroids basally and in response to ACTH stimulation including pregnenolone, hydroxypregnenolone, dehydroepiandrosterone DHEA , androstenedione, deoxycortisol, and possibly cortisol 45 , Estradiol levels are constantly in the early to midfollicular range without the normal midcycle increases 47 , Estrone levels are increased 47 because of extraglandular aromatization of increased circulating androstenedione levels The decreased SHBG levels typical of PCOS result in increased non-SHBG bound or bioavailable estradiol as well as T levels 38 , 50 , Although PCOS is considered a part of the spectrum of normogonadotropic normoestrogenic anovulation 35 , serum LH concentrations and the LH to FSH ratio are frequently elevated in affected women FSH levels are normal to slightly suppressed and do not increase to threshold levels required during the early follicular phase of the menstrual cycle to stimulate normal follicular maturation However, gonadotropin levels have never been included in any of the diagnostic criteria for PCOS because the characteristic derangements can escape detection on random blood samples because of the pulsatile nature of LH release 24 , 54 — Furthermore, LH levels may be lower in obese women with PCOS and may decrease after an ovulatory cycle in oligo-ovulatory affected women 56 , PCO are characterized by an increase in antral follicles and ovarian stroma as well as by theca cell hyperplasia and ovarian cortical thickening 55 , Careful histological examination of PCO has revealed an excess of growing follicles, the number of which is 2- to 3-fold that of normal ovaries A more recent study of ovarian cortical biopsies from normal and PCOS women 59 confirmed this observation, finding that the number of small, preantral follicles, both primordial and primary follicles, was substantially increased in anovulatory PCO compared with normal ovaries.
In both ovulatory and anovulatory PCO, the proportion of early growing primary follicles is significantly increased, with a reciprocal decrease in the proportion of primordial follicles compared with normal ovaries These differences are particularly striking in anovulatory PCO There is decreased atresia of follicles from PCO in culture compared with those from normal ovaries Markers of cell proliferation are significantly increased in granulosa cells from anovulatory PCO Thus, it now appears that the gonadotropin-independent development of preantral follicles is disordered in PCOS Theca cells from PCO secrete more androgens, basally and in response to LH and insulin 63 , due to constitutive increases in the activity of multiple steroidogenic enzymes in these cells Thus, enhanced ovarian androgen production in PCOS results from the combined effects of intrinsically increased thecal androgen secretion and increased responsiveness to trophic hormone stimulation.
Whereas the increases in androgen production are found in theca cells isolated from ovulatory as well as anovulatory women with PCOS 63 , granulosa cell steroidogenesis differs by ovulatory status 62 , Granulosa cells from ovulatory women with PCO are similar in terms of responses to FSH and estradiol production to those from normal women 65 , In contrast, granulosa cells isolated from some small-to-medium sized antral follicles obtained from anovulatory women with PCO showed increased estradiol production in response to FSH and premature responsiveness to LH 65 , These abnormalities may contribute to the arrest of follicular development.
However, the arrest of antral follicle development in the otherwise normal follicle population is most likely accounted for by lower circulating FSH levels because FSH administration can produce normal follicular maturation and ovulation 62 , 67 , All criteria require exclusion of other disorders: hyperprolactinemia, nonclassic congenital adrenal hydroxylase deficiency, thyroid dysfunction, androgen-secreting neoplasms, and Cushing's syndrome.
All of the diagnostic criteria for PCOS 24 , 54 , 69 — 71 have been based on expert opinion, the lowest level of evidence 72 — None of these criteria were based on a formal consensus process 75 , htm whatistheCDP. The panel is made up of individuals who are experts in their own fields but are not closely aligned with the subject.
Thus, these Consensus Development Conferences permit an independent assessment of the issues in the field by an unbiased panel. An NIH conference on PCOS using this court model will be held in December After a series of landmark studies in the s identifying insulin resistance as a cardinal feature of the syndrome 21 , 34 , 79 — 81 , the metabolic sequelae of the disorder began to be appreciated.
This renaissance of interest in PCOS created a need for a better working definition of the syndrome; an issue of that was addressed at the NICHD Conference on PCOS This conference was a meeting of experts who discussed various features of the syndrome.
Participants were asked to vote on potential diagnostic features Table 2 ; those receiving the most votes, hyperandrogenism and chronic anovulation, with the exclusion of secondary causes, became what are known as the NICHD or NIH criteria 54 and are often and inaccurately referred to as consensus criteria.
The NICHD criteria did not include ovarian morphology because of the lack of specificity of this finding Percentage of participants agreeing on various criteria at NICHD PCOS conference In Europe, ovarian imaging was used for the diagnosis PCOS 27 , 84 , Moreover, with the widespread use of assisted reproductive technologies, it became evident that women with PCO, even those who were reproductively normal, were hyperresponsive to exogenous gonadotropin stimulation and thus at risk for ovarian hyperstimulation syndrome 86 — Accordingly, defining ovarian morphology became an essential component of infertility management In , another conference on diagnostic criteria was convened in Rotterdam Despite being identified as a consensus conference, the recommendations were also based on expert opinion rather than a formal consensus process.
The result of the conference was that polycystic ovarian morphology on ultrasound examination was added to the NICHD diagnostic criteria The Rotterdam criteria 69 , 70 for the diagnosis of PCOS required the presence of two of the following findings, after the exclusion of disorders of the pituitary, ovary, or adrenals that could present in a manner similar to PCOS: 1 hyperandrogenism clinical or biochemical ; 2 chronic anovulation; and 3 PCO Table 1.
These criteria have extended the diagnosis to include two new groups of affected women: 1 PCO and hyperandrogenism without chronic anovulation; and 2 PCO and chronic anovulation without hyperandrogenism 71 Fig. Features of PCOS. The diagnostic criteria for PCOS Table 1 include two or more of these features: hyperandrogenism blue circle , anovulation pink circle , and PCO green circle , resulting in several PCOS phenotypes depending on the diagnostic criteria applied Table 3.
The Rotterdam Criteria do not discriminate between the cardinal features of PCOS, placing equal diagnostic importance on PCO, chronic anovulation, and hyperandrogenism 24 , In , an expert panel of the AES recommended criteria that hyperandrogenism be considered as an essential component of PCOS These criteria require the combination of biochemical or clinical hyperandrogenism with chronic anovulation or PCO 24 , 71 Table 1.
Nevertheless, these AES criteria included the additional phenotype of hyperandrogenism, ovulatory cycles and PCO 71 Table 3. Even before Rotterdam, studies 34 , 89 had suggested that these additional subgroups differed metabolically from the group with classic PCOS identified by the NICHD criteria Fig.
Women with ovulatory cycles and hyperandrogenemia 34 or PCO 89 had normal insulin sensitivity. Furthermore, ovarian morphology did not correlate with the severity of symptoms in PCOS 90 , The hyperandrogenic woman with PCO but documented normal ovulation was recognized as a distinct phenotype of PCOS by both the Rotterdam criteria and the AES criteria 24 , 70 , 71 Table 3.
It has been suggested that this ovulatory form of PCOS may represent a transitional, intermediate stage between normality and the classic anovulatory form of PCOS. Women with this phenotype are often leaner than those with classic PCOS 92 — In addition, they have milder metabolic abnormalities or may even be metabolically normal 92 , 95 — This PCOS group may potentially convert to classic PCOS under the influence of environmental factors like weight gain However, there have been no longitudinal studies to follow the natural course of women with ovulatory PCOS.
lean HA and control , suggesting that hyperinsulinemia is a unique feature of PCOS and not hyperandrogenic states in general. Dunaif et al. J Clin Endocrinol Metab —, 34 , with permission.
The anovulatory woman with normal androgen levels and PCO is a second distinct phenotype of PCOS according to the Rotterdam criteria 24 , 71 Table 3.
Women in this group most often have normal insulin sensitivity 97 — Women with ovulatory cycles and PCO but no hyperandrogenism do not fulfill NICHD, Rotterdam, or AES criteria for PCOS Table 3.
However, these groups of nonhyperandrogenic women with PCO may have subtle endocrine aberrations, like higher LH and lower SHBG levels 82 , 92 , 97 , Moreover, they may have hyperandrogenic responses to GnRH analog GnRHa testing, despite normal androgen levels at baseline 95 , Women with isolated PCO are at increased risk to develop ovarian hyperstimulation during ovulation induction, analogous to women with hyperandrogenic forms of PCOS PCO from ovulatory women do have abnormalities in folliculogenesis 62 and constitutive increases in theca cell androgen production 62 , Taken together, these findings suggest that PCO have constitutive increases in androgen biosynthesis and responsiveness to gonadotropins in the absence of ovulatory disturbances 62 , However, a follow-up study of eumenorrheic women with the isolated PCO has shown that this ultrasound finding is unstable and irreproducible across the reproductive period Women with PCO at baseline did not demonstrate any tendency to develop PCOS during the follow-up arguing against the hypothesis that PCO could represent an early, preclinical stage in the natural continuum of PCOS The prevalence of PCO is also age-related and decreases in frequency with increasing age There appears to be a genetic susceptibility to PCO because they are highly heritable in affected sister pairs These prevalence estimates for PCOS using the NICHD criteria are remarkably consistent across racial and ethnic groups , , — This observation suggests that PCOS is an ancient evolutionary trait that was present before humans migrated out of Africa.
The recent confirmation in European PCOS cohorts , of two gene loci identified in a genome-wide association of Han Chinese women with PCOS supports this hypothesis the genetics of PCOS is discussed later in Section V. However, a recent study comparing Black and White women with PCOS found no differences in reproductive features and mild differences in metabolic features The prevalence of PCOS is higher using the Rotterdam criteria because it includes additional phenotypes 70 Table 3.
The Rotterdam-PCOS group was 1. Although PCOS is commonly associated with obesity, there is no evidence that the prevalence of PCOS is increasing with the increasing prevalence of obesity Prevalence of glucose intolerance and T2D in PCOS.
The prevalence of IGT and T2D in four large multiethnic PCOS cohorts is substantially increased. The true prevalence of diabetes was likely underestimated in these studies because diagnosed women with type 1 or type 2 diabetes were not included in the cohorts.
NGT, Normal glucose tolerance. Ehrmann et al. Diabetes Care —, , with permission. Sinai data were reported by R. Legro et al. J Clin Endocrinol Metab —, , with permission. Azziz et al. Despite the fact that hyperinsulinemia reflecting some degree of peripheral insulin resistance was well recognized in PCOS by the mid s, glucose tolerance was not systematically investigated until This study reported that obese women with PCOS had significantly increased glucose levels during an oral glucose tolerance test OGTT compared with age- and weight-comparable reproductively normal control women.
However, obese ovulatory hyperandrogenemic women had OGTT-glucose responses similar to control women, suggesting that derangements in glucose homeostasis were a feature of the anovulatory PCOS phenotype i. Twenty percent of the obese women with PCOS met criteria for impaired glucose tolerance IGT or type 2 diabetes T2D Conversely, there were no significant differences in OGTT- glucose responses in lean women with PCOS compared with age- and weight-comparable reproductively normal control women.
This study also suggested that metabolic features varied by PCOS phenotype, a finding that has been confirmed with investigation of the Rotterdam PCOS phenotypes discussed in Section III.
and reviewed in Ref. Accordingly, differing diagnostic criteria for PCOS will affect the results of metabolic investigations. The majority of the studies assessing glucose tolerance and insulin resistance have used the NICHD criteria for the diagnosis of PCOS.
The prevalence of IGT and T2D in U. women with PCOS has been assessed in three large cross-sectional studies in racially and ethnically diverse cohorts — Fig. Furthermore, prevalence rates of IGT and T2D did not change in a subgroup analysis limited to non-Hispanic white women The prevalence rate of IGT in PCOS was 3-fold higher than the population prevalence rate in women of similar age from the National Health and Nutrition Survey NHANES II and twice the prevalence rate in age- and weight-comparable reproductively normal control women The prevalence rate of undiagnosed T2D was 7.
Moreover, these studies likely underestimated the prevalence of diabetes mellitus in PCOS because they excluded women with diagnosed type 1 or type 2 diabetes — However, even lean women with PCOS had increased rates of IGT and T2D A first-degree relative with T2D increased risk for dysglycemia , The majority of women in these studies were in their third and fourth decades of life; however, the prevalence rates of IGT and T2D were similarly increased in U.
adolescents with PCOS Fasting and post-challenge dysglycemia in PCOS. The individual fasting and 2-h post g oral glucose challenge glucose data from women with PCOS are shown.
Most women with PCOS have post-challenge rather than fasting dysglycemia. Prevalence rates of dysglycemia are elevated in non-U. women with PCOS but not to the same magnitude as those in U. women with PCOS. The prevalence rates of IGT and T2D were A telephone interview study of Dutch women with PCOS found a significant increase in diagnosed T2D compared with population prevalence estimates Another European study did not show increased prevalence rates of IGT and T2D in women with NICHD PCOS from Spain compared with age-, BMI-, and ethnicity-comparable control women.
Although the prevalence of obesity is higher and its severity is greater in U. PCOS populations , , such differences alone cannot account for differing rates of dysglycemia, which persist between European and U.
PCOS cohorts in comparable BMI categories , , A recent meta-analysis reviewed more than studies of glucose tolerance in PCOS from which only 30 full-text studies were assessed for the final analysis. The increased prevalence of IGT and T2D in women with PCOS compared with women without PCOS, in both BMI- and non-BMI-matched studies, was confirmed.
In the meta-analysis, the odds ratios OR and confidence intervals CI were significantly increased: IGT—OR, 2. This meta-analysis confirms that the risk for IGT and T2D is increased in PCOS. PCOS is now recognized as a diabetes risk factor by the American Diabetes Association Nevertheless, the magnitude of risk is unclear because most studies have been cross-sectional, relatively small, and lacking concurrently studied control women Large cross-sectional and prospective population-based studies are needed to accurately estimate the magnitude of T2D risk in PCOS.
A recent prospective study in an Italian PCOS cohort confirmed an increased risk for T2D In Pima Indians and in the Nurses Health Study II , the risk for T2D was significantly increased in women with menstrual irregularity.
In the Nurses Health Study , a multivariate analysis adjusting for multiple confounders, including BMI at age 18, race, physical activity, first-degree relative with diabetes, smoking, and oral contraceptive use, found the relative risk for diabetes was 1.
The risk was increased by obesity but remained significant in lean women with irregular menses This association was not confirmed in a relatively small U. prospective cohort study , but it was supported in a more recent and larger Dutch study These data suggest that PCOS increases the risk for T2D across a woman's lifespan.
There have been very few follow-up studies to assess conversion rates from normal glucose tolerance to IGT and from IGT to T2D. The conversion rate from normal to IGT or from IGT to T2D in PCOS has been estimated to range from 2. This discrepancy likely represents an underestimate in conversion rates in PCOS because the studies have been limited by small sample size , — Women with PCOS most commonly have postprandial dysglycemia , , which reflects peripheral, primarily skeletal muscle, insulin resistance rather than fasting dysglycemia Fig.
Therefore, 2-h postchallenge glucose values are optimal for the diagnosis of IGT and T2D in PCOS , , and the AES position statement has recommended screening of all women with PCOS with a g OGTT. The optimal time period for repeat OGTT is uncertain.
A hemoglobin A1c value between 5. A recent study that assessed the utility of hemoglobin A1c to detect IGT and diabetes in PCOS found that this test had low sensitivity when compared with OGTT assessment of glucose tolerance. This discrepancy in diagnostic accuracy may be because affected women have mainly post-glucose challenge rather than fasting dysglycemia , Insulin acts to regulate glucose homeostasis by stimulating glucose uptake by insulin-responsive target tissues, adipocytes, and skeletal and cardiac muscle, as well as by suppressing hepatic glucose production , Insulin also suppresses lipolysis, resulting in a decrease in circulating free fatty acid levels , which may mediate the action of insulin on hepatic glucose production — Accordingly, insulin resistance is characterized by increased circulating insulin levels, basally and in response to a glucose load, if pancreatic β-cell function is intact , Insulin has other metabolic as well as mitogenic and reproductive actions discussed in Sections IV.
and V. and in Refs. This technique quantitatively assesses insulin action on whole-body glucose uptake by infusing a desired dose of insulin and maintaining euglycemia using a variable glucose infusion where the rate is adjusted based on frequent arterialized blood glucose determinations and a negative feedback principle , At steady state, the amount of glucose that is infused equals the amount of glucose taken up by the peripheral tissues, and it can be used as a measure of peripheral sensitivity to insulin, known as insulin-mediated glucose disposal IMGD or M , As fat mass increases, it accounts for a larger amount of IMGD Endogenous glucose production, which reflects both hepatic and renal glucose production , — , can be determined by the infusion of isotopically labeled glucose at baseline and during the euglycemic clamp , The suppression of hepatic glucose production can be assessed by determining the decrease in endogenous glucose production in response to insulin , Whole-body insulin sensitivity can also be accurately measured in subjects without diabetes using the frequently sampled iv glucose tolerance test FSIGT with minimal model analysis The minimal model determines insulin sensitivity sensitivity index , which reflects insulin action to stimulate glucose uptake as well as to suppress glucose production The acute insulin response to glucose AIRg is also determined from the FSIGT data.
The disposition index DI , the product of AIRg and insulin sensitivity, assesses insulin secretion in the context of insulin sensitivity and is a robust parameter of pancreatic β-cell function , that will be discussed in Section IV.
It is possible to model hepatic glucose production with the administration of isotopically labeled glucose during the FSIGT , , but this measurement is rarely performed because the tracer is expensive and the model is complex.
The standard FSIGT is substantially easier and less expensive to perform than the clamp, although it is still an investigational procedure that requires frequent blood sampling. The FSIGT provides quantitative, reproducible measurements of insulin sensitivity in individuals without T2D; in patients with diabetes, it may not be possible to differentiate between very low insulin sensitivity values , The FSIGT also provides a simultaneous assessment of insulin secretion , The euglycemic clamp provides a quantitative, reproducible measurement of insulin action across a spectrum of insulin sensitivities and can be used in patients with T2D , Endogenous, primarily hepatic, glucose production can also be assessed during the clamp , The measurement of insulin secretion requires a separate, hyperglycemic clamp study , , The glucose clamp procedure requires highly trained personnel and specialized equipment , It is also substantially more expensive to perform than the FSIGT Because of the complexity and expense of the clamp and the FSIGT, there has been a desire to use fasting parameters of glucose homeostasis as surrogate measures of insulin resistance.
These measures include homeostatic model assessment , fasting glucose:insulin ratio , and quantitative insulin sensitivity check index They are all based on fasting glucose and insulin levels and essentially provide identical information Fasting glucose levels reflect endogenous glucose production , an index of hepatic rather than peripheral insulin action Fasting insulin levels reflect not only insulin sensitivity but also insulin secretion and clearance Accordingly, fasting insulin levels will not provide accurate information on insulin sensitivity in individuals with β-cell dysfunction OGTT-derived parameters of insulin action have also been shown to be insensitive to large changes in insulin sensitivity Although fasting measures and OGTT-derived parameters may correlate with clamp or FSIGT measures of insulin sensitivity, they lack precision for quantitatively measuring insulin resistance in the general population These measures have been found to be similarly imprecise for the assessment of insulin sensitivity in women with PCOS PCOS women have an increased prevalence of obesity 19 , , , and women with upper as opposed to lower body obesity have an increased frequency of hyperandrogenism Androgens can also increase visceral fat mass in women Muscle is the major site of insulin-mediated glucose use , and androgens can increase muscle mass Thus, potential changes in lean body primarily muscle and fat mass as well as in fat distribution should be considered to accurately assess insulin action in PCOS 81 , The decrease in IMGD in PCOS was of a similar magnitude to that reported in T2D Fig.
Furthermore, IMGD was significantly decreased per kilogram of fat free, primarily muscle, mass IMGD was also significantly decreased in lean PCOS women, all of whom had normal glucose tolerance.
Decreased IMGD in PCOS. This decrease is similar in magnitude to that reported in T2D open bars Body fat topography, upper compared with lower body, can affect insulin sensitivity 7 , with increases in upper body and visceral fat being associated with decreased insulin sensitivity 7 , The study of Dunaif et al.
However, visceral fat mass accurately quantified by magnetic resonance imaging MRI , or by computerized tomography does not differ in women with PCOS compared with BMI-matched control women. Thus, the study of PCOS and control women of comparable BMI appears to be sufficient to control for the confounding effects of obesity as well as of fat distribution on insulin sensitivity.
Insulin has concentration-dependent saturable actions that can be examined in vivo using sequential multiple insulin dose euglycemic clamp studies The concentration required for a half-maximal ED 50 response defines insulin sensitivity and usually reflects insulin receptor binding or phosphorylation, whereas the maximal biological effect is defined as insulin responsiveness and usually reflects postreceptor events, for example, translocation of the GLUT4 glucose transporter for IMGD Dose-response studies have indicated that the ED 50 insulin for glucose uptake was significantly increased and that maximal rates of IMGD were significantly decreased in lean and in obese women with PCOS women Fig.
It appears, however, that body fat has a more pronounced negative effect on insulin sensitivity in women with PCOS , Basal endogenous glucose production and the ED 50 insulin for suppression of endogenous glucose production were significantly increased only in obese PCOS women 81 , Fig.
This synergistic negative effect of obesity and PCOS on endogenous glucose production is an important factor in the pathogenesis of glucose intolerance 34 , 81 , , Insulin action in isolated sc adipocytes and in vivo.
The dose-response of insulin-stimulated glucose uptake was determined in isolated sc adipocytes in vitro and in vivo during sequential multiple insulin dose euglycemic glucose clamp studies.
Maximal rates of glucose uptake insulin responsiveness in isolated sc adipocytes are depicted in vitro A, left and in vivo , which reflects primarily skeletal muscle glucose uptake B, left. Rates of postabsorptive endogenous glucose production EGP C, left and its suppression by insulin were also assessed during the euglycemic glucose clamp study.
The ED 50 insulin insulin sensitivity for stimulation of glucose uptake and suppression of EGP are depicted in the graphs on the right A, sc adipocytes in vitro ; B, in vivo ; C, EGP.
Women with PCOS, gray bars ; normal control women NL , open bars. Diabetes —, , with permission. Many subsequent studies using euglycemic glucose clamps or FSIGTs have confirmed that women with PCOS have profound resistance to the action of insulin to stimulate glucose uptake for example, see Refs.
There is general consensus that obese women with PCOS are insulin resistant However, several studies have failed to demonstrate insulin resistance in lean women with PCOS for example, see Refs. Some of these conflicting results can be accounted for by differences in the diagnostic criteria for PCOS that resulted in the inclusion of women with ovulatory cycles and hyperandrogenism who have minimal to absent evidence for insulin resistance see discussion in Section III.
of diagnostic criteria and Refs. Attempts to quantitate the prevalence of insulin resistance in PCOS are limited by the methods used to determine insulin sensitivity. Even when insulin resistance is assessed using the euglycemic glucose clamp, it is clear that some women with PCOS have normal insulin sensitivity 81 Fig.
Thus, defects in insulin action on glucose metabolism are not a universal feature of the syndrome. Indeed, two of the PCOS phenotypes identified with the Rotterdam criteria Table 3 —hyperandrogenism and PCO with ovulatory cycles, and anovulation and PCO without hyperandrogenism—have modest or absent 99 evidence for insulin resistance using surrogate markers.
Nevertheless, it remains possible that there is increased sensitivity to the reproductive actions of insulin in PCOS because hyperandrogenism and anovulation improve during metformin treatment in women with PCOS without evidence for insulin resistance Alternatively, these improvements may be related to a direct action of metformin on steroidogenesis Fasting and dynamic measures of insulin resistance.
Fasting measure of insulin sensitivity, the glucose:insulin ratio and insulin levels are shown in the top graphs. Dynamic measures of insulin sensitivity, the euglycemic glucose clamp determined IMGD, and sensitivity index SI assessed by minimal model analysis of FSIGT are shown in the bottom graphs.
For all measures of insulin action, there is considerable overlap between control open triangles and PCOS gray circles women. The data have been previously published 81 , , and were adapted for use in this figure, which is used with the permission of Andrea Dunaif.
Insulin receptor signaling pathways. The insulin receptor is a heterotetramer consisting of two α, β dimers linked by disulfide bonds. The α-subunit contains the ligand binding domain, and the β-subunit contains a ligand-activated tyrosine kinase.
Tyrosine autophosphorylation increases the receptor's intrinsic tyrosine kinase activity, whereas serine phosphorylation inhibits it.
The tyrosine-phosphorylated insulin receptor phosphorylates intracellular substrates, such as IRS 1—4, Shc, and APS, initiating signal transduction pathways mediating the pleiotropic actions of insulin. The inhibition of GSK3 results in dephosphorylation of glycogen synthase increasing glycogen synthesis.
The mTOR pathway is also important in nutrient sensing. Insulin signaling can be terminated by dephosphorylation of the receptor by tyrosine phosphatases, such as PTP1B, or dephosphorylation of PI3-K by PTEN.
Serine phosphorylation of the insulin receptor and IRSs can also decrease insulin signaling and may be mediated by serine kinases in the insulin signaling pathway providing a feedback mechanism to terminate insulin action.
There is a post-binding defect in insulin signaling in PCOS affecting metabolic but not mitogenic pathways see Fig. The signaling steps that are compromised in PCOS are circled with a dotted line. Signaling steps downstream of these abnormalities may also be compromised. SOS, Son-of-sevenless. Insulin signaling defects in PCOS.
There is a post-binding defect in insulin signaling in PCOS resulting in marked decreases in insulin sensitivity see Fig. There is a more modest defect in insulin responsiveness. The signaling defect is due to serine phosphorylation of the insulin receptor and IRS-1 secondary to intracellular serine kinases.
This results in decreased insulin-mediated activation of PI3-K and resistance to the metabolic actions of insulin. Serine phosphorylation of Pc17 increases its activity, and it has been postulated that the same kinase may inhibit insulin signaling and increase androgen production in PCOS.
S-S, Disulfide bond; Y, tyrosine; S, serine; P, phosphate. Insulin has multiple cellular actions beyond the regulation of glucose uptake It has other anabolic effects to increase storage of lipids and proteins as well as to promote cell growth and differentiation Insulin acts on cells by binding to its cell surface receptor , The insulin receptor is a heterotetramer made up of two α,β dimers linked by disulfide bonds Each α,β dimer is the product of one gene , The α-subunit is extracellular and contains the ligand-binding domain; it also inhibits the intrinsic kinase activity of the β-subunit , The β-subunit spans the membrane, and the cytoplasmic portion contains intrinsic protein tyrosine kinase activity, which is activated further by ligand-mediated autophosphorylation The insulin receptor shares substantial structural homology the IGF-I receptor and the insulin-related receptor The α,β dimer of the insulin receptor can assemble with similar dimers of the IGF-I receptor or insulin-related receptor to form hybrid receptors Ligand binding induces autophosphorylation of the insulin receptor on specific tyrosine residues and further activation of its intrinsic kinase activity — The activated insulin receptor then tyrosine-phosphorylates intracellular substrates, such as insulin receptor substrates IRS 1—4, src homolog and collagen homolog Shc , and APS [adapter protein with a PH and homology 2 SH2 domain], to initiate signal transduction , , The IRS are phosphorylated on specific motifs, and these phosphorylated sites then bind signaling molecules, such as the SH2 domain of phosphatidylinositol 3-kinase PI3-K or the adaptor molecule, Nck , , , leading to activation of downstream signaling pathways.
Insulin stimulates glucose uptake by increasing the translocation of the insulin-responsive glucose transporter, GLUT4, from intracellular vesicles to the cell surface , This pathway is mediated by activation of PI3-K, which then phosphorylates membrane phospholipids and phosphatidylinositol 4,5-bisphosphate, leading to activation of the 3-phosphoinositide-dependent protein kinases PDK-1 and PDK-2 , Both of these pathways stimulate the translocation of GLUT4 to the cell surface , Glycogen synthase activity is constitutively inhibited via phosphorylation by glycogen synthase kinase-3 GSK3 , Insulin stimulates cell growth and differentiation through the MAPK-ERK , pathway , This pathway is activated by insulin receptor-mediated phosphorylation of Shc or IRS, leading to association with Grb2 and Son-of-sevenless resulting in Ras activation This so-called mitogenic pathway can be disrupted without affecting the metabolic actions of insulin and vice versa , — As a result, insulin resistance can be selective and affect only metabolic but not mitogenic pathways of insulin action , , Insulin regulates protein synthesis and degradation via mammalian target of rapamycin mTOR , which is activated via PI3-K.
The mTOR pathway is also important in nutrient sensing The insulin signal can be terminated by dephosphorylation of proximal signaling molecules. Multiple tyrosine phosphatases, such as protein tyrosine phosphatase 1B PTP1B , can dephosphorylate the insulin receptor to terminate the insulin signal , Phosphatase and tension homolog deleted on chromosome 10 PTEN , a lipid phosphatase, decreases PI3-K signaling by dephosphorylating lipid signaling molecules , , Serine phosphorylation of the insulin receptor and IRS can also inhibit insulin signaling , — It has been postulated that PKC-mediated serine phosphorylation of the insulin receptor is important in the pathogenesis of hyperglycemia-induced insulin resistance — and that the mechanism of TNF-α-mediated insulin resistance is serine phosphorylation of IRS-1 The cellular and molecular mechanisms of insulin action in PCOS have been characterized in cultured skin fibroblasts, which are not classic insulin target tissues Defects in fibroblast insulin action that persist in cells that have been removed from the in vivo environment for many passages suggest that the changes are the result of mutations in genes regulating these pathways 10 , Consistent with this hypothesis, decreases in insulin receptor binding or autophosphorylation in cultured skin fibroblasts have reflected mutations in the insulin receptor gene in patients with the syndromes of extreme insulin resistance 10 , Insulin action has also been examined in the classic insulin target tissues for glucose uptake, adipocytes and skeletal muscle , The size of sc adipocytes isolated from both lean and obese women with PCOS was increased , However, decreased insulin receptor β-subunit abundance has been reported in homogenates of omental adipose tissue from women with PCOS The most striking and consistent defect in adipocyte insulin action in PCOS was a marked increase in the ED 50 for insulin-mediated glucose uptake , , , indicating a decrease in insulin sensitivity, when compared with isolated adipocytes from appropriately weight-comparable reproductively normal control women Fig.
The decrease in insulin sensitivity suggested that there was a defect in insulin receptor binding or phosphorylation Most studies have also found less striking, but significant, decreases in maximal rates of insulin-stimulated glucose transport , , insulin responsiveness, suggesting a decrease in post-receptor events , Fig.
Significant decreases in the abundance of GLUT4 glucose transporters in sc adipocytes from women with PCOS most likely accounted for the decrease in insulin responsiveness , However, a recent study failed to find decreases in insulin responsiveness or GLUT4 abundance in sc adipocytes isolated from women with PCOS, despite the fact the euglycemic clamp studies in these PCOS subjects showed decreased insulin responsiveness for IMGD consistent with a postbinding defect in insulin action.
The reasons for these discrepant results in isolated sc adipocytes are unclear because both studies used the same diagnostic criteria NICHD for PCOS and contained control women of comparable BMI , Similar defects in adipocyte insulin action have been reported in T2D and in obesity but are ameliorated by control of hyperglycemia and hyperinsulinemia as well as by weight-reduction, suggesting acquired rather than intrinsic defects — In contrast, in PCOS such defects can occur in the absence of obesity and glucose intolerance , Moreover, these abnormalities are not significantly correlated with sex hormone levels 55 , These studies are constrained by the fact that signaling protein abundance and basal phosphorylation may be unaltered, but insulin-stimulated activation may still be defective in insulin-resistant states Studies using maximally stimulating doses of insulin may fail to detect alterations in insulin sensitivity Furthermore, downstream signaling events may be decreased if there are defects in signaling at the level of the insulin receptor Insulin receptor function in PCOS was investigated in receptors isolated from cultured skin fibroblasts.
Consistent with findings in isolated adipocytes , , there was no change in insulin binding or receptor affinity compared with control women Insulin-dependent receptor tyrosine autophosphorylation was significantly decreased , Insulin-independent receptor serine phosphorylation was markedly increased , and these receptors had reduced intrinsic tyrosine kinase activity, suggesting that serine phosphorylation inhibited normal receptor signaling Although fibroblasts are not a classic insulin target tissue for glucose uptake, insulin receptors isolated from skeletal muscle biopsies from women with PCOS had similar abnormalities in phosphorylation, suggesting that this defect was physiologically relevant Isolating insulin receptors from lysates of PCOS skin fibroblasts by immunopurification before insulin-stimulated autophosphorylation corrected constitutive increases in receptor serine phosphorylation Furthermore, mixing lysates from PCOS skin fibroblasts with purified human insulin receptors resulted in increased receptor serine phosphorylation Taken together, these findings suggested that a serine kinase extrinsic to the insulin receptor was responsible for the abnormal pattern of receptor phosphorylation These findings were supported by an independent group of investigators who confirmed significant decreases in PCOS skin fibroblast insulin receptor autophosphorylation.
Furthermore, they demonstrated that decreased receptor autophosphorylation could be corrected immunocapture of the insulin receptor before insulin stimulation, consistent with the presence of a factor extrinsic to the receptor as the cause of the defect Most importantly, serine kinase inhibitors corrected the phosphorylation defect, supporting the role of a serine kinase extrinsic to the insulin receptor as the cause of decreased receptor autophosphorylation This defect in the early steps of the insulin signaling pathway may cause the insulin resistance in a subpopulation of women with PCOS Fig.
Increased insulin-independent serine phosphorylation in PCOS insulin receptors appears to be a unique disorder of insulin action because other insulin-resistant states, such as obesity, T2D, Type A syndrome, and leprechaunism, do not exhibit this abnormality , , This observation suggests that a defect downstream of insulin receptor phosphorylation, such as phosphorylation of IRS-1 or activation of PI3-K, was responsible for insulin resistance in some PCOS women , , Studies of insulin signaling in vivo have shown a significant decrease in insulin-mediated IRSassociated PI3-K activation in serial skeletal muscle biopsies obtained during a euglycemic clamp study in association with decreased IMGD in women with PCOS The abundance of IRS-2 was increased, suggesting a change to compensate for decreased signaling via IRS-1 Analogous to in vitro studies, the signaling changes occurred rapidly and were evident in biopsies at and min time points during each insulin dose, but the changes had returned to baseline by 90 min of each infusion This study confirmed that there is a physiologically relevant defect in rapid insulin receptor-mediated signaling in the major insulin target tissue for IMGD, skeletal muscle.
Højlund et al. Nevertheless, this finding is consistent with the time course of these signaling changes determined in the previous study of Dunaif et al. The decrease in insulin receptor-mediated IRS-1 phosphorylation and PI3-K activation identified in PCOS skeletal muscle could account for these changes because these signaling events are downstream in the pathway of insulin-stimulated glucose uptake Fig.
In contrast, Ciaraldi et al. However, they used maximally stimulating doses of insulin, whereas Højlund et al. It is possible to isolate myoblasts from human skeletal muscle biopsies, culture these cells in vitro , and differentiate them into myotubes — This culture system has been used to investigate whether the defects in insulin action in PCOS skeletal muscle are the result of the in vivo hormonal environment or reflect intrinsic abnormalities , — Cultured myotubes from women with PCOS had a distinctive phenotype: despite similar population doublings, they had an increase in markers of differentiation compared with myotubes from control women Insulin action findings in PCOS myotubes have been conflicting.
Corbould et al. GLUT1 abundance was increased in PCOS myotubes and correlated with the increases in basal, non-insulin-mediated glucose transport, whereas GLUT4 abundance was unchanged in PCOS compared with control myotubes PCOS myotube GLUT4 abundance did not differ in PCOS and control myotubes in this study Eriksen et al.
lower body, e. Alterations in any of these parameters could potentially contribute to insulin resistance in PCOS. PCOS women have an increased prevalence of obesity 6 , 47 , and women with upper, as opposed to lower body, obesity have an increased frequency of hyperandrogenism Since muscle is the major site of insulin-mediated glucose use 60 and androgens can increase muscle mass 67 , potential androgen-mediated changes in lean body primarily muscle mass must also be controlled for in PCOS 54 , Studies in which body composition, assessed by the most precise available method hydrostatic weighing , has been matched to normal control women, and in which lean PCOS women, who had body composition and waist to hip girth ratios similar to controls, were studied, have confirmed that PCOS women are insulin resistant, independent of those potentially confounding parameters 1 , 55 , The impact of hyperandrogenism on insulin sensitivity is discussed below, but studies in cultured cells have confirmed the impression from these in vivo studies that an intrinsic defect in insulin action is present in PCOS This decrease is similar in magnitude to that seen in NIDDM.
Basal hepatic glucose production and the ED 50 value of insulin for suppression of hepatic glucose production are significantly increased only in obese PCOS women 54 , 55 Fig. This synergistic negative effect of obesity and PCOS on hepatic glucose production is an important factor in the pathogenesis of glucose intolerance 49 , 54 , 55 , This is analogous to NIDDM in general where defects in insulin action, presumably genetic, synergize with environmentally induced insulin resistance, primarily obesity-related, to produce glucose intolerance 51 , Sequential multiple-insulin-dose euglycemic clamp studies have indicated that the ED 50 insulin for glucose uptake is significantly increased, and that maximal rates of glucose disposal are significantly decreased in lean and in obese PCOS women 55 Fig.
It appears, however, that body fat has a more pronounced negative effect on insulin sensitivity in women with PCOS 68 , Basal rates of hepatic glucose production HGP are not significantly different in the four groups bottom left.
Diabetes —, In the presence of peripheral insulin resistance, pancreaticβ -cell insulin secretion increases in a compensatory fashion. NIDDM develops when the compensatory increase in insulin levels is no longer sufficient to maintain euglycemia 72 , It is essential, therefore, to examine β-cell function in the context of peripheral insulin sensitivity.
Under normal circumstances, this relationship is constant 72 , 74 Fig. β-Cell dysfunction is felt to be present for values falling below this hyperbolic curve 73 , This relationship can be quantitated as the product of insulin sensitivity and first-phase insulin release known as the disposition index The relationship between insulin sensitivity SI determined by frequently sampled intravenous glucose tolerance test and first-phase insulin secretion to an intravenous glucose load AIRg.
The majority of PCOS women fall below the normal curve determined in concurrently studied age- and weight-matched control women as well as normative data in the literature. Fasting hyperinsulinemia is present in obese PCOS women and this is, in part, secondary to increased basal insulin secretion rates Fig.
Insulin responses to an oral glucose load are increased in lean and obese PCOS women Fig. When the relationship between insulin secretion and sensitivity is examined, lean and obese PCOS women fall below the relationship in weight-matched control women, and the disposition index is significantly decreased by PCOS as well as by obesity 57 Fig.
Further evidence for β-cell dysfunction in PCOS is provided by the elegant studies of Erhmann et al. These defects are much more pronounced in PCOS women who have a first-degree relative with NIDDM, suggesting that such women may be at particularly high risk to develop glucose intolerance In summary, the most compelling evidence suggests that β-cell dysfunction, in addition to insulin resistance, is a feature of PCOS.
The ability to diagnose PCOS at the time of puberty will make possible prospective longitudinal studies of the ontogeny of these defects. Hyperinsulinemia can result from decreases in insulin clearance as well as from increased insulin secretion.
Thus, PCOS would be expected to be associated with decreases in insulin clearance; however, relatively few studies have examined this question. Direct measurement of posthepatic insulin clearance during euglycemic clamp studies has not been abnormal in PCOS 54 , Circulating insulin to C-peptide molar ratios are increased in PCOS, suggesting decreased hepatic extraction of insulin, but such ratios also reflect insulin secretion 28 , Direct measurement of hepatic insulin clearance in non-PCOS hyperandrogenic women has found it to be decreased The one study of this question in PCOS found decreased hepatic insulin extraction by model analysis of C-peptide levels Therefore, in PCOS, hyperinsulinemia is probably the result of a combination of increased basal insulin secretion and decreased hepatic insulin clearance.
Molecular mechanisms of insulin action Figs. Insulin acts on cells by binding to its cell surface receptor 51 , 82 , The insulin receptor is a heterotetramer made up of two α,β- dimers linked by disulfide bonds 84 Fig.
Each α,β-dimer is the product of one gene 85 , The α-subunit is extracellular and contains the ligand-binding domain whereas the β-subunit spans the membrane, and the cytoplasmic portion contains intrinsic protein tyrosine kinase activity, which is activated further by ligand-mediated autophosphorylation on specific tyrosine residues 87 Fig.
The insulin receptor belongs to a family of protein tyrosine kinase receptors that includes the insulin-like growth factor-I IGF-I receptor, with which it shares substantial sequence and structural homology, as well as the epidermal growth factor EGF , fibroblast growth factor, platelet-derived growth factor, and colony-stimulating factor-1 receptors A number of oncogene products are also protein tyrosine kinases 85 , The insulin receptor is a heterotetramer consisting of two α,β-dimers linked by disulfide bonds.
Theα -subunit contains the ligand-binding site, and the β-subunit contains a ligand-activated tyrosine kinase. Kahn: Diabetes —, The tyrosine-phosphorylated insulin receptor phosphorylates intracellular substrates, such as insulin receptor substrate IRS -1 and IRS-2, initiating signal transduction and the plieotropic actions of insulin.
The activation of PI3-K PI3-kinase by tyrosine-phosphorylated IRS-1 appears to be the pathway for insulin-mediated glucose transport. The Ras-MAP kinase pathway appears to regulate cell growth and glycogen synthesis.
Ligand binding induces, probably via conformational changes, autophosphorylation of the insulin receptor on specific tyrosine residues and further activation of its intrinsic kinase activity Fig. The activated insulin receptor then tyrosine phosphorylates intracellular substrates to initiate signal transduction Fig.
Over the last few years a number of these substrates have been characterized. The first was insulin receptor substrate-1 IRS-1 , which serves as a docking molecule for signaling and adaptor molecules 93 , The tyrosine-phosphorylated insulin receptor tyrosine phosphorylates IRS-1 on specific motifs, and these phosphorylated sites then bind signaling molecules, such as the SH2 domain of phosphatidylinositol 3-kinase PI3-K , or the adaptor molecule, Nck 51 , 82 , This leads to activation of downstream signaling pathways, such as that leading to insulin-mediated glucose transport, which appears to be modulated through the PI3-K signal cascade More recently, insulin receptor substrate-2 IRS-2 , another substrate for the insulin receptor, has been identified 95 , Shc an adaptor molecule can also bind directly to the insulin receptor initiating signal transduction 82 , Insulin has numerous target tissue actions, such as stimulation of glucose uptake, gene regulation, DNA synthesis, and amino acid uptake 51 , The mechanisms of insulin receptor signal specificity are currently a subject of intense investigation.
It now appears that the Ras-Raf-MEK pathway is involved in the regulation of cell growth and metabolism whereas the PI3-K pathway is involved in glucose uptake 98 — The mechanisms by which the insulin signal is terminated remain incompletely understood.
Receptor-mediated endocytosis and recycling are well known to occur and may be important to signal termination 83 , Serine phosphorylation has been shown to terminate signaling by the EGF receptor , , another tyrosine kinase growth factor receptor, and it can be shown under a variety of experimental conditions that insulin receptor serine phosphorylation decreases its tyrosine kinase activity — It has been postulated that protein kinase C PKC -mediated serine phosphorylation of the insulin receptor is important in the pathogenesis of hyperglycemia-induced insulin resistance , Recent evidence suggests that tumor necrosis factor-α TNF-α -mediated serine phosphorylation of IRS-1 inhibits insulin receptor signaling and is the mechanism of TNF-α-induced insulin resistance Studies addressing this important question have been constrained by a lack of sensitive anti-phosphoserine antibodies.
Identification of phosphoserine residues usually requires painstaking phosphoamino acid analysis of 32 P-labeled receptors The use of fluorophore labeling of phosphoserine promises to provide a sensitive methodology for examining in vivo serine phosphorylation events In summary, insulin action is mediated through a ligand-activated tyrosine kinase receptor, similar to a number of other growth factors.
A variety of phosphorylation-dephosphorylation signaling cascades are then activated, leading to the pleiotropic actions of insulin. The mechanisms of signal specificity and termination require further investigation. Molecular insulin action defects in PCOS. The one adipocyte study reporting a decrease in insulin receptor number used a control group consisting primarily of lean individuals Studies of insulin action in isolated PCOS adipocytes have revealed marked decreases in insulin sensitivity together with less striking, but significant, decreases in maximal rates of insulin-stimulated glucose transport 55 , Fig.
There is evidence for decreases in adipocyte levels of adenosine in PCOS , but whether this is a primary defect or secondary to hyperinsulinemia is unclear. The decrease in maximal rates of adipocyte glucose uptake is secondary to a significant decrease in the abundance of GLUT4 glucose transporters Similar defects are present in NIDDM and in obesity but are ameliorated by control of hyperglycemia and hyperinsulinemia as well as by weight reduction, suggesting acquired rather than intrinsic defects 65 , — In contrast, in PCOS such defects can occur in the absence of obesity, glucose intolerance, or changes in waist to hip girth ratios 55 , Moreover, these abnormalities are not significantly correlated with sex hormone levels, suggesting that abnormalities of insulin action in PCOS may be intrinsic 55 , Maximal insulin-stimulated increments above basal are significantly decreased in PCOS vs.
The ED 50 insulin is increased significantly in PCOS vs. normal and in obese vs. nonobese women inset. To further evaluate the postbinding defect in insulin action in PCOS, we examined insulin receptor function in receptors isolated from cultured skin fibroblasts.
Because fibroblasts are removed from the in vivo environment for several generations, they provide a constant source of insulin receptors that are not influenced by the hormonal imbalance of PCOS. Consistent with our earlier results from the adipocyte studies, fibroblasts from PCOS women showed no change in insulin binding or receptor affinity This was secondary to markedly increased basal autophosphorylation with minimal further insulin-stimulated autophosphorylation Fig.
Phosphoamino acid analysis revealed decreased insulin-dependent receptor tyrosine phosphorylation and increased insulin-independent receptor serine phosphorylation 69 Fig.
The ability of the PCOS-ser insulin receptors to phosphorylate an artificial substrate was also significantly reduced Fig. Representative autoradiograms of autophosphorylated skin fibroblast insulin receptor β-subunits top and phosphoamino acid analysis bottom ± 1 μ m insulin from a normal control , a PCOS woman with normal insulin-stimulated tyrosine phosphorylation PCOS-nl and a PCOS woman with high basal autophosphorylation on serine residues PCOS-ser ; S-serine, Y-tyrosine.
Basal autophosphorylation is increased and there is minimal further insulin-stimulated phosphorylation in the PCOS-serβ -subunits. The high basal phosphorylation represents phosphoserine, and phosphotyrosine content does not increase in response to insulin in the PCOS-ser β-subunits.
Phosphorylation of poly GLU4:TYR1 by partially purified skin fibroblast insulin receptors. Skin fibroblast insulin receptors were directly extracted from confluent cell cultures, partially purified, and incubated in the presence of 0— n m , and assays of the phosphorylation of poly GLU4:TYR1 were performed.
Thus, this defect in the early steps of the insulin-signaling pathway may cause the insulin resistance in PCOS-ser women. Increased insulin-independent serine phosphorylation in PCOS-ser insulin receptors appears to be a unique disorder of insulin action since other insulin-resistant states, such as obesity, NIDDM, type A syndrome, and leprechaunism, do not exhibit this abnormality 1 , 51 , 65 , 69 Table 1.
The PCOS-ser phosphorylation abnormality appears to be physiologically relevant because it is present in insulin receptors partially purified from skeletal muscle, a classic insulin target tissue, and because the same pattern of abnormal phosphorylation occurs in insulin receptors phosphorylated in intact cells Although these women demonstrate the same PCOS phenotype and the same degree of insulin resistance as the PCOS-ser women with abnormal phosphorylation, insulin receptor phosphorylation in fibroblasts and skeletal muscle from these women is similar to that of control women This observation suggests that a defect downstream of insulin receptor signaling, such as phosphorylation of IRS-1 or activation of PI3-K, is responsible for insulin resistance in PCOS-nl women 51 , 69 , Indeed, our recent human studies demonstrate a significant decrease in muscle PI3-K activation during insulin infusion in PCOS women , consistent with a physiologically relevant defect in the early steps of insulin receptor signaling.
We found no insulin receptor mutations in two PCOS-ser women by direct sequencing of genomic DNA , and sequence analysis of the tyrosine kinase domain in the β-subunit of an additional eight PCOS-ser women also revealed no mutations This finding has recently been confirmed by other investigators Immunoprecipitation and mixing experiments suggest that a factor extrinsic to the insulin receptor is responsible for the excessive serine phosphorylation PCOS-ser insulin receptors autophosphorylate normally, if they are first immunoprecipitated from wheat-germ agglutinin WGA lectin eluates.
Furthermore, mixing control human insulin receptors and WGA eluates from PCOS-ser fibroblasts results in increased insulin-independent serine phosphorylation and decreased insulin-stimulated tyrosine phosphorylation of the normal receptors 69 Fig. Both experiments suggest that a factor present in WGA eluates is responsible for the abnormal phosphorylation.
Phosphoamino acid analysis of immunopurified human insulin receptors hIR β-subunits basally and mixed with WGA-Sepharose eluates from control or PCOS-ser fibroblasts. hIRs were immunopurified from WGA-Sepharose eluates, mixed in a ratio of 10 fmol hIR:1 fmol PCOS-ser or control lectin eluate insulin-binding activity, and autophosphorylation ± 1 μ m insulin was examined.
Phosphoamino acid analysis revealed a striking increase in phosphoserine content and a marked decrease in insulin-stimulated phosphotyrosine content after mixing hIR with PCOS-ser lectin eluates as compared with mixing hIR with control lectin eluates or in the absence of mixing.
However, evidence against this possibility includes the observation that no phosphothreonine is detected in the PCOS-ser insulin receptors, and PKC has been shown to phosphorylate threonine of the insulin receptor Furthermore, the IGF-I receptor, which is a known substrate of PKC under certain conditions, phosphorylates normally in PCOS-ser women 69 , Finally, preliminary Western blot analyses showed no significant differences in the abundance of PKC isoforms in PCOS-ser fibroblasts compared with controls A.
Dunaif, unpublished observations. However, the casein kinase I-like enzyme has been shown to phosphorylate insulin-stimulated insulin receptors twice as well as unstimulated insulin receptors This phosphorylation pattern differs from what we observe with PCOS-ser insulin receptors, namely excessive serine phosphorylation in the absence of insulin.
cAMP-dependent protein kinase is a candidate because increases in cAMP cause serine phosphorylation of insulin receptors in cultured lymphocytes However, insulin receptor phosphorylation by cAMP-dependent protein kinase is probably indirect because the human insulin receptor β-subunit does not contain the amino acid sequences classically recognized by this kinase Because it is present in WGA eluates, the PCOS-ser factor is either a membrane glycoprotein or a protein associated with a glycoprotein.
In some respects, our putative serine phosphorylation factor is similar to a recently identified inhibitor of insulin receptor tyrosine kinase, the membrane glycoprotein PC-1 Fig. Both factors are extrinsic to the insulin receptor, both are present in WGA eluates from human skin fibroblasts, and both appear to inhibit insulin receptor tyrosine kinase activity.
This represents an important new mechanism for human insulin resistance related to factors that modulate the tyrosine kinase activity of the insulin receptor 51 Fig.
The major difference between the two factors is that PC-1 is not associated with increased insulin-independent serine phosphorylation characteristic of the PCOS-ser insulin receptors 69 , , Recent studies suggest that TNF-α produces insulin resistance by a related mechanism: serine phosphorylation of IRS-1, which then inhibits insulin receptor tyrosine kinase activity Fig.
Isolation and characterization of the factor in PCOS-ser fibroblasts are now in progress, as is the mapping of phosphorylated serine residues in PCOS-ser insulin receptors. Serine phosphorylation of IRS-1 appears to be the mechanism for TNFα-mediated insulin resistance.
The membrane glycoprotein PC-1 also inhibits insulin receptor kinase activity, but it does not cause serine phosphorylation of the receptor. Thus, the presence of the putative serine phosphorylation factor in cultured cells of PCOS-ser women suggests that the abnormal insulin receptor phosphorylation is genetically programmed.
In addition, we have found that some first degree relatives of PCOS women are insulin resistant, including brothers, consistent with a genetic defect Recent twin and family studies have also suggested that insulin resistance is a genetic defect in PCOS.
Our putative serine phosphorylation factor is a candidate gene for a mutation producing the insulin resistance associated with PCOS see below. There is general consensus in the literature that obese PCOS women are insulin resistant.
Controversy remains as to the pathogenesis of the insulin resistance, and there are studies that suggest that obesity per se or increased central adiposity are responsible for the associated defects in insulin action , Many of the conflicting studies can be explained by differing diagnostic criteria for PCOS and by the inclusion of both lean and obese women in the experimental sample.
Our studies 49 and those in the United Kingdom , strongly suggest that anovulation is associated with insulin resistance. We found insulin resistance only in women with hyperandrogenism and anovulation Fig. Studies using ovarian morphology to ascertain women have found that only anovulatory women with PCO morphology are insulin resistant , Women with regular ovulatory menses and hyperandrogenism [elevated plasma androgen levels 49 ] Fig.
Therefore, studies that have defined PCOS by PCO morphology without further assessment of ovulation could have included women who were not insulin resistant. Similarly, studies that have included ovulatory hyperandrogenic women will bias the sample with insulin-sensitive subjects.
One reason for the general acceptance of the diagnostic criteria for PCOS of hyperandrogenism and anovulation 1 Table 2 , see above is that they define the insulin-resistant subset. Even with subjects so identified, not all are insulin resistant, despite using the relatively lenient criterion of 1 sd below the control mean value for insulin action.
There is clearly heterogeneity in this feature of the syndrome. Obesity is another important factor, and it appears that it has a more pronounced effect on insulin action in PCOS than in control women Ideally, lean and obese PCOS women should be studied separately 30 , 49 , 54 , 55 , If groups are pooled, PCOS women should be matched to controls so that the spectrum of body weights are equally represented.
This is often not the case so that, although mean body mass may be similar, the PCOS group often contains more obese individuals, thereby skewing the results Moreover, there are very few studies in the literature in which lean PCOS woman have been separately studied 30 , 54 , 55 , 68 , There are also major ethnic variations in insulin sensitivity, and this is another less well appreciated potential confounding factor Recent studies from Denmark suggest that adiposity accounts for insulin resistance in their PCOS population in contrast to our US population , We have consistently found significant decreases in insulin-mediated glucose disposal in both lean and obese PCOS women 54 — Insulin resistance has been found in PCOS women of many racial and ethnic groups including Japanese, Caribbean and Mexican Hispanics, non-Hispanic Whites, and African Americans 55 , 56 , , IR, insulin receptor; Ser, serine; Tyr, tyrosine; HNF, hepatic nuclear factor; FABP 2 , fatty acid binding protein 2; MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes; Rad, Ras-related protein;?
Our studies in premenopausal women, extrapolated data based on prevalence estimates of PCOS and glucose intolerance, and studies in postmenopausal women with a history of PCOS all suggest that PCOS-related insulin resistance confers a significantly increased risk for NIDDM see above.
Familial clustering of affected individuals as well as studies in monozygotic twins indicate that NIDDM has an important genetic component 51 , , — Insulin resistance is a major inherited abnormality, but studies in which insulin secretion has been examined in the context of insulin sensitivity demonstrate that β-cell dysfunction may also be an important contributing factor to the ultimate development of the NIDDM phenotype 51 , , There is clearly genetic heterogeneity with insulin resistance being absent in some affected individuals , Defects in a number of candidate genes, such as GLUT4, GLUT2, and hexokinase, have been excluded , The major cause of insulin resistance in typical NIDDM is reduced insulin-stimulated muscle glycogen synthesis.
Only one study has shown an intrinsic abnormality in NIDDM-cultured cells : decreased insulin-stimulated glycogen synthesis. In contrast, in PCOS, intrinsic abnormalities in the early steps of insulin receptor signaling are present, making this the first common NIDDM subphenotype in which such defects have been identified 69 , , Moreover, the defective pattern of insulin receptor phosphorylation is unique, suggesting it should be possible to distinguish PCOS-related insulin resistance from that related to other NIDDM genotypes.
This should make it possible to assign affected status accurately for linkage studies of the genetics of PCOS-related insulin resistance Do androgens cause insulin resistance? If glucose utilization is expressed as a function of muscle mass rather than total body mass, women do appear to be more insulin sensitive than men , Moreover, when isolated fat cells are compared, female adipocytes are more sensitive than male adipocytes to insulin-mediated glucose uptake These are subtle differences, however, and do not approach the degree of impairment in insulin sensitivity observed in PCOS 54 , Finally, in the rare syndromes of extreme insulin resistance and hyperandrogenism, specific molecular defects in insulin action have been clearly identified as the cause of insulin resistance 19 , It is possible, however, that androgens may produce mild insulin resistance.
Prolonged testosterone administration to female-to-male transsexuals, which produced circulating testosterone levels in the normal male range, resulted in significant decreases in insulin-mediated glucoses uptake in euglycemic clamp studies Studies in testosterone-treated castrated female rats have suggested that androgen-mediated insulin resistance may be the result of an increase in the number of less insulin-sensitive type II b skeletal muscle fibers and an inhibition of muscle glycogen synthase activity Hyperinsulinemic euglycemic clamp studies basally and during treatment with virilizing doses of testosterone in 13 female-to-male transsexuals.
Insulin-mediated glucose disposal decreased significantly at low and at high doses of insulin. Polderman et al. It has been more difficult to demonstrate that decreasing androgen levels improve insulin sensitivity in PCOS.
Diamanti-Kandarakis and colleagues reported that antiandrogen therapy did not alter insulin sensitivity in PCOS. Other investigators have found modest improvements in insulin sensitivity in PCOS during androgen suppression or antiandrogen therapy , Fig.
Such changes were apparent in less insulin-resistant, less obese, or nonobese PCOS women , Moreover, insulin resistance was improved but not abolished Fig. It is of considerable interest that the effects of sex steroids on insulin sensitivity appear to be sexually dimorphic.
Testosterone administration to obese males improves insulin sensitivity , and synthetic estrogen administration to male-to-female transsexuals produces insulin resistance Basal and insulin-mediated glucose disposal in 43 hyperandrogenic women and 12 control women. The hyperandrogenic women were studied before and after 3—4 months of antiandrogen therapy with spironolactone, flutamide, or Buserelin.
Moghetti et al. Givens and colleagues have proposed that androgens have differential effects on insulin action, with testosterone worsening insulin sensitivity and the adrenal androgen, dehydroepiandrosterone DHEA , improving it.
This hypothesis is based on differing correlations of these steroids with insulin-binding studies in blood cells and on their observation that women with elevated dehydroepiandrosterone sulfate DHEAS levels have normal insulin sensitivity Studies in which DHEA or DHEAS have been administered to humans have failed to support this hypothesis.
Administration of supraphysiological amounts of DHEA which also result in testosterone elevations since DHEA is a testosterone prehormone has produced mild hyperinsulinemia in women, but had no effects on insulin sensitivity in men, as would be expected given the sexually dimorphic effects of androgens on insulin action , Moreover, PCOS women with elevated DHEAS levels similar to those in ovulatory hyperandrogenic women are significantly more insulin resistant, arguing against an insulin-sensitizing action of DHEA 49 , In summary, the modest hyperandrogenism characteristic of PCOS may contribute to the associated insulin resistance.
Additional factors are necessary to explain the insulin resistance, since suppressing androgen levels does not completely restore normal insulin sensitivity , Further, androgen administration does not produce insulin resistance of the same magnitude as that seen in PCOS 54 , 55 , Finally, there are clearly defects in insulin action that persist in cultured PCOS skin fibroblasts removed from the hormonal milieu for generations see above Does hyperinsulinemia cause hyperandrogenism?
The syndromes of extreme insulin resistance are commonly associated with hyperandrogenism when they occur in premenopausal women 19 , 20 Table 1. Accordingly, it has been proposed that hyperinsulinemia causes hyperandrogenism.
Insulin can be shown experimentally to have a variety of direct actions on steroidogenesis in humans 1 , 9 , Insulin can stimulate ovarian estrogen, androgen, and progesterone secretion in vitro 1 , 20 , Although some of these actions have been observed at physiological insulin concentrations, most actions have been observed at higher concentrations 1 , The presence of insulin receptors in crude ovarian membranes does not necessarily indicate a physiological role for insulin in the regulation of steroidogenesis since such receptors are widely distributed through the body 51 , Insulin is present in human follicular fluid but in concentrations most likely representing an ultrafiltrate of plasma rather than local production In contrast, IGF-I is produced by human ovarian tissue, and IGF-I receptors are present in the ovary , IGF-I and its receptor share considerable sequence, structural, and functional homology with insulin and its receptor, respectively The IGF-I receptor is a heterotetramer with twoα ,β-dimers assembled analogous to the insulin receptor 85 , 88 , — see above.
Insulin can bind to the ligand-binding domain of the IGF-I receptor and activate the tyrosine kinase activity of theβ -subunit and the intracellular events normally mediated by IGF-I 85 , 88 , , IGF-I can bind to and activate the insulin receptor, resulting in rapid effects on glucose metabolism 85 , 88 , In general, the affinity of the IGF-I receptor for insulin is considerably less than it is for IGF-I and vice versa However, this varies by tissue; thus data on receptor affinity cannot be extrapolated from one tissue to another.
α,β-Dimers of the insulin and IGF-I receptor can assemble together to form hybrid heterotetramers 11 , , , Insulin-like growth factor-binding proteins IGFBPs are major regulators of IGF action.
IGFBPs can specifically bind IGF-I and modulate its cellular actions by altering its bioavailability , Insulin decreases hepatic production of IGFBP-1 and may, thus, make IGF-I more biologically available Growth factor regulation of ovarian steroidogenesis appears to be primarily a paracrine system with locally produced IGF-I and IGFBPs acting on neighboring cells in concert with gonadotropins 1 , , , A number of other growth factors, including IGF-II, EGF, and transforming growth factor-α and -β, appear to have a role in the regulation both stimulatory and inhibitory of ovarian steroidogenesis 1 , , Insulin cannot interact directly with the receptors for these hormones 84 , 88 , , However, the receptors for some of these growth factors, such as the EGF receptor which binds both EGF and transforming growth factor-α , are also protein kinases 1 , 84 , For example, serine phosphorylation of the EGF receptor also decreases its tyrosine kinase activity , In rodents, hyperinsulinemia can result in up-regulation of ovarian IGF-I-binding sites, and this may provide yet another mechanism by which insulin can modulate growth factor action Insulin in high concentrations can mimic IGF-I actions by occupancy of the IGF-I receptor 1 , , , and this has been a proposed mechanism for insulin-mediated hyperandrogenism 8 — However, it has recently been shown that insulin has specific actions on steroidogenesis acting through its own receptor Moreover, these actions appear to be preserved in insulin-resistant states , , presumably because of differences in receptor sensitivity to this insulin action or because of differential regulation of the receptor in this tissue.
Our studies in cultured skin fibroblasts suggest that a mechanism for this may be selective defects in insulin action. Both insulin- and IGF-I-stimulated glycogen synthesis are significantly decreased in PCOS fibroblasts whereas thymidine incorporation is similar to control fibroblasts Fig.
Thus only the signaling pathways regulating carbohydrate metabolism may be impaired in PCOS, while those involved in steroidogenesis are preserved. This would explain the paradox of persistent insulin-stimulated androgen production in insulin-resistant PCOS women.
Insulin decreases hepatic IGFBP-1 production, the major circulating IGF-I-binding protein Thus, bioavailable IGF-I levels are increased in insulin-resistant PCOS women, and this may contribute to the ovarian steroidogenic abnormalities via activation of the IGF-I receptor In lean PCOS women, increases in GH release may also affect ovarian steroidogenesis There were no significant differences in thymidine incorporation in the PCOS fibroblasts right panel.
The dose-response curves for IGF-I were similar to those for insulin data not shown. Dunaif It has been more difficult to demonstrate insulin actions on steroidogenesis in humans in vivo because it is not feasible to administer insulin to nondiabetics for prolonged periods 1 , — However, these increases are minor and are not in the range seen in women with hyperandrogenism.
Furthermore, such transient meal-related increases in insulin do not result in increased androgen levels, whereas the more sustained increases produced by continuous insulin infusion can slightly increase androgen levels Studies in which insulin levels have been lowered for prolonged periods have been much more informative.
This has been accomplished for 7 days to 3 months with agents that either decrease insulin secretion, diazoxide or somatostatin , or that improve insulin sensitivity, metformin or troglitazone Circulating androgen levels have decreased significantly in women with PCOS in these studies.
Sex hormone binding globulin SHBG levels have increased , , compatible with a major role for insulin in regulating hepatic production of this protein , Abnormalities in apparent 17,lyase activity have improved in parallel with reduced circulating insulin levels consistent with insulin-mediated stimulation of this enzyme However, estrogen levels also decreased significantly, suggesting that insulin has diffuse effects on steroidogenesis Changes in estrogen levels were seen only when insulin levels were lowered with troglitazone and thus, alternatively, these changes might be the result of troglitazone-mediated increases in sex steroid metabolism, a recently reported action of this agent Rezulin Package Insert, Parke-Davis, Morris Plains, NJ.
It is also possible that troglitazone has direct effects on steroidogenesis. Indeed, the thiazolidinediones have been shown to have such effects on granulosa cell steroidogenesis Most of the reported actions of insulin on steroidogenesis are observed only in women with PCOS , and are greatly enhanced by the addition of gonadotropins when measured in in vitro experiments 1 , 20 , , , In the one study in normal women in which insulin levels were lowered by diazoxide administration, no significant changes in androgen levels were noted These observations suggest that, if insulin is to produce ovarian hyperandrogenism in women, polycystic ovarian changes e.
In normal women insulin does not appear to have any acute effects on ovarian function under physiological circumstances , , Although insulin has been shown to stimulate gonadotropin release in isolated rat pituitary cells , human studies of insulin action on gonadotropin release have yielded conflicting results.
Acute insulin infusion has not changed pulsatile LH or FSH release or gonadotrope sensitivity to GnRH in normal or in PCOS women, despite direct effects on gonadal steroidogenesis in PCOS women Long-term suppression of insulin levels with diazoxide, which resulted in decreases in circulating testosterone levels, did not alter circulating LH levels In contrast, decreases in LH levels were observed after 7 days of somatostatin-mediated insulin lowering , after metformin for 8 weeks , or after troglitazone for 3 months It is possible that insulin-mediated changes in gonadotropin release contribute to the changes of steroidogenesis produced by insulin in humans Fig.
Studies in which insulin levels have been lowered with the insulin-sensitizing agent, troglitazone, suggest that insulin is a general augmentor of steroidogenesis and LH release. Acute insulin infusions decrease DHEAS levels in men and women, suggesting that insulin is a negative modulator of adrenal androgen metabolism When insulin levels are chronically lowered, however, circulating DHEA and DHEAS levels rise in men but not in women, suggesting that this regulation of adrenal androgen metabolism is sexually dimorphic Lowering insulin levels with insulin-sensitizing agents, such as troglitazone, has resulted in decreases in DHEAS levels in PCOS women Fig.
The mechanism of this appears to be a direct action of insulin to increase adrenal sensitivity to ACTH in hyperandrogenic women Insulin can directly decrease hepatic SHBG production , explaining the frequently observed inverse correlation between peripheral insulin and SHBG levels Indeed, insulin rather than sex steroids appears to be the major regulator of SHBG production In summary, studies in which insulin levels have been lowered by a variety of modalities indicate that hyperinsulinemia augments androgen production in PCOS Fig.
Moreover, this action appears to be directly mediated by insulin acting through its cognate receptor rather than by spillover occupancy of the IGF-I receptor. Intrinsic abnormalities in steroidogenesis appear to be necessary for this insulin action to be manifested since lowering insulin levels does not affect circulating androgen levels in normal women.
Further, in many PCOS women, lowering insulin levels ameliorates but does not abolish hyperandrogenism. Family studies of PCOS. Familial aggregation of PCOS suggesting a genetic etiology has been clearly established 1 , — Cooper et al.
The proposed mechanism of inheritance was autosomal dominant with decreased penetrance. Givens and colleagues have reported multiple kindreds showing affected women in several generations and have examined some males in considerable detail 1 , Diagnostic criteria for PCOS were hirsutism and enlarged ovaries.
There was a high frequency of metabolic disorders, such as NIDDM and hyperlipidemia, in both male and female pedigree members. This would suggest inheritance in either an autosomal or X-linked dominant manner. Ferriman and Purdie studied women; affected status was assigned on the basis of hirsutism and enlarged ovaries assessed by gynecography.
The frequency of various abnormalities in relatives was determined by history provided by the proband; no relatives were examined. Oligomenorrhea and infertility were most common in women who had both hirsutism and enlarged ovaries.
Forty-six percent of female relatives were reported to be similarly affected. There was an increased incidence of baldness reported in male relatives. Similar results were found in a study of Norwegian PCOS probands identified by ovarian wedge resection Information on pedigree members was obtained by questionnaire.
Female first-degree relatives had a significantly increased frequency of PCOS symptoms i. There have been case reports of polyploidies and X-chromosome aneuploidies in PCOS , Larger studies, however, have found normal karyotypes Studies from the United Kingdom have phenotyped women on the basis of polycystic ovarian morphology detected by ultrasound The proportion of females affected in all sibships was However, not all women in each kindred were examined and, thus, an accurate ratio of affected to unaffected women could not be established for segregation analysis.
Further, the male phenotype was not sought. A more recent study prospectively examined the families of probands consecutively identified on the basis of polycystic ovarian morphology on ultrasound The first-degree relatives in 10 families were evaluated by history, measurement of physical indices, and hirsutism as well as serum levels of androgens, hydroxyprogesterone, gonadotropins, and PRL.
Transabdominal ultrasound was performed in female first-degree relatives. Glucose and insulin levels were assessed in obese but not lean probands. Twenty-two males were screened; eight had premature before age 30 yr fronto-parietal hair loss, 10 did not, and four were too young to assess.
Female affected status was assigned on the basis of ultrasound evidence of polycystic ovaries. If male affected status was considered to be premature balding, and a history of menstrual irregularity was used to assign postmenopausal affected status, the segregation ratio for affected families, excluding the proband, was Studies in monozygotic twins, however, have not found complete concordance of polycystic ovary morphology, arguing against this mode of inheritance The study contained only 19 pairs of monozygotic twins as well as a sample of 15 dizygotic twins.
This raises concern about the accuracy of the detection of polycystic ovaries. In several studies, PCOS affected status has been assigned on the basis of ovarian morphology rather than hormonal abnormalities.
Only one study has proposed a male phenotype on the basis of examination of male relatives, and this study was constrained by a small sample size Nevertheless, these studies strongly suggest that PCOS has a genetic component, most likely with an autosomal dominant mode of transmission , If this is true, are there other phenotypes in affected kindreds?
The studies cited above have suggested that premature male balding may be a male phenotype , This finding could be an artifact, since it is also possible that bald men choose to marry hirsute women. Recent studies in these families, however, suggesting linkage of this phenotype with a candidate gene in the steroidogenic enzyme pathway Ref.
Our studies have suggested that insulin resistance may be an additional male phenotype as well as a prepubertal and postmenopausal female phenotype , Table 4. This has been also reported recently in a series of Australian PCOS kindreds.
In the small number of families that we have studied , , when women of reproductive age are insulin resistant, they usually have possessed the other endocrine features of PCOS.
The one insulin-resistant prepubertal girl was also hyperandrogenic and developed chronic anovulation after menarche consistent with the diagnosis of PCOS That insulin resistance and hyperandrogenism may be a prepubertal phenotype is supported by recent studies suggesting that PCOS develops in insulin-resistant girls with premature adrenarche 58 , , Table 4.
Our studies suggest that hyperandrogenism without insulin resistance is another phenotype in female PCOS kindred members of reproductive age Table 4. Finally, we have found postmenopausal hyperandrogenic female family members with normal insulin sensitivity, which may represent an additional postmenopausal phenotype Table 4.
This possibility is supported by the study of Dahlgren and colleagues 53 , which found that postmenopausal women with a history of PCOS had higher androgen levels than age-matched control women.
We have found that hyperandrogenism and insulin resistance can segregate independently in PCOS kindreds It is not yet possible to determine whether this reflects separate genetic traits or variable penetrance of a single defect. These studies also indicate that there is considerable phenotypic variation, even within kindreds.
Candidate genes for PCOS. The biochemical reproductive phenotype in PCOS is characterized by increased LH secretion and acyclic FSH release 2 , The ovaries in response to LH and, often, the adrenals secrete excessive androgens, and there is decreased ovarian aromatization of androgens to estrogens The circulating androgens feed back on the hypothalamic-pituitary axis directly or via their extragonadal aromatization to estrogen to increase LH relative to FSH release, producing a self-sustaining syndrome 34 — 37 , The defect that initiates these reproductive disturbances in PCOS is unknown, but it can be shown experimentally that factors that increase either androgen secretion or LH release can reproduce these disturbances 1 , 2 , 12 , 38 , Indeed, polycystic ovaries and hyperandrogenism were present in a girl with an aromatase gene mutation leading to an inactive enzyme Transgenic mice overexpressing the LH β-subunit gene in their gonadotropes develop polycystic ovary morphology, androgen elevations, and LH hypersecretion The insulin resistance in PCOS is secondary to a postbinding defect in insulin receptor signaling, as discussed above When this enzyme is identified, it will make an excellent candidate gene for insulin resistance in PCOS.
This enzyme may also be responsible for altering Pc17 activity that results in hyperandrogenism and the PCOS reproductive phenotype Polymorphisms in the Pc17 gene itself were found not to cosegregate with the polycystic ovary-premature balding phenotypes in the families reported by Carey et al.
However, the polymorphism did affect the promoter region of the gene, and the frequency of the polymorphism was significantly increased in PCOS, suggesting that it might play a role in modifying the phenotype Further candidate gene searches in these families suggest a linkage with the steroid synthesis gene CYP11a, and an association study indicated a significant increase in a CYP11a polymorphism in hirsute PCOS women The polymorphism was also significantly associated with elevated testosterone levels.
These investigators have recently reported that an insulin gene VNTR-regulatory polymorphism was significantly associated with PCO in the same families Case-control studies suggested that the polymorphism was associated with anovulation and higher insulin levels , women who would be considered to have the endocrine syndrome.
This observation suggests that there may be a genetic basis for the finding of insulin resistance only in anovulatory women with hyperandrogenism or the PCO morphology. This insulin gene VNTR has been associated with decreased levels of islet cell insulin RNA and may thus result in decreased insulin secretion.
The mechanism by which this might cause hyperinsulinemia and insulin resistance is unknown. Polymorphisms in the dopamine and androgen receptors have not been significantly associated with PCOS , , There have been no mutations in the coding portions of the insulin receptor gene detected in PCOS 69 , , Extreme caution must be exercised, however, in the interpretation of both linkage and association studies.
Case-control association studies can give false-positive results because of subtle genetic differences between the populations This appears to have occurred in the association studies of the polymorphism in the Pc17 gene promoter with PCO Subsequent larger studies by these investigators failed to confirm the finding a.
Linkage studies of many candidate genes in the same families must have the level of significance for positive results adjusted for multiple tests. Thus log of odds scores greater than the traditional threshold of 3 must be used to prove linkage Such log of odds scores have not been achieved in the reported studies in PCOS , Does insulin resistance produce PCOS in women with PCO?
The polycystic ovary morphology detected by ultrasonography has been reported to be inherited as an autosomal dominant, if premature balding is used as the male phenotype see above.
We have found that Caribbean Hispanic women have twice the prevalence of PCOS compared with other ethnic groups Brothers, as well as sisters, of PCOS women can be insulin resistant , The insulin-resistant sisters usually also have PCOS All of these observations support the hypothesis that there is a genetic component to PCOS and the insulin resistance associated with it.
Caribbean Hispanic women are also significantly more insulin resistant than non-Hispanic White women by euglycemic clamp determination of insulin-mediated glucose disposal PCOS independently further decreases insulin action. Non-Hispanic White PCOS women have similar degrees of insulin resistance to Caribbean Hispanic normal ovulatory women These findings suggest that the increased prevalence of PCOS in this ethnic group may be secondary to an increased prevalence of insulin resistance.
Hyperinsulinemia resulting from a spectrum of defects in insulin action, at least some of which are genetic, may play a permissive role in the development of PCOS in genetically susceptible women Fig. This hypothesis is supported by the finding of the full-blown polycystic ovary syndrome hyperandrogenism and anovulation primarily in women with polycystic ovaries who are also hyperinsulinemic , A proposed schema for the association of insulin resistance and PCOS.
A single factor that causes serine phosphorylation of the insulin receptor and serine phosphorylation of Pc17, the key regulatory enzyme controlling androgen biosynthesis, could produce both the insulin resistance and the hyperandrogenism characteristic of PCOS.
It is also possible that the insulin resistance and the reproductive abnormalities reflect separate genetic defects and that the insulin resistance unmasks the syndrome in genetically susceptible women. Recent studies suggest that insulin acting through its own receptor augments steroidogenesis and LH release.
Androgens amplify the associated insulin resistance. Could PCOS and insulin resistance result from a single defect? An exciting recent finding by Miller and colleagues is the observation that serine phosphorylation of human Pc17, the key regulatory enzyme of both ovarian and adrenal androgen biosynthesis, increases its 17,20 lyase activity.
This would result in increased androgen secretion A modulation of steroidogenic enzyme activity by serine phosphorylation has been reported for 17β-hydroxysteroid dehydrogenase If the same factor that serine-phosphorylates the insulin receptor causing insulin resistance also serine-phosphorylates Pc17 causing hyperandrogenism, this could explain the association of PCOS and insulin resistance by a single genetic defect Fig.
Making a diagnosis of insulin resistance in an individual is problematic. Second, clinically available measures of insulin action, such as fasting or glucose-stimulated insulin values , do not correlate well with more detailed measurements of insulin sensitivity in research settings In view of these constraints, it is prudent to consider all PCOS women at risk for insulin resistance and the associated metabolic abnormalities of the insulin resistance syndrome: dyslipidemia, coronary artery disease, and hypertension.
Lipid and lipoprotein levels should be obtained on all PCOS women, and obese PCOS women should also have fasting and 2-h post g glucose load glucose levels as a screen for glucose intolerance.
Individual values for fasting and 2-h post g oral glucose load insulin levels are shown in PCOS and in weight-matched control women. Although the means differ significantly, there is substantial overlap such that an individual value in a PCOS woman may not fall outside the normal range.
Dyslipidemia, dysfibrinolysis, and coronary artery disease. Women with PCOS would be predicted to be at high risk for dyslipidemia because they have elevated androgen levels and are frequently obese — Moreover, since they are also often hyperinsulinemic and insulin resistant, they would also be expected to be at increased risk for the dyslipidemia associated with insulin resistance Insulin, rather than androgen, levels correlate best with lipid abnormalities, and suppressing androgen levels does not alter lipid profiles in PCOS PCOS women also have impaired fibrinolytic activity with increased circulating levels of plasminogen activator inhibitor, PAI-1 , Elevated PAI-1 levels are associated with insulin resistance and are considered to be an independent cardiovascular risk factor by increasing the risk of intravascular thrombosis In PCOS, increased PAI-1 levels are also associated with insulin resistance, and these levels decrease with improvements in insulin sensitivity mediated by weight loss or insulin-sensitizing agents There are several intriguing cross-sectional studies that suggest that PCOS women may indeed be at increased risk for cardiovascular disease.
Women coming to cardiac catheterization who have a history of symptoms of hyperandrogenism have an increased prevalence of coronary artery disease Postmenopausal women with a history of ovarian wedge resection for PCOS have a significantly increased frequency of cardiovascular events compared with age-matched control women Women with PCO detected by ovarian ultrasound have more extensive coronary artery disease by angiography than women with sonographically normal ovaries The women with PCO also have higher free testosterone, triglyceride, and C-peptide levels and lower LDL levels than the women with normal ovaries, suggesting that they have both the endocrine and the metabolic derangements of PCOS Finally, increased carotid wall thickness measured by ultrasonography was found in PCOS women compared with case-controls The carotid wall thickness was significantly positively correlated with fasting insulin levels and body mass index, after adjustment for possible confounding variables However, since the PCOS women were significantly heavier than the controls, it was not possible to determine the independent impact of obesity on these findings As with studies of insulin action, studies of lipid metabolism in PCOS have been confounded by differences in body weight and ethnicity between patient and control groups.
Inconsistencies in diagnostic criteria, in particular, basing the diagnosis on ultrasound morphology rather than hormonal parameters, have resulted in heterogenous patient populations that have included women with regular ovulation and normal insulin sensitivity — Some investigators have found that LDL and HDL changes in PCOS can be accounted for by obesity and that only modest increases in total triglyceride levels appear secondary to PCOS-related insulin resistance , , A recent case control study does suggest that there are lipid abnormalities in PCOS after statistical adjustments for obesity However, Legro and colleagues found atherogenic alterations in lipoprotein levels in normal Hispanic women that did not differ further in Hispanic PCOS women.
Thus, there appear to be important additional genetic and environmental factors influencing lipid metabolism in PCOS.
It has been suggested that insulin resistance causes hypertension; thus PCOS women would be expected to be hypertensive Significant increases in systolic blood pressure, albeit within the normal range, have been reported in obese PCOS women, but this study did not include a weight-matched control group Moreover, lean PCOS women in the study were not hypertensive, consistent with an effect of obesity rather than PCOS on blood pressure.
Careful studies of h blood pressures and left ventricular mass have failed to find evidence for hypertension in PCOS women in their second to fourth decades of life This has been confirmed in another recent study The studies discussed above in postmenopausal PCOS women, however, have found a significant increase in prevalence of hypertension It may be that hypertension is not manifested until later in life in PCOS women.
Conversely, it remains possible that the association between insulin resistance and hypertension does not exist in PCOS, analogous to observations in African Americans and in Pima Indians Gestational diabetes mellitus GDM.
Women with a history of GDM are insulin resistant, at increased risk to develop NIDDM, and have defects in the β-cell function that can be detected in the absence of glucose tolerance , PCOS women share these traits, and it would be expected that they would be at increased risk to develop GDM, if GDM is yet another manifestation of insulin resistance.
Two small studies of this have yielded conflicting results: one study found no increase in GDM while another detected an increased risk for GDM in PCOS women , A large prospective study in PCOS women containing appropriately matched control women is required to address this issue.
Until such a study has been completed, it is prudent to advise PCOS women contemplating pregnancy that they may be at increased risk to develop GDM. Leptin in PCOS. Leptin, the recently identified product of the ob gene , has been investigated in PCOS. Since leptin is a fat cell product that acts on the hypothalamus , it could link the metabolic and neuroendocrine derangements characteristic of PCOS.
Leptin production is regulated by insulin and could be modulated in insulin-resistant PCOS women via this mechanism An initial report suggested that leptin levels were elevated in some PCOS women
Risk of diabetes Low-carb snacks high if left Mediterranean diet and blood sugar regulation. Polycystic Insuli syndrome PCOS can put you nad risk for insulin resistance. Signs to watch for include certain food cravings and the need to urinate more frequently. These symptoms occur because your body is not responding to insulin as it should. Insulin resistance is an inadequate response to the hormone insulin.Video
PCOS Insulin Resistance Explained Story by: Norton Healthcare on Resiztance 13, But were you aware that diet plays resisgance Mediterranean diet and blood sugar regulation in insulin resistance, one of anv main causes of the hormone imbalance? Infertility is just one of many possible complications. Patients with PCOS usually have higher than normal insulin levels. Insulin lowers your blood sugar by storing the glucose in cells. Type 2 diabetes occurs when the cells become resistant to insulin.Log Inwulin to check out faster. In this article, we Proper form and technique the connection between resisstance resistance resisance PCOSas well as everything we know about managing symptoms and treatment options. Polycystic Ovary Syndrome PCOSsometimes Insluin Polycystic Ovarian Syndrome, is a hormonal disorder that occurs PCCOS women of reproductive age Innsulin Insulin resistance and PCOSannd an overproduction of male hormones called androgens anc ovulation.
Rexistance include ovarian cysts, irregular menstruation, acneweight gain, hair loss, and hirsutism anv a condition that thickens facial hair. Mediterranean diet and blood sugar regulation is commonly Proper form and technique that insulin Nutrition periodization for endurance is also Ijsulin symptom of PCOS.
Andd, the exact cause of PCOS remains unproven and some Insklin believe that Lycopene and muscle recovery resistance could be part of the cause of PCOS resisstance than a symptom.
Other experts resistahce that PCOS is rseistance than likely linked xnd genetics, causing Insulinn messages from the pituitary gland to result in an overproduction of androgens.
In any case, insulin resistance requires management, lifestyle changes, and sometimes medication, therefore resistancw is always advisable for any woman with PCOS to Insulin resistance and PCOS their Injury prevention through proper nutrient timing levels tested.
Understanding the important role of reslstance in the body can help to comprehend what happens when the body becomes insulin resistajce due to PCOS or type 2 diabetes.
Effectively, insulin resiistance two roles in the body; the first resiistance to regulate blood sugar levels and the second is to Mood boosting supplements and pills excess glucose as energy that can amd used at a later stage.
Once sugar Ad detected in the Inssulin, insulin is normally resistanec from POCS pancreas to anf the body PCOOS the glucose and use PCO as energy. Any Mediterranean diet and blood sugar regulation glucose is stored in the liver in the form anx glycogen and resietance when xnd levels Leafy greens for sandwiches low, usually between meals, nad maintain blood sugar levels.
Resishance resistance is when the body fails to use Isulin effectively. Meaning that although insulin is released as usual by the pancreas in response to increased glucose levels in the bloodstream, the glucose is not absorbed by the cells of the body as it should be.
As a result, glucose levels continue to increase without being properly broken down, causing energy levels and metabolism to drop.
Over time, as glucose builds up in the bloodstream, more and more insulin is needed to help break it down and absorb it into the body. When left untreated, insulin resistance can lead to pre-diabetes diabetes, and gestational diabetesas well as further complications like kidney damage, vascular disease, and blindness.
For instance, even though PCOS symptoms like ovarian cysts, irregular menstruation, and infertility can manifest in advance of symptoms associated with insulin resistance, some experts suggest that increased levels of insulin may contribute to the metabolic complications connected to PCOS.
No, not all women with PCOS have insulin resistance, which is why the cause of PCOS is unclear. In addition, insulin resistance does not affect everyone in the same way.
Some women with insulin resistance experience few to no symptoms at all until it escalates into pre-diabetes or diabetes when left untreated. However, due to the connection between insulin resistance and PCOS, women should understand that some symptoms are similar to both conditions.
Common symptoms include the following:. If the above symptoms are familiar to you, schedule an appointment with your healthcare provider and request blood tests to determine how effectively your body is dealing with sugar. Bear in mind that testing for glucose levels often requires patients to fast beforehand, so be sure to check on the details with your doctor.
The first signs of Polycystic Ovary Syndrome PCOS typically include irregular or infrequent menstrual cycles and signs of high androgen levelssuch as excess facial and body hair, severe acne, and male-pattern baldness. Additionally, many women with PCOS experience weight gain and may have difficulty conceiving.
Being diagnosed with insulin resistance or PCOS does not necessarily mean you will develop diabetes. Making healthy lifestyle changes and incorporating natural remedies can reduce insulin resistance symptoms to a manageable rate and prevent the necessity of medical treatment.
Reducing sugar intake, and replacing processed foods with whole grains, vegetables, and low-fat dairy products will help to lower blood sugar levels and decrease insulin resistance over time. Regular exercise will help you to lose weight gained due to the slowed metabolism associated with the condition, as well as increase your energy levels and improve sleep.
Concerning women with PCOS, researchers have found that a combination of Myo and D-Chiro Inositol in supplement form can promote hormonal balance and positively influence the use of insulin.
Inositol is a type of sugar naturally made in the body to balance moods, fertility, cholesterol, blood sugar, and metabolism. The added ashwagandha and vitamin D in the Myo and D Chiro Inositol Supplement from Intimate Rose also regulate brain hormones like serotonin and dopamine to relieve stress and feelings of depression associated with PCOS.
In addition, due to its effects on blood sugar and metabolism, the Myo and D Chiro Inositol supplement helps to reduce acne, hair loss, and weight gain. Medical treatment options for insulin resistance include mild doses of diabetes medication to lower blood sugar levels.
If you have PCOS, health experts highly recommend scheduling an appointment with your doctor at your earliest convenience to get tested for insulin resistance. With some healthy lifestyle changes like regular exercise and a well-balanced food plan, insulin resistance can be managed and does not have to result in diabetes.
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: Insulin resistance and PCOS| The Five Faces of PCOS | For people who are overweight, increased physical activity can lower the risk for Type 2 diabetes, as well as other health issues. Carricato said. When it comes to diet, adding high-fiber vegetables, lean proteins and healthy fats is essential. PCOS is treatable and can be managed effectively. Polycystic ovary syndrome PCOS and insulin resistance are related. Changes in your diet can help. Controlling blood sugar through diet and lifestyle changes can help restore hormone balance Story by: Norton Healthcare on September 13, Schedule an Appointment Select an appointment date and time from available spots listed below. Most women with PCOS have post-challenge rather than fasting dysglycemia. Prevalence rates of dysglycemia are elevated in non-U. women with PCOS but not to the same magnitude as those in U. women with PCOS. The prevalence rates of IGT and T2D were A telephone interview study of Dutch women with PCOS found a significant increase in diagnosed T2D compared with population prevalence estimates Another European study did not show increased prevalence rates of IGT and T2D in women with NICHD PCOS from Spain compared with age-, BMI-, and ethnicity-comparable control women. Although the prevalence of obesity is higher and its severity is greater in U. PCOS populations , , such differences alone cannot account for differing rates of dysglycemia, which persist between European and U. PCOS cohorts in comparable BMI categories , , A recent meta-analysis reviewed more than studies of glucose tolerance in PCOS from which only 30 full-text studies were assessed for the final analysis. The increased prevalence of IGT and T2D in women with PCOS compared with women without PCOS, in both BMI- and non-BMI-matched studies, was confirmed. In the meta-analysis, the odds ratios OR and confidence intervals CI were significantly increased: IGT—OR, 2. This meta-analysis confirms that the risk for IGT and T2D is increased in PCOS. PCOS is now recognized as a diabetes risk factor by the American Diabetes Association Nevertheless, the magnitude of risk is unclear because most studies have been cross-sectional, relatively small, and lacking concurrently studied control women Large cross-sectional and prospective population-based studies are needed to accurately estimate the magnitude of T2D risk in PCOS. A recent prospective study in an Italian PCOS cohort confirmed an increased risk for T2D In Pima Indians and in the Nurses Health Study II , the risk for T2D was significantly increased in women with menstrual irregularity. In the Nurses Health Study , a multivariate analysis adjusting for multiple confounders, including BMI at age 18, race, physical activity, first-degree relative with diabetes, smoking, and oral contraceptive use, found the relative risk for diabetes was 1. The risk was increased by obesity but remained significant in lean women with irregular menses This association was not confirmed in a relatively small U. prospective cohort study , but it was supported in a more recent and larger Dutch study These data suggest that PCOS increases the risk for T2D across a woman's lifespan. There have been very few follow-up studies to assess conversion rates from normal glucose tolerance to IGT and from IGT to T2D. The conversion rate from normal to IGT or from IGT to T2D in PCOS has been estimated to range from 2. This discrepancy likely represents an underestimate in conversion rates in PCOS because the studies have been limited by small sample size , — Women with PCOS most commonly have postprandial dysglycemia , , which reflects peripheral, primarily skeletal muscle, insulin resistance rather than fasting dysglycemia Fig. Therefore, 2-h postchallenge glucose values are optimal for the diagnosis of IGT and T2D in PCOS , , and the AES position statement has recommended screening of all women with PCOS with a g OGTT. The optimal time period for repeat OGTT is uncertain. A hemoglobin A1c value between 5. A recent study that assessed the utility of hemoglobin A1c to detect IGT and diabetes in PCOS found that this test had low sensitivity when compared with OGTT assessment of glucose tolerance. This discrepancy in diagnostic accuracy may be because affected women have mainly post-glucose challenge rather than fasting dysglycemia , Insulin acts to regulate glucose homeostasis by stimulating glucose uptake by insulin-responsive target tissues, adipocytes, and skeletal and cardiac muscle, as well as by suppressing hepatic glucose production , Insulin also suppresses lipolysis, resulting in a decrease in circulating free fatty acid levels , which may mediate the action of insulin on hepatic glucose production — Accordingly, insulin resistance is characterized by increased circulating insulin levels, basally and in response to a glucose load, if pancreatic β-cell function is intact , Insulin has other metabolic as well as mitogenic and reproductive actions discussed in Sections IV. and V. and in Refs. This technique quantitatively assesses insulin action on whole-body glucose uptake by infusing a desired dose of insulin and maintaining euglycemia using a variable glucose infusion where the rate is adjusted based on frequent arterialized blood glucose determinations and a negative feedback principle , At steady state, the amount of glucose that is infused equals the amount of glucose taken up by the peripheral tissues, and it can be used as a measure of peripheral sensitivity to insulin, known as insulin-mediated glucose disposal IMGD or M , As fat mass increases, it accounts for a larger amount of IMGD Endogenous glucose production, which reflects both hepatic and renal glucose production , — , can be determined by the infusion of isotopically labeled glucose at baseline and during the euglycemic clamp , The suppression of hepatic glucose production can be assessed by determining the decrease in endogenous glucose production in response to insulin , Whole-body insulin sensitivity can also be accurately measured in subjects without diabetes using the frequently sampled iv glucose tolerance test FSIGT with minimal model analysis The minimal model determines insulin sensitivity sensitivity index , which reflects insulin action to stimulate glucose uptake as well as to suppress glucose production The acute insulin response to glucose AIRg is also determined from the FSIGT data. The disposition index DI , the product of AIRg and insulin sensitivity, assesses insulin secretion in the context of insulin sensitivity and is a robust parameter of pancreatic β-cell function , that will be discussed in Section IV. It is possible to model hepatic glucose production with the administration of isotopically labeled glucose during the FSIGT , , but this measurement is rarely performed because the tracer is expensive and the model is complex. The standard FSIGT is substantially easier and less expensive to perform than the clamp, although it is still an investigational procedure that requires frequent blood sampling. The FSIGT provides quantitative, reproducible measurements of insulin sensitivity in individuals without T2D; in patients with diabetes, it may not be possible to differentiate between very low insulin sensitivity values , The FSIGT also provides a simultaneous assessment of insulin secretion , The euglycemic clamp provides a quantitative, reproducible measurement of insulin action across a spectrum of insulin sensitivities and can be used in patients with T2D , Endogenous, primarily hepatic, glucose production can also be assessed during the clamp , The measurement of insulin secretion requires a separate, hyperglycemic clamp study , , The glucose clamp procedure requires highly trained personnel and specialized equipment , It is also substantially more expensive to perform than the FSIGT Because of the complexity and expense of the clamp and the FSIGT, there has been a desire to use fasting parameters of glucose homeostasis as surrogate measures of insulin resistance. These measures include homeostatic model assessment , fasting glucose:insulin ratio , and quantitative insulin sensitivity check index They are all based on fasting glucose and insulin levels and essentially provide identical information Fasting glucose levels reflect endogenous glucose production , an index of hepatic rather than peripheral insulin action Fasting insulin levels reflect not only insulin sensitivity but also insulin secretion and clearance Accordingly, fasting insulin levels will not provide accurate information on insulin sensitivity in individuals with β-cell dysfunction OGTT-derived parameters of insulin action have also been shown to be insensitive to large changes in insulin sensitivity Although fasting measures and OGTT-derived parameters may correlate with clamp or FSIGT measures of insulin sensitivity, they lack precision for quantitatively measuring insulin resistance in the general population These measures have been found to be similarly imprecise for the assessment of insulin sensitivity in women with PCOS PCOS women have an increased prevalence of obesity 19 , , , and women with upper as opposed to lower body obesity have an increased frequency of hyperandrogenism Androgens can also increase visceral fat mass in women Muscle is the major site of insulin-mediated glucose use , and androgens can increase muscle mass Thus, potential changes in lean body primarily muscle and fat mass as well as in fat distribution should be considered to accurately assess insulin action in PCOS 81 , The decrease in IMGD in PCOS was of a similar magnitude to that reported in T2D Fig. Furthermore, IMGD was significantly decreased per kilogram of fat free, primarily muscle, mass IMGD was also significantly decreased in lean PCOS women, all of whom had normal glucose tolerance. Decreased IMGD in PCOS. This decrease is similar in magnitude to that reported in T2D open bars Body fat topography, upper compared with lower body, can affect insulin sensitivity 7 , with increases in upper body and visceral fat being associated with decreased insulin sensitivity 7 , The study of Dunaif et al. However, visceral fat mass accurately quantified by magnetic resonance imaging MRI , or by computerized tomography does not differ in women with PCOS compared with BMI-matched control women. Thus, the study of PCOS and control women of comparable BMI appears to be sufficient to control for the confounding effects of obesity as well as of fat distribution on insulin sensitivity. Insulin has concentration-dependent saturable actions that can be examined in vivo using sequential multiple insulin dose euglycemic clamp studies The concentration required for a half-maximal ED 50 response defines insulin sensitivity and usually reflects insulin receptor binding or phosphorylation, whereas the maximal biological effect is defined as insulin responsiveness and usually reflects postreceptor events, for example, translocation of the GLUT4 glucose transporter for IMGD Dose-response studies have indicated that the ED 50 insulin for glucose uptake was significantly increased and that maximal rates of IMGD were significantly decreased in lean and in obese women with PCOS women Fig. It appears, however, that body fat has a more pronounced negative effect on insulin sensitivity in women with PCOS , Basal endogenous glucose production and the ED 50 insulin for suppression of endogenous glucose production were significantly increased only in obese PCOS women 81 , Fig. This synergistic negative effect of obesity and PCOS on endogenous glucose production is an important factor in the pathogenesis of glucose intolerance 34 , 81 , , Insulin action in isolated sc adipocytes and in vivo. The dose-response of insulin-stimulated glucose uptake was determined in isolated sc adipocytes in vitro and in vivo during sequential multiple insulin dose euglycemic glucose clamp studies. Maximal rates of glucose uptake insulin responsiveness in isolated sc adipocytes are depicted in vitro A, left and in vivo , which reflects primarily skeletal muscle glucose uptake B, left. Rates of postabsorptive endogenous glucose production EGP C, left and its suppression by insulin were also assessed during the euglycemic glucose clamp study. The ED 50 insulin insulin sensitivity for stimulation of glucose uptake and suppression of EGP are depicted in the graphs on the right A, sc adipocytes in vitro ; B, in vivo ; C, EGP. Women with PCOS, gray bars ; normal control women NL , open bars. Diabetes —, , with permission. Many subsequent studies using euglycemic glucose clamps or FSIGTs have confirmed that women with PCOS have profound resistance to the action of insulin to stimulate glucose uptake for example, see Refs. There is general consensus that obese women with PCOS are insulin resistant However, several studies have failed to demonstrate insulin resistance in lean women with PCOS for example, see Refs. Some of these conflicting results can be accounted for by differences in the diagnostic criteria for PCOS that resulted in the inclusion of women with ovulatory cycles and hyperandrogenism who have minimal to absent evidence for insulin resistance see discussion in Section III. of diagnostic criteria and Refs. Attempts to quantitate the prevalence of insulin resistance in PCOS are limited by the methods used to determine insulin sensitivity. Even when insulin resistance is assessed using the euglycemic glucose clamp, it is clear that some women with PCOS have normal insulin sensitivity 81 Fig. Thus, defects in insulin action on glucose metabolism are not a universal feature of the syndrome. Indeed, two of the PCOS phenotypes identified with the Rotterdam criteria Table 3 —hyperandrogenism and PCO with ovulatory cycles, and anovulation and PCO without hyperandrogenism—have modest or absent 99 evidence for insulin resistance using surrogate markers. Nevertheless, it remains possible that there is increased sensitivity to the reproductive actions of insulin in PCOS because hyperandrogenism and anovulation improve during metformin treatment in women with PCOS without evidence for insulin resistance Alternatively, these improvements may be related to a direct action of metformin on steroidogenesis Fasting and dynamic measures of insulin resistance. Fasting measure of insulin sensitivity, the glucose:insulin ratio and insulin levels are shown in the top graphs. Dynamic measures of insulin sensitivity, the euglycemic glucose clamp determined IMGD, and sensitivity index SI assessed by minimal model analysis of FSIGT are shown in the bottom graphs. For all measures of insulin action, there is considerable overlap between control open triangles and PCOS gray circles women. The data have been previously published 81 , , and were adapted for use in this figure, which is used with the permission of Andrea Dunaif. Insulin receptor signaling pathways. The insulin receptor is a heterotetramer consisting of two α, β dimers linked by disulfide bonds. The α-subunit contains the ligand binding domain, and the β-subunit contains a ligand-activated tyrosine kinase. Tyrosine autophosphorylation increases the receptor's intrinsic tyrosine kinase activity, whereas serine phosphorylation inhibits it. The tyrosine-phosphorylated insulin receptor phosphorylates intracellular substrates, such as IRS 1—4, Shc, and APS, initiating signal transduction pathways mediating the pleiotropic actions of insulin. The inhibition of GSK3 results in dephosphorylation of glycogen synthase increasing glycogen synthesis. The mTOR pathway is also important in nutrient sensing. Insulin signaling can be terminated by dephosphorylation of the receptor by tyrosine phosphatases, such as PTP1B, or dephosphorylation of PI3-K by PTEN. Serine phosphorylation of the insulin receptor and IRSs can also decrease insulin signaling and may be mediated by serine kinases in the insulin signaling pathway providing a feedback mechanism to terminate insulin action. There is a post-binding defect in insulin signaling in PCOS affecting metabolic but not mitogenic pathways see Fig. The signaling steps that are compromised in PCOS are circled with a dotted line. Signaling steps downstream of these abnormalities may also be compromised. SOS, Son-of-sevenless. Insulin signaling defects in PCOS. There is a post-binding defect in insulin signaling in PCOS resulting in marked decreases in insulin sensitivity see Fig. There is a more modest defect in insulin responsiveness. The signaling defect is due to serine phosphorylation of the insulin receptor and IRS-1 secondary to intracellular serine kinases. This results in decreased insulin-mediated activation of PI3-K and resistance to the metabolic actions of insulin. Serine phosphorylation of Pc17 increases its activity, and it has been postulated that the same kinase may inhibit insulin signaling and increase androgen production in PCOS. S-S, Disulfide bond; Y, tyrosine; S, serine; P, phosphate. Insulin has multiple cellular actions beyond the regulation of glucose uptake It has other anabolic effects to increase storage of lipids and proteins as well as to promote cell growth and differentiation Insulin acts on cells by binding to its cell surface receptor , The insulin receptor is a heterotetramer made up of two α,β dimers linked by disulfide bonds Each α,β dimer is the product of one gene , The α-subunit is extracellular and contains the ligand-binding domain; it also inhibits the intrinsic kinase activity of the β-subunit , The β-subunit spans the membrane, and the cytoplasmic portion contains intrinsic protein tyrosine kinase activity, which is activated further by ligand-mediated autophosphorylation The insulin receptor shares substantial structural homology the IGF-I receptor and the insulin-related receptor The α,β dimer of the insulin receptor can assemble with similar dimers of the IGF-I receptor or insulin-related receptor to form hybrid receptors Ligand binding induces autophosphorylation of the insulin receptor on specific tyrosine residues and further activation of its intrinsic kinase activity — The activated insulin receptor then tyrosine-phosphorylates intracellular substrates, such as insulin receptor substrates IRS 1—4, src homolog and collagen homolog Shc , and APS [adapter protein with a PH and homology 2 SH2 domain], to initiate signal transduction , , The IRS are phosphorylated on specific motifs, and these phosphorylated sites then bind signaling molecules, such as the SH2 domain of phosphatidylinositol 3-kinase PI3-K or the adaptor molecule, Nck , , , leading to activation of downstream signaling pathways. Insulin stimulates glucose uptake by increasing the translocation of the insulin-responsive glucose transporter, GLUT4, from intracellular vesicles to the cell surface , This pathway is mediated by activation of PI3-K, which then phosphorylates membrane phospholipids and phosphatidylinositol 4,5-bisphosphate, leading to activation of the 3-phosphoinositide-dependent protein kinases PDK-1 and PDK-2 , Both of these pathways stimulate the translocation of GLUT4 to the cell surface , Glycogen synthase activity is constitutively inhibited via phosphorylation by glycogen synthase kinase-3 GSK3 , Insulin stimulates cell growth and differentiation through the MAPK-ERK , pathway , This pathway is activated by insulin receptor-mediated phosphorylation of Shc or IRS, leading to association with Grb2 and Son-of-sevenless resulting in Ras activation This so-called mitogenic pathway can be disrupted without affecting the metabolic actions of insulin and vice versa , — As a result, insulin resistance can be selective and affect only metabolic but not mitogenic pathways of insulin action , , Insulin regulates protein synthesis and degradation via mammalian target of rapamycin mTOR , which is activated via PI3-K. The mTOR pathway is also important in nutrient sensing The insulin signal can be terminated by dephosphorylation of proximal signaling molecules. Multiple tyrosine phosphatases, such as protein tyrosine phosphatase 1B PTP1B , can dephosphorylate the insulin receptor to terminate the insulin signal , Phosphatase and tension homolog deleted on chromosome 10 PTEN , a lipid phosphatase, decreases PI3-K signaling by dephosphorylating lipid signaling molecules , , Serine phosphorylation of the insulin receptor and IRS can also inhibit insulin signaling , — It has been postulated that PKC-mediated serine phosphorylation of the insulin receptor is important in the pathogenesis of hyperglycemia-induced insulin resistance — and that the mechanism of TNF-α-mediated insulin resistance is serine phosphorylation of IRS-1 The cellular and molecular mechanisms of insulin action in PCOS have been characterized in cultured skin fibroblasts, which are not classic insulin target tissues Defects in fibroblast insulin action that persist in cells that have been removed from the in vivo environment for many passages suggest that the changes are the result of mutations in genes regulating these pathways 10 , Consistent with this hypothesis, decreases in insulin receptor binding or autophosphorylation in cultured skin fibroblasts have reflected mutations in the insulin receptor gene in patients with the syndromes of extreme insulin resistance 10 , Insulin action has also been examined in the classic insulin target tissues for glucose uptake, adipocytes and skeletal muscle , The size of sc adipocytes isolated from both lean and obese women with PCOS was increased , However, decreased insulin receptor β-subunit abundance has been reported in homogenates of omental adipose tissue from women with PCOS The most striking and consistent defect in adipocyte insulin action in PCOS was a marked increase in the ED 50 for insulin-mediated glucose uptake , , , indicating a decrease in insulin sensitivity, when compared with isolated adipocytes from appropriately weight-comparable reproductively normal control women Fig. The decrease in insulin sensitivity suggested that there was a defect in insulin receptor binding or phosphorylation Most studies have also found less striking, but significant, decreases in maximal rates of insulin-stimulated glucose transport , , insulin responsiveness, suggesting a decrease in post-receptor events , Fig. Significant decreases in the abundance of GLUT4 glucose transporters in sc adipocytes from women with PCOS most likely accounted for the decrease in insulin responsiveness , However, a recent study failed to find decreases in insulin responsiveness or GLUT4 abundance in sc adipocytes isolated from women with PCOS, despite the fact the euglycemic clamp studies in these PCOS subjects showed decreased insulin responsiveness for IMGD consistent with a postbinding defect in insulin action. The reasons for these discrepant results in isolated sc adipocytes are unclear because both studies used the same diagnostic criteria NICHD for PCOS and contained control women of comparable BMI , Similar defects in adipocyte insulin action have been reported in T2D and in obesity but are ameliorated by control of hyperglycemia and hyperinsulinemia as well as by weight-reduction, suggesting acquired rather than intrinsic defects — In contrast, in PCOS such defects can occur in the absence of obesity and glucose intolerance , Moreover, these abnormalities are not significantly correlated with sex hormone levels 55 , These studies are constrained by the fact that signaling protein abundance and basal phosphorylation may be unaltered, but insulin-stimulated activation may still be defective in insulin-resistant states Studies using maximally stimulating doses of insulin may fail to detect alterations in insulin sensitivity Furthermore, downstream signaling events may be decreased if there are defects in signaling at the level of the insulin receptor Insulin receptor function in PCOS was investigated in receptors isolated from cultured skin fibroblasts. Consistent with findings in isolated adipocytes , , there was no change in insulin binding or receptor affinity compared with control women Insulin-dependent receptor tyrosine autophosphorylation was significantly decreased , Insulin-independent receptor serine phosphorylation was markedly increased , and these receptors had reduced intrinsic tyrosine kinase activity, suggesting that serine phosphorylation inhibited normal receptor signaling Although fibroblasts are not a classic insulin target tissue for glucose uptake, insulin receptors isolated from skeletal muscle biopsies from women with PCOS had similar abnormalities in phosphorylation, suggesting that this defect was physiologically relevant Isolating insulin receptors from lysates of PCOS skin fibroblasts by immunopurification before insulin-stimulated autophosphorylation corrected constitutive increases in receptor serine phosphorylation Furthermore, mixing lysates from PCOS skin fibroblasts with purified human insulin receptors resulted in increased receptor serine phosphorylation Taken together, these findings suggested that a serine kinase extrinsic to the insulin receptor was responsible for the abnormal pattern of receptor phosphorylation These findings were supported by an independent group of investigators who confirmed significant decreases in PCOS skin fibroblast insulin receptor autophosphorylation. Furthermore, they demonstrated that decreased receptor autophosphorylation could be corrected immunocapture of the insulin receptor before insulin stimulation, consistent with the presence of a factor extrinsic to the receptor as the cause of the defect Most importantly, serine kinase inhibitors corrected the phosphorylation defect, supporting the role of a serine kinase extrinsic to the insulin receptor as the cause of decreased receptor autophosphorylation This defect in the early steps of the insulin signaling pathway may cause the insulin resistance in a subpopulation of women with PCOS Fig. Increased insulin-independent serine phosphorylation in PCOS insulin receptors appears to be a unique disorder of insulin action because other insulin-resistant states, such as obesity, T2D, Type A syndrome, and leprechaunism, do not exhibit this abnormality , , This observation suggests that a defect downstream of insulin receptor phosphorylation, such as phosphorylation of IRS-1 or activation of PI3-K, was responsible for insulin resistance in some PCOS women , , Studies of insulin signaling in vivo have shown a significant decrease in insulin-mediated IRSassociated PI3-K activation in serial skeletal muscle biopsies obtained during a euglycemic clamp study in association with decreased IMGD in women with PCOS The abundance of IRS-2 was increased, suggesting a change to compensate for decreased signaling via IRS-1 Analogous to in vitro studies, the signaling changes occurred rapidly and were evident in biopsies at and min time points during each insulin dose, but the changes had returned to baseline by 90 min of each infusion This study confirmed that there is a physiologically relevant defect in rapid insulin receptor-mediated signaling in the major insulin target tissue for IMGD, skeletal muscle. Højlund et al. Nevertheless, this finding is consistent with the time course of these signaling changes determined in the previous study of Dunaif et al. The decrease in insulin receptor-mediated IRS-1 phosphorylation and PI3-K activation identified in PCOS skeletal muscle could account for these changes because these signaling events are downstream in the pathway of insulin-stimulated glucose uptake Fig. In contrast, Ciaraldi et al. However, they used maximally stimulating doses of insulin, whereas Højlund et al. It is possible to isolate myoblasts from human skeletal muscle biopsies, culture these cells in vitro , and differentiate them into myotubes — This culture system has been used to investigate whether the defects in insulin action in PCOS skeletal muscle are the result of the in vivo hormonal environment or reflect intrinsic abnormalities , — Cultured myotubes from women with PCOS had a distinctive phenotype: despite similar population doublings, they had an increase in markers of differentiation compared with myotubes from control women Insulin action findings in PCOS myotubes have been conflicting. Corbould et al. GLUT1 abundance was increased in PCOS myotubes and correlated with the increases in basal, non-insulin-mediated glucose transport, whereas GLUT4 abundance was unchanged in PCOS compared with control myotubes PCOS myotube GLUT4 abundance did not differ in PCOS and control myotubes in this study Eriksen et al. Insulin action on other metabolic parameters, such as glycogen synthesis and lipid uptake, also did not differ in PCOS compared with control myotubes The most comprehensive study of insulin signaling in PCOS myotubes by Corbould et al. However, the abundance of IRS-1 was increased in PCOS myotubes. When normalized for IRS-1 abundance, PI3-K activity was decreased in PCOS myotubes. Furthermore, phosphorylation of the IRS-1 inhibitory serine was increased in PCOS myotubes. IRSassociated PI3-K activity was also decreased in PCOS myotubes. These findings suggest that there are intrinsic abnormalities in insulin signaling in PCOS myotubes, despite the fact that glucose transport is not compromised It is possible that these abnormalities confer increased susceptibility to circulating factors that induce insulin resistance, such as free fatty acids or TNF-α Ciaraldi et al. In addition to insulin signaling defects, it has also been suggested that mitochondrial dysfunction may contribute to insulin resistance in PCOS skeletal muscle. In T2D, decreased numbers of skeletal muscle mitochondria have been reported Skeletal muscle biopsies from women with PCOS have shown decreased expression of genes involved in mitochondrial oxidative metabolism Furthermore, pioglitazone-mediated improvements in insulin sensitivity were associated with increased expression of genes involved in mitochondrial phosphorylation pathways in these affected women However, there were no differences in mitochondrial number or function in cultured myotubes from women with PCOS These findings suggest that changes in mitochondrial oxidative gene expression in PCOS skeletal muscle are not a primary defect. There have been limited studies of insulin action lipid homeostasis in PCOS. Fasting free fatty acid levels have been increased or unchanged in obese women with PCOS compared with control women of similar weight. There has been decreased insulin-mediated suppression of lipid oxidation during euglycemic clamp studies in obese women with PCOS However, lipid uptake and oxidation did not differ from control in PCOS myotubes Alterations in catecholamine regulation of lipolysis have been reported in PCOS. There was decreased sensitivity to catecholamine-stimulated lipolysis in adipocytes isolated from the sc fat depot of lean women with PCOS, which may favor increased fat cell size In contrast, adipocytes isolated from the visceral fat depot of lean women with PCOS had increased catecholamine-stimulated lipolysis The cellular mechanisms of this defect, alterations in protein kinase A subunit expression and decreases in hormone sensitive lipase, differed from those in visceral adipocytes in subjects with the metabolic syndrome This increase in catecholamine-stimulated lipolysis may contribute to hepatic insulin resistance by increasing portal free fatty acid delivery to the liver Insulin action to suppress lipolysis was similar in visceral adipocytes from lean women with PCOS and control women There are no reports of insulin action on protein turnover in PCOS. The metabolic pathway can be disrupted without altering the mitogenic pathway Such so-called selective insulin resistance has been found in cultured skin fibroblasts from patients with extreme insulin resistance A similar selective defect in insulin action was found in cultured skin fibroblasts from women with PCOS Both insulin- and IGF-I-stimulated glycogen synthesis were significantly decreased in PCOS fibroblasts, whereas thymidine incorporation was similar to that in control fibroblasts The activity of p21 Ras was significantly decreased, and the abundance of Raf-1 was increased, suggesting that the alteration of signaling began at this molecule. Furthermore, these findings suggest that a primary activation of mitogenic signaling pathways produces metabolic insulin resistance by serine phosphorylating proximal metabolic signaling molecules, such as IRS-1 Fig. However, the biopsies were performed 15—20 min after a bolus dose of insulin, which is cleared rapidly , as part of an insulin tolerance test rather than during the continuous infusion of insulin as part of a euglycemic clamp study. The clearance of insulin is also altered in insulin-resistant states , Therefore, differences in the kinetics of the insulin bolus in PCOS compared with control women could have confounded the results. Moreover, a counterregulatory hormone response due to insulin-induced hypoglycemia could also confound the results In summary, the major defect in insulin action in PCOS is a post-binding defect in the early steps of insulin signal transduction Figs. This defect is present in the two main target tissues for insulin-stimulated glucose uptake: adipocytes , and skeletal muscle , Furthermore, in at least some tissues, such as skin fibroblasts and ovarian granulosa-lutein cells see in Section V. and Ref. However, both metabolic and mitogenic pathways may be compromised in PCOS skeletal muscle The post-binding defect in insulin signaling appears to be secondary to increased inhibitory serine phosphorylation of the insulin receptor and IRS Our group and Li et al. This observation suggests that a kinase extrinsic to the insulin receptor causes the increased receptor serine phosphorylation. This hypothesis is supported by the finding of Li et al. The activation of these kinases contributes to serine phosphorylation of IRS-1 and inhibition of metabolic signaling There are lots of myths and misconceptions about how pregnancy happens. Endometriosis is a leading cause of pelvic pain, and painful sex—up to 1 in 10 women of reproductive age may Homepage Close main menu Homepage Encyclopedia. Menstrual Cycle. Birth Control. About Clue. Choose your language English EN Português PT Español ES Deutsch DE Français FR. App Store Play Store. Now you can sync Oura with Clue Unlock deeper cycle insights and discover your unique patterns. What is insulin resistance? The relationship between insulin resistance and PCOS Insulin resistance is a key feature of both obese and lean PCOS. The role of fructose in insulin resistance For my patients with PCOS, I find that the most effective dietary intervention is to reduce fructose. Nutritional supplements for insulin resistance and PCOS Inositol is an intracellular messenger involved in insulin signaling and can be taken as a nutritional supplement myo-inositol and di-chiro inositol. Yes No. You might also like to read. Popular Articles. Fertility Can I get pregnant from that? by Jen Bell. |
| Insulin Resistance Explained | The good news is that simple lifestyle changes, such as diet and exercise, can help make PCOS very manageable. If a person is overweight because of an unhealthy diet and lack of physical activity, losing just 10 to 15 pounds often will improve PCOS symptoms no matter what caused the insulin resistance. Our specialists care for the whole person — mind, body and spirit. Learn more. PCOS mostly affects people in their late teens and 20s. It often begins after the first menstrual period. A diet high in refined carbohydrates, such as starchy and sugary foods, can make insulin resistance, and therefore weight loss, more difficult to control. In people who are insulin resistant, the body may try to pump out high levels of insulin in order to keep blood sugar levels normal. Increased levels of insulin can cause ovaries to produce testosterone. For people who are overweight, increased physical activity can lower the risk for Type 2 diabetes, as well as other health issues. Carricato said. When it comes to diet, adding high-fiber vegetables, lean proteins and healthy fats is essential. Although it is more prevalent among obese women, the research confirmed that insulin resistance seems to have an independent relationship to PCOS and is not wholly caused by obesity. Common PCOS symptoms include heavy bleeding, irregular or painful periods, and infertility. PCOS can also cause acne, an increase in facial hair, weight gain around the waist and dark patches of skin in the neck, armpits, groin and waistline. High insulin levels worsen these symptoms by causing women to produce more testosterone. This leads to even more acne, hair growth and irregular or absent periods. Women with insulin resistance are also at higher risk for developing chronic conditions such as diabetes, obesity, heart disease and hypertension. Managing PCOS symptoms is key to helping your patients achieve a better quality of life in the face of this condition. Controlling insulin levels is an essential component, as PCOS patients can easily find themselves in a cycle of spiking insulin levels, leading to more cravings for carbs and sweets. Diet and exercise are the most fundamental ways for patients to manage insulin levels and control PCOS symptoms. Encourage them to engage in at least moderate exercise for 30 minutes a day to regulate blood glucose levels, even if all they can fit in is a walk at lunch. Also provide general guidance for healthy eating. Discourage fad diets or any eating plan that is likely to lead to dramatic gains and losses. They do not need to be too restrictive; they just need to follow a balanced diet. PCOS affects about 5 percent to 10 percent of women in the United States, according to the American Diabetes Association. It is often diagnosed via a pelvic exam, clinical workup and an ultrasound to assess the ovaries. Patients' quality of life greatly decreases when symptoms get out of control. Talk to patients about the relationship between PCOS and insulin resistance symptoms, and emphasize the importance of diet and exercise to help keep those symptoms in check. Ultrasound can help look for patterns to diagnose polycystic ovary syndrome and predict outcomes. Sign up to get the latest articles and updates from GE HealthCare Women's Health. The information on this web page is intended for healthcare professionals only. Follow GE HealthCare for the latest updates. Stay informed. Patricia Chaney December 27, |
| PCOS and Insulin Resistance | In addition, Resistancf review provides a comprehensive fesistance of resistanfe current progress in the efficacy of insulin sensitization therapy in the Proper form and technique of PCOS, providing the Muscle recovery nutrition evidence for Insulkn clinical treatment of women Mediterranean diet and blood sugar regulation PCOS resistnce IR. These studies are constrained by resistsnce fact that signaling protein abundance and basal phosphorylation may be unaltered, but insulin-stimulated activation may still be defective in insulin-resistant states But were you aware that diet plays a role in insulin resistance, one of the main causes of the hormone imbalance? Insulin sensitivity can also be negatively affected by changes in diet, the environment, and mood. Metformin, the most widely used insulin sensitizer for PCOS, reduces hepatic glucose production, inhibits gluconeogenesis and adipogenesis, improves peripheral tissue sensitivity to insulin, and prevents excessive insulin activity in the ovary [ ]. Shi Y, Zhao H, Shi Y, Cao Y, Yang D, Li Z, et al. |
| Polycystic ovary syndrome (PCOS) and insulin resistance are related. Changes in your diet can help | Magnesium deficiency affects at least one-third of individuals, and probably more, and cannot be easily or reliably diagnosed by a blood test 19, A recent meta-analysis concluded that magnesium supplementation is effective for treating insulin resistance in people with magnesium deficiency 21 and one small study found that co-supplementation of magnesium, zinc, calcium and vitamin D improved the insulin metabolism of PCOS patients Download Clue to track your cycle. Her book is the Period Repair Manual —soon to be available in German as well as English. Follow her on Twitter and Instagram. There are lots of myths and misconceptions about how pregnancy happens. Endometriosis is a leading cause of pelvic pain, and painful sex—up to 1 in 10 women of reproductive age may Homepage Close main menu Homepage Encyclopedia. Menstrual Cycle. Birth Control. About Clue. Choose your language English EN Português PT Español ES Deutsch DE Français FR. App Store Play Store. Now you can sync Oura with Clue Unlock deeper cycle insights and discover your unique patterns. What is insulin resistance? The relationship between insulin resistance and PCOS Insulin resistance is a key feature of both obese and lean PCOS. The role of fructose in insulin resistance For my patients with PCOS, I find that the most effective dietary intervention is to reduce fructose. Nutritional supplements for insulin resistance and PCOS Inositol is an intracellular messenger involved in insulin signaling and can be taken as a nutritional supplement myo-inositol and di-chiro inositol. Yes No. You might also like to read. Popular Articles. Fertility Can I get pregnant from that? by Jen Bell. The simply answer is: yes! by Maegan Boutot. Fertility Clue Pregnancy Mode The science-based pregnancy mode designed for all pregnant people by Sarah Toler, DNP, CNM. by Sarah Toler, DNP, CNM. Endometriosis Endometriosis Endometriosis is a leading cause of pelvic pain, and painful sex—up to 1 in 10 women of reproductive age may Insulin lowers your blood sugar by storing the glucose in cells. Type 2 diabetes occurs when the cells become resistant to insulin. When that happens, an abnormal amount of insulin is made. The good news is that simple lifestyle changes, such as diet and exercise, can help make PCOS very manageable. If a person is overweight because of an unhealthy diet and lack of physical activity, losing just 10 to 15 pounds often will improve PCOS symptoms no matter what caused the insulin resistance. Our specialists care for the whole person — mind, body and spirit. Learn more. PCOS mostly affects people in their late teens and 20s. It often begins after the first menstrual period. A diet high in refined carbohydrates, such as starchy and sugary foods, can make insulin resistance, and therefore weight loss, more difficult to control. In people who are insulin resistant, the body may try to pump out high levels of insulin in order to keep blood sugar levels normal. Increased levels of insulin can cause ovaries to produce testosterone. |
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