The Link between Polycystic Ovary Syndrome and both Type 1 and Type 2 Diabetes Mellitus: What Do we Know Today?

Abstract

Polycystic ovary syndrome (PCOS) and Type 2 diabetes mellitus (T2D) are both obesity-related conditions that share epidemiological and pathophysiological factors. Insulin resistance is a key factor whereby obesity influences the expression of each condition. However, the mechanisms by which insulin resistance contributes towards the manifestation of PCOS and T2D differ in important ways: in PCOS, compensatory hyperinsulinemia results in pleiotropic effects including co-gonadotrophic stimulation of ovarian and adrenal steroidogenesis; in T2D, insulin resistance contributes towards β-cell exhaustion and ultimately to hyposecretion of insulin with resultant dysglycemia. The link between PCOS and Type 1 diabetes mellitus is believed to implicate supraphysiological concentrations of insulin within the systemic circulation. Further progression of the obesity epidemic will ensure even greater prominence of important obesity-related conditions such as PCOS and T2D. Research to gain a clearer understanding of the mechanisms linking each condition should be a priority.

Keywords

diabetes mellitus insulin resistance obesity polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common condition with prevalence among Caucasian premenopausal women between 6–10% [1]. PCOS affects women of premenopausal age and is characterized by hyperandrogenic features (e.g., hirsutism, acne and alopecia) that result from hyperandrogenemia, and menstrual disturbance including subfertility [2]. PCOS is associated with obesity: between 38 and 88% of women with PCOS are overweight or obese, although PCOS can also manifest in lean women [2]. PCOS also associates with other features of the metabolic syndrome including Type 2 diabetes mellitus (T2D), hypertension, dyslipidemia and insulin resistance, although long-term prospective data are lacking [3 –5]. Estimates of prevalence of metabolic syndrome in women with PCOS are between 34 and 46%, using the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII) criteria [3 –6]. It is also clear that hyperandrogenism is frequently associated with T2D in women [7].

The importance of obesity stems from its association with comorbidities and other obesity-related conditions. As the obesity epidemic ensues, obesity-related conditions will become ever more prevalent. Obesity-related conditions are therefore relevant to all healthcare professionals and will assume even greater relevance in the future provision of healthcare. Given the frequent concurrence of PCOS and T2D and the similarities between these two common conditions, it is important to examine the link between them. In this article, we discuss the epidemiological, pathophysiological and genetic links between diabetes (both T2D and Type 1 diabetes mellitus [T1D]) and PCOS.

PCOS

Diagnostic criteria & epidemiology

There are three main sets of diagnostic criteria for PCOS currently in use for both clinical and research purposes. The 1990 NIH diagnostic criteria require the presence of hyperandrogenism (defined biochemically and/or clinically) and menstrual disturbance (without reference to ovarian morphology) [8]. The 2003 Rotterdam diagnostic criteria for PCOS are based on the presence of at least two of the following three cardinal features: polycystic ovarian morphology on ultrasound scan, hyperandrogenic features and oligo-amenorrhea (defined as an intermenstrual interval >42 days) [9,10]. More recently in 2009, the Androgen Excess Society published diagnostic criteria for PCOS, which state that PCOS should be defined by the presence of hyperandrogenism (defined on either clinical and/or biochemical grounds) and ovarian dysfunction (defined by oligo-anovulation and/or polycystic ovaries), with the exclusion of other related disorders [11].

The Rotterdam criteria for PCOS have broadened the diagnostic range of PCOS [9,10]. It has been demonstrated by our group that metabolic heterogeneity exists between Rotterdam-defined phenotypic subgroups [9,10], with metabolic dysfunction (including insulin resistance) being restricted to the subgroup with both oligo-amenorrhea and hyperandrogenic features [12]. Owing to a lack of long-term prospective studies in this field, the long-term effect of such metabolic heterogeneity on the future development of T2D and cardiovascular events is not clear, and should be a focus for future research.

Pathogenesis

A detailed discussion of the pathogenesis of PCOS is beyond the scope of this article (reviewed in [2,13]). An important aspect of PCOS pathogenesis is genetic predisposition, based on data from twin and family-based association studies [14,15]. Data from >1300 monozygotic twins and >1800 dizygotic twins/singleton sisters of twins from The Netherlands Twin Register have demonstrated a high heritability of PCOS with a monozygotic twin correlation of 0.71 [14]. Genetic data on metabolic traits from male relatives of women with PCOS provide further evidence to support a genetic predisposition to PCOS [16 –18]. Although the actual gene variants that influence development of PCOS remain unknown, important candidates are those involved in ovarian and adrenal steroidogenesis, given that hyperandrogenemia is an important biochemical feature of PCOS. It is likely that hyperinsulinemia (resulting from insulin resistance/obesity) augments steroidogenesis through its action as a co-gonadotrophin on ovarian theca cells [13].

The pathophysiology of PCOS is complex and factors such as chronic inflammation and increased oxidant stress are likely to be implicated, with increased levels of advanced glycation end products having been demonstrated in women with PCOS [19]. Endocrine disruptors such as bisphenol A may also be implicated in pathogenesis [20]. Weight gain is also often an important pathogenic factor, with PCOS usually becoming clinically manifest in women with a presumable generic predisposition for PCOS who subsequently gain weight. Therefore, environmental (particularly dietary) factors are important. However, BMI is also influenced by genetic factors such as the fat mass and obesity-associated protein (FTO) [21], and obesity is a highly heritable condition [22]. Therefore, the weight gain responsible for the manifestation of PCOS in many women with this condition is itself influenced by genetic factors. Recent generic evidence from our own group has demonstrated that variants within FTO are associated with the development of PCOS, at least in part through effects on BMI [23]. This was the first published evidence to genetically corroborate a link between obesity and PCOS.

It is likely that PCOS is an oligogenic condition with a handful of gene variants, each with relatively small effect sizes implicated in the genetic predisposition to the development of PCOS [13]. The existing literature on the generics of PCOS (mainly based on candidate-gene studies) is generally disappointing. The first genome-wide association study (GWAS) in PCOS, published recently by Chen and colleagues, demonstrated associations between PCOS and three loci: 2p16.3, 2p21 and 9q33.3 [24]. Future GWAS on large numbers of subjects are likely to identify further genome variants implicated in PCOS susceptibility. PCOS is a disease with an ovarian origin and it is likely that gene variants that influence pathways such as those involved in androgen biosynthesis and function, insulin resistance and proinflammatory mechanisms are implicated in susceptibility to the development of PCOS [25]. In this review, we focus on variants relevant to T2D pathogenesis such as those that influence weight gain and insulin secretion.

Links between obesity, insulin resistance & PCOS

It is clear that obesity and PCOS are closely linked. Between 30 and 70% of women with PCOS are obese [26], and modest weight loss of just 5% can significantly improve many of the clinical and biochemical features of PCOS [27]. Furthermore, PCOS often manifests following weight gain. In one study, PCOS was shown to be highly prevalent among women with morbid obesity (PCOS present in 17 of the 36 morbidly obese premenopausal women included in the study). Features of PCOS (e.g., hirsutism, testosterone levels, insulin resistance, menstrual cyclicity and ovulation) showed marked improvements, and PCOS frequently resolved after substantial weight loss induced by bariatric surgery [28]. These observations support the view that obesity is one of the major factors implicated in the development of PCOS.

The link between obesity and PCOS is likely to be mediated by a variety of mechanisms, although the effects of insulin resistance and compensatory hyperinsulinemia seem to be of particular importance [2]. Insulin resistance, as with many other features of the condition, manifests heterogeneity amongst women with PCOS. Our own group have demonstrated that insulin resistance and other dysmetabolic features appear to be confined to the subgroup of women with PCOS who have both hyperandrogenism and oligo-amenorrhea [12]. Despite this heterogeneity, the majority of women with PCOS (between 50 and 90%) have been reported to be insulin resistant [29,30], and improved insulin sensitivity is associated with improvements of many clinical features of PCOS [31]. However, there is also substantial data available to support the notion that many women with PCOS, especially lean women with the condition, are not insulin resistant [32,33].

The mechanism by which hyperinsulinemia is implicated in the development of PCOS includes the co-gonadotrophic effects of insulin (i.e., augmentation of gonadotrophin action by insulin) on ovarian and adrenal steroidogenesis, reflected by an association between levels of insulin and testosterone [34]. Other mechanisms include the inhibitory effects of insulin on ovarian folliculo-genesis [35] and on the synthesis of sex hormone-binding globulin within the liver [36]. The development of PCOS and T2D share many common features, including a prerequisite for a genetic predisposition (although the commonality of the genetic variants implicated is incompletely understood), coupled with subsequent weight gain and associated insulin resistance. The links between PCOS and T2D are discussed in more detail in the next section.

Link between PCOS & T2D

Epidemiology

The epidemiological evidence linking PCOS with T2D derives mainly from cross-sectional observational studies, retrospective studies and short-term prospective studies. In one study by Gambineri and colleagues, a high prevalence of impaired glucose tolerance (IGT) of 15.7% among women with PCOS was demonstrated [37]. More recently, Moran and colleagues published a meta-analysis on the prevalence of IGT and T2D among women with PCOS that included 35 studies from a selection of >2100 studies [38]. Compared with control women, there was an increased prevalence of IGT (odds ratio [OR]: 2.48; BMI-matched studies: OR: 2.54), and T2D (OR: 4.43; BMI-matched studies: OR: 4.00) among women with PCOS [38]. In addition to T2D, PCOS is also associated with metabolic syndrome. As outlined previously, estimates of prevalence rates of metabolic syndrome in PCOS range between 34 and 46% [3,4,6].

Given that PCOS and T2D are both obesity-related conditions, and the importance of insulin resistance in the pathogenesis of each, it is perhaps not surprising that there are similarities in epidemiology. However, what is also clear from the published data is that even when BMI is matched for between PCOS and control women, an epidemiological link between PCOS and T2D is still apparent. One implication of these data is that there are likely to be factors independent of obesity (e.g., PCOS-related insulin resistance) that link PCOS and T2D epidemio-logically, in addition to obesity-related factors. Although current evidence supports an increased prevalence of IGT and T2D amongst women with PCOS, our current lack of long-term prospective studies in this field obviates the ability to quantify the lifetime risk of developing T2D in women with PCOS, and the risk-factors for the development of T2D associated with PCOS.

Pathogenic links (insulin resistance, hyperinsulinemia & β-cell dysfunction)

Given the epidemiological concurrence of PCOS and T2D, the question arises regarding pathogenic overlap between these two conditions. The pathogenesis of T2D includes a combination of insulin resistance and β-cell dysfunction [39]. Insulin resistance is also a feature of many women with PCOS, particularly those with obesity [2]. As outlined previously, there is some controversy regarding insulin resistance in lean women with PCOS, with some data to support a lack of insulin resistance in this subgroup [32,33]. However, the majority of obese women with PCOS appear to manifest insulin resistance [2,12]. The presence of insulin resistance in PCOS was first reported over 30 years ago [40], and insulin resistance in PCOS is now well recognized [2,30]. The association of weight loss and use of insulin-sensitizing drugs with improvements in phenotypic features of PCOS support the hypothesis that insulin resistance plays an important role in the development of PCOS [2]. It would therefore seem clear that PCOS and T2D are linked pathogenically by insulin resistance, which in turn is influenced by obesity.

One of the cardinal features of T2D is β-cell dysfunction and consequent insulin deficiency [39]. By contrast, hyperinsulinemia (secondary to insulin resistance) is likely to play a key role in the development of PCOS. Therefore, a key difference between T2D and PCOS would appear to be related to β-cell function. In women with PCOS, insulin stimulates ovarian theca cells, enhancing biosynthesis of ovarian androgens such as testosterone and causing arrest of ovarian follicle development [41,42]. Hyperinsulinemia is also likely to have adverse effects on other tissues including the liver (i.e., suppression of sex hormone-binding globulin production), adrenal and pituitary gland [2]. The steroidogenic effects of insulin in the context of insulin resistance can be explained through impairment of the PI3K-mediated insulin signal transduction pathway, with preservation of signaling through the alternative MAPK pathway (which typically mediates the effects of insulin on cell growth) [43]. These postinsulin receptor effects are likely to pertain to both T2D and PCOS [43,44]. Evidence from in vitro studies of such an effect in PCOS comes from the observation of reduced abundance of GLUT4 from adipocytes in women with PCOS (compared with adipocytes from weight-matched control women) despite there being no abnormalities in insulin receptor number or affinity [45].

Although hyperinsulinemia is likely to be important in the development of PCOS, data from studies on β-cell function in PCOS are conflicting, including reports of reduced β-cell function [46 –48] and enhanced β-cell acute insulin secretion during an oral glucose tolerance test [49 –51]. It seems likely, therefore, that β-cell function, as with many other aspects of PCOS, is heterogeneous among women with this condition. A suggestion for future research in this field would be to explore the progression of β-cell function over time in women with PCOS. While insulin resistance appears to be an important factor in the development of both PCOS and T2D, β-cell decline and failure with consequent insulin deficiency appears to be confined to T2D and represents an important distinction between T2D and PCOS.

Genetic links

The epidemiology and etiology of PCOS and T2D are closely linked [15]. It is logical, therefore, to examine the role of T2D-genetic susceptibility variants as candidate genes for the development of PCOS. Variants in two genes, TCF7L2 and KCNJ11, have been demonstrated to display powerful associations with T2D [52 –55] and this is likely to be mediated via impairment of insulin secretion [53,55]. The question arises, therefore, whether such T2D genetic variants are also implicated in susceptibility to the development of PCOS. Our own group have published data from an association study based on a large cohort of women from the UK with PCOS (n = 369) versus 2574 UK population controls, and in 540 symptomatic PCOS cases and 1083 controls (recruited from the Northern Finland Birth Cohort of 1966 [NFBC66]) [56]. We demonstrated no association of TCF7L2 single nucleotide polymorphisms (SNPs) rs7903146 and rs12255372, which are significantly associated with the risk of T2D, with susceptibility to the development of PCOS or with androgen levels in the UK group, and no association of either TCF7L2 SNP with features of PCOS in the Finnish group. Our data were corroborated by a large study on 58 SNPs mapping to TCF7L2 in >600 PCOS cases and >550 control women, data from which also showed no association of TCF7L2 variants with susceptibility to the development of PCOS [57]. Our group also published data on the E23K polymorphism within KCNJ11, based on a large UK cohort of >370 PCOS cases and >2570 population controls and on 550 women with symptoms of PCOS and >1100 controls from the NFBC66 [58]. We also showed no association between the KCNJ11 E23K polymorphism and PCOS, or between this polymorphism and androgen measures [58]. Our data were supported by the findings of a Greek study that also showed no association between KCNJ11 E23K variants and susceptibility to development of PCOS [59].

Given the importance of impaired insulin secretion in the development of T2D, it is also logical to examine any association between variants in the insulin gene and susceptibility to development of PCOS. The insulin gene variable number of tandem repeats is a series of 14bp or 15bp repeats that regulate insulin gene transcription, and is located within the 5' regulatory element of the insulin gene [60]. Although controversy exists in the literature [13], we found, in a large multicohort study involving >400 UK PCOS cases, >1000 UK controls and >1500 women from the NFBC66, no evidence for an association of the insulin gene variable number of tandem repeats with susceptibility to development of PCOS [60].

Data from a GWAS on subjects with T2D showed that variants within the FTO gene are associated with the development of T2D, and that this association is likely to be driven by effects on BMI [21]. Our group showed for the first time, association of a genome-sequence variant (FTO rs9939609) and susceptibility for development of PCOS in 463 women from the UK with PCOS versus >1300 female controls [23]. Following adjustments for differences in BMI, the analyses suggested that the effects of FTO variants on PCOS susceptibility are at least, in part, driven by effects on fat mass, although other effects could not be excluded [23].

To summarize, the association of obesity with PCOS is genetically corroborated by data on FTO variants from our own group [23,61], and the association of FTO variants with T2D is well established [21]. However, despite the influence on fat mass that genetically links T2D and PCOS, there is no evidence to implicate other T2D-susceptibility variants, such as TCF7L2 and KCNJ11, in the development of PCOS. Based on both the genetic and clinical characteristics of PCOS and T2D, it would appear, therefore, that the genetic architecture of these two conditions is qualitatively distinct and that impairment of β-cell function, in contrast to T2D, does not appear to be an essential element in the development of PCOS.

Link between PCOS & T1D

Epidemiology

There are relatively few studies reported in the literature on the prevalence of PCOS in women with T1D. The prevalence reported is influenced by the population studied and the diagnostic criteria employed. In one study from Spain on 85 women with T1D, hyperandrogenic disorders were demonstrated in 33 women (38.8%). Of those with hyperandrogenic disorders, 16 (18.8%) had PCOS (NIH diagnostic criteria [8]) and 17 (20%) had hirsutism without menstrual dysfunction [62]. For comparison, the prevalence of PCOS (NIH criteria [8]) was shown to be much lower at 6.5% within the Spanish general adult female population [1]. In a Chilean study by Codner and colleagues on 42 women with T1D, the prevalence of PCOS was 12% using NIH criteria, 40.5% using the Rotterdam diagnostic criteria, and just 2.6% in the female control group [63]. Using Rotterdam diagnostic criteria, the relative risk of PCOS in T1D versus female controls was 15.4 (p < 0.0001) [63]. In the studies outlined by Escobar-Morreale and Codner, up to 30% of women with T1D also have hirsutism, compared with rates of hirsutism of 7.1 and 3% in the Spanish and Chilean general female populations, respectively [62,63]. Chronic oligo-amenorrhea was reported in approximately 20% of women with T1D [62,63], compared with a prevalence of just 8%) in nondiabetic women [14]. Oligo-amenorrhea has been shown to be particularly prevalent in young women with T1D [64].

Pathogenesis

While insulin resistance plays a central role in the pathogenesis of PCOS [2], the key pathogenic factors implicated in the development of T1D are β-cell dysfunction and insulin deficiency [65]. The increased prevalence of PCOS in women with T1D therefore requires further discussion and explanation. Although obesity, insulin resistance and endogenous hyperinsulinemia are not prerequisites for the development of T1D, the treatment of T1D does involve exogenous insulin administration. Endogenous insulin, following release into the portal circulation, has direct effects on hepatic glucose production and undergoes some hepatic extraction prior to release into the systemic circulation. Conversely, exogenous insulin therapy is absorbed directly into the systemic circulation (without direct effects on the liver). For portal insulin concentrations to reach sufficient levels to suppress hepatic glucose generation, supraphysiological concentrations of insulin must be reached in the systemic circulation [66]. Supraphysiological concentrations of insulin in the systemic circulation have direct effects on the peripheral tissues, including the ovarian theca cells, with consequent stimulation of ovarian steroidogenesis [67].

Consistent with the hypothesis that implicates iatrogenic insulin excess as a causal factor, is the observation that the proportion of women with T1D who also manifest features of PCOS is influenced by the intensity of the insulin regimen. Codner and colleagues showed that 75% of women with T1D on intensive insulin therapy had either PCOS or asymptomatic polycystic ovarian morphology, in contrast to just 33% of women with T1D on conservative conventional therapy (twice-daily insulin injections) [63,66]. In addition to the adverse effects of supraphysiological systemic concentrations of insulin, a further explanation for the development of PCOS in adolescent girls with T1D is likely to be the increased fat mass, weight gain and insulin resistance demonstrated during the pubertal transition [68].

Future perspective

The link between PCOS and T2D stems from the association of each condition with obesity and insulin resistance. T2D develops in the context of insulin resistance combined with β-cell dysfunction, insulin deficiency and hyperglycemia. By contrast, PCOS develops in the context of insulin resistance and compensatory hyperinsulinemia. Insulin has pleiotropic actions including co-gonadotrophic effects on tissues, such as the ovaries, that remain insulin sensitive, thus augmenting ovarian theca cell steroidogenesis. By contrast, the link between T1D and PCOS does not result from obesity and insulin resistance, but rather from adverse effects of hyperinsulinemia that in turn result from exogenous administration of insulin with supraphysiological concentrations within the systemic circulation.

An inherent problem associated with complex obesity-related conditions such as PCOS, is the disentanglement of factors pertaining to PCOS per se versus obesity-related factors. A challenge for future research in this field is to gain a clearer understanding of the nonobesity related factors that influence susceptibility to development of PCOS. Over the next 5–10 years we will see published studies from GWAS in PCOS that will provide new insights into the pathogenesis of this complex condition. It is likely that hitherto unexpected genome sequences will be identified as susceptibility variants for PCOS. This will provide an opportunity for the development of genetic screening for the condition, and also enable future developments of novel therapeutic strategies for women with PCOS. As the obesity epidemic grows, obesity-related conditions such as PCOS and T2D will assume greater prominence. It is important to maintain close collaboration between the fields of obesity and the obesity-related conditions, to complement our understanding of pathogenesis, to broaden opportunities for future research and, ultimately, improve patient care.

Executive summary

Links between polycystic ovary syndrome, obesity & Type 2 diabetes

Polycystic ovary syndrome (PCOS) is a hyperandrogenic disorder that is associated with a high-risk of development of Type 2 diabetes mellitus (T2D).

PCOS and T2D are both obesity-related conditions that share insulin resistance as an important pathogenic factor.

β-cell function in PCOS & diabetes

β-cell dysfunction and hypoinsulinemia are clearly important in the pathogenesis of diabetes. By contrast, women with PCOS often manifest hyperinsulinemia and controversy exists regarding β-cell function, which is likely to be heterogeneous.

Genetic corroboration between PCOS, obesity &T2D

Our best evidence for a genetic link between T2D & PCOS relates to variants within the FTO gene; this genetic link is likely to result from effects of FTO variants on fat mass, with each condition being obesity-related.

The genetic architecture of PCOS and T2D (with regards to variants that influence β-cell function) are qualitatively distinct.

Links between PCOS & T1D

The link between PCOS and Type 1 diabetes mellitus results from the effects of supraphysiological concentrations of insulin within the systemic circulation following exogenous subcutaneous dosing of insulin, and the consequent co-gonadotrophic effects of insulin on ovarian and adrenal steroidogenesis.

Footnotes

Acknowledgements

The authors acknowledge the many patients, relatives, nurses and physicians who contributed to the ascertainment of the various clinical samples and data referred to in this review article.

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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