Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting 6–15% of women of reproductive age depending on ethnic variability as well as the criteria used for diagnosis [1]. PCOS presents with a very wide spectrum of clinical features due to its unusually complex pathophysiology. It is a disorder characterized by the intricate interplay between a multitude of factors, incorporating genetic, epigenetic, and environmental stimuli. All these parameters lead to two major etiopathological factors which are believed to lie at the heart of the disorder, namely, androgen excess and insulin resistance (IR) [2].

PCOS is associated with a large number of reproductive and metabolic sequelae, with impaired glucose homeostasis constituting one of the cardinal metabolic features. Indeed, the two prerequisites for type 2 diabetes mellitus (T2DM) development, IR and β-cell dysfunction, are commonly observed in women suffering from PCOS. IR is in fact a fundamental player in PCOS pathophysiology and is further amplified by the presence of obesity [3], while a higher prevalence of pancreatic β-cell dysfunction, associated with increasing age, is observed in women with PCOS compared to their normal peers [4].

Dysglycemia, on the other hand, is thought to occur mainly in older women with PCOS, while there are several as yet largely unclarified issues in younger women suffering from the syndrome [5]. Of note, the incidence of impaired glucose homeostasis as well as the ideal methods for evaluation and management of the disorder in this specific population have also not to date been fully elucidated. It must be mentioned that in this particular age group, androgens are considerably higher than those in women with PCOS older than 35 years of age: as a consequence, amplification of IR is anticipated, which may moreover lead to T2DM development [6].

2. Pathophysiology of T2DM Development in PCOS

Ovarian androgens are found in higher concentrations in the majority of women with PCOS compared to the general population, a small but significant proportion of these being derived from the adrenal glands [7]. Based on current research, although the exact etiological origins of hyperandrogenemia are not entirely clear, prenatal (in utero) exposure to higher androgen concentrations have been tentatively linked to the syndrome [8]. In addition, higher amplitude of the pulsatile secretion of the gonadotrophin-releasing hormone (GnRH) is seen during puberty in girls affected by PCOS, leading to a more potent excitation of the androgen-producing ovarian cells. This leads to hyperandrogenic symptoms, such as hirsutism, acne, male type hair loss, and ovulatory dysfunction (chronic oligo-anovulation), which produces menstrual irregularity (most commonly oligomenorrhea, i.e., <8 menstrual cycles per year) as well as polycystic ovarian morphology on ultrasound examination, which could lead to infertility in some cases [9]. Even though hyperandrogenemia is the main clinical finding of PCOS in the reproductive years, the metabolic features of the syndrome are equally important. A significant number of teenagers affected by PCOS present with IR, which is in part mediated by genetic predisposition [10]. The disorder is frequently accompanied by pancreatic β-cell dysfunction, hepatic and visceral fat accumulation, increased food intake, and increased waist circumference (central obesity). This, in turn, leads to hyperinsulinemia, which arises due to the inability of the pancreatic islets to enable insulin to exert its actions adequately. The latter is mediated in part by pronounced adipose tissue dysfunction and lipotoxicity frequently found in women with PCOS [11]. Due to this, laboratory findings of this condition could include impaired fasting glucose (IFG), postprandial hyperglycemic excursions (impaired glucose tolerance, IGT), elevations in LDL-cholesterol and triglycerides, lowering of HDL cholesterol, and increased adiponectin and serum markers of inflammation. The sum total of these metabolic derangements can result in the development of T2DM when pancreatic stress reaches a threshold at which insulin production becomes unable to match insulin needs. IR is an almost universal feature of PCOS, it being found with great frequency, ranging between 44 and 70%, in affected patients [12]. While this finding is more common in obese women with PCOS, it is also often present in their lean counterparts [13]. In adolescents with PCOS, peripheral insulin sensitivity was 50% lower than that found in controls, independent of their body mass index, when measured via hyperinsulinemic euglycemic clamp techniques [14]. IR and β-cell dysfunction are the two prerequisites for development of T2DM both in women with PCOS and in those without the syndrome. The most important trigger of the latter metabolic alteration, however, is obesity. Nevertheless, there is an enduring argument whether PCOS itself constitutes a risk factor for T2DM or whether T2DM predominantly ensues due to obesity in PCOS ^[15][16][16,17]. A well-designed meta-analysis of genetic studies proposed that PCOS does not possess an inherent risk for T2DM and that, instead, T2DM develops due to elevated androgen levels or as a result of adiposity ^[17][18].  Dysglycemia, which is an imbalance in the body’s ability to maintain blood sugar levels, is one of the most characteristic metabolic abnormalities in PCOS and should be considered as a continuum, progressing from normoglycemia to impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) and overt T2DM. However, it should be noted that IFG is mostly detected in subjects with mostly hepatic IR and normal muscle insulin sensitivity. On the contrary, severe muscle IR accompanied with normal liver insulin sensitivity is found in those subjects with isolated IGT ^[18][20]. This observation is of major importance given that IR in women with PCOS is amplified by androgens and vice versa. Indeed, progression of T2DM is significantly higher in hyperandrogenic women with PCOS ^[19][21].

3. Prevalence and Methods of Assessment of Dysglycemia in Women with PCOS

In general, the prevalence of dysglycemia, including T2D, IGT, and IFG, is higher in women with PCOS compared to healthy BMI-matched women of reproductive age: namely, in PCOS it ranges from 1.5 to 12.4%, while in normal women of reproductive age, it is 1–3% ^[20][37]. With regard to young women with PCOS, the prevalence of these conditions ranges from 2–14.5% for IFG, from 5.9 to 34% for IGT, and from 1.5–10% for IFG, as illustrated in Table 1. However, the above numbers are extrapolated from the literature data, since the vast majority of available studies provide no strict classification according to age. In addition, there is significant variability among the available data due to the different definitions applied for IFG status (the American Diabetes Association (ADA) or the World Health Organization (WHO) criteria) and the PCOS criteria used. The reality is that a higher degree of dysglycemia is expected in women diagnosed with the more strict NIH criteria compared to the mild phenotype D of the Rotterdam criteria (namely, the coexistence of ovulatory dysfunction and polycystic ovaries on ultrasound) due to the lower grade of IR demonstrated in this subgroup ^[21][38]. However, this hypothesis was not corroborated in a large study analyzing data of 2000 women wherein a similar T2DM prevalence was documented among different PCOS phenotypes ^[22][39]. The considerable heterogeneity observed could, furthermore, be partly due to the wide range of different countries and races discussed in the studies

Group	Year	n	Country	PCOS Criteria	T2DM Criteria	Age (Years)	BMI (kg/m	2	)	IFG (%)	IGT (%)	T2DM (%)
Rajkhowa et al. [23]	Rajkhowa et al. [52]	1996	90	UK	N	W	26	31	?	9	2
Sweden
R
A
29 (25–34)
28 (23–33)
11
12
3
Zhang et al. [22]	Zhang et al. [39]	2018	378	China	R	IDF	27 ± 4.4	30 ± 4.3	31.5		8.7
Ortiz-Flores et al. [39]	Ortiz-Flores et al. [66]	2019	400	Spain	R	W	26 (14–49)	28.6	14	14.5	2.5
Choi et al. [40]	Choi et al. [67]	2021	262	Korea	R	A	23 ± 5.7	22.7 ± 4.2	19.5%		1.6%