†These authors contributed equally.
Academic Editor: Giuseppe Ricci
Background: Despite the active
researches recently conducted into the relationship between 1-h postload glucose
(1-h PG) during standard oral glucose tolerance test and future risk of type 2
diabetes, research regarding the clinical capacity of 1-h PG to assess insulin
resistance in those with polycystic ovary syndrome (PCOS) is still insufficient.
The purpose of this study was to investigate the optimal 1-h PG cutoff value to
identify insulin resistance in women with PCOS. Methods: One hundred
fifty-three women aged 18 to 35 years who were diagnosed with PCOS were enrolled
in this study. Insulin resistance was defined as having abnormal insulin
sensitivity or hyperglycemia. Spearman’s rank correlation coefficient and
receiver operating characteristic (ROC) curve analyses were conducted to assess
the relationship between 1-h PG and other parameters and to determine the optimal
1-h PG cutoff for identifying insulin resistance, respectively. Results:
Significant correlations were observed between 1-h PG, 2-h PG and fasting
glucose, and other fasting-state insulin sensitivity assessment indices, other
than fasting insulin level. The optimal 1-h PG threshold value for identifying
insulin resistance was 138.5 mg/dL. Categorization of patients based on the 1-h
PG threshold showed significant differences for all laboratory variables related
to insulin sensitivity/resistance, other than fasting insulin.
Conclusions: Our results suggest that a 1-h PG value of
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age [1, 2]. Insulin resistance and the resulting hyperinsulinemia play a crucial role in the pathogenesis of reproductive disorders such as PCOS [1, 2, 3, 4]. Indeed, PCOS is a leading risk factor for prediabetes and type 2 diabetes mellitus (T2DM) in reproductive-aged women [5]; moreover, up to 35% of women with PCOS exhibit impaired glucose tolerance (IGT) and up to 10% meet the criteria for T2DM. Approximately 80% of women with PCOS and 95% of obese women with PCOS have insulin resistance [6]. Therefore, some authors suggest referring to PCOS as “syndrome XX”, just as metabolic syndrome is alternatively termed “syndrome X” [5].
Insulin sensitivity reflects the opposite effect of insulin resistance [7]. However, there remains no universal testing modality for insulin resistance, and this lack of standardization makes the diagnosis of insulin resistance difficult [7]. While the hyperinsulinemic-euglycemic clamp is the gold standard method for assessing insulin sensitivity/resistance, it is difficult to apply in real-world clinical situations owing to its cost and various technical difficulties [7]. Fasting insulin concentration, homeostatic model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and glucose-to-insulin ratio (GIR) are uncomplicated and inexpensive quantitative fasting-state (homeostatic) methods used to evaluate insulin sensitivity; therefore, these insulin sensitivity assessment indices (ISAIs) are currently the most common measures for evaluating insulin sensitivity and resistance [7].
The oral glucose tolerance test (OGTT) is another standard method used to evaluate insulin sensitivity/resistance because it assesses hyperinsulinemia and glucose tolerance. Hyperglycemia, which consists of prediabetes (increased risk of diabetes) and diabetes, can be assessed by measuring fasting glucose levels and postprandial or postload glucose levels after a glucose challenge [8]. A standard 2-h 75-g OGTT, rather than the measurement of fasting blood glucose levels alone, is recommended to screen for IGT and T2DM in women with PCOS [9, 10].
While postprandial glucose concentrations peak 60 min after a meal in the normal population, they generally do not peak until approximately 2 hours after a meal in patients with diabetes [11]. Thus, the measurement of glucose levels 2 hours after the start of a meal is practical in general [8] and 1-h postload glucose (1-h PG) level during OGTT has been overlooked thus far compared to fasting and 2-h postload glucose (2-h PG) levels, except in specific clinical conditions such as gestational diabetes [12]. Recently, however, some authors have suggested that 1-h PG can identify insulin resistance in the presence of normal glucose tolerance and is superior to fasting and 2-h PG levels as a predictor of T2DM and its associated complications [13, 14, 15, 16, 17, 18, 19, 20].
Despite active researches on the relationship between 1-h PG and future T2DM risk, research on the clinical capacity of 1-h PG to assess insulin resistance in patients with PCOS remains insufficient. The present study investigated the relationship between 1-h PG during the standard 75-g OGTT and a variety of parameters related to insulin sensitivity/resistance, including fasting glucose, 2-h PG, and other fasting ISAIs, and further identified the optimal threshold value of 1-h PG to predict insulin resistance (determined by ISAIs) in women with PCOS.
This retrospective study recruited Korean women aged 18–35 years who first visited Inje University Haeundae Paik Hospital between January 2010 and December 2013 and were diagnosed with PCOS according to the Rotterdam diagnostic criteria [2]. Among these patients, this study enrolled only those who met the recently revised diagnostic criteria in the international consensus guidelines for PCOS [21]. The exclusion criteria were [22, 23]: patients previously diagnosed with diabetes, thyroid disease or hyperprolactinemia, had undergone ovarian surgery, or taking medications known to affect the level of any sex hormone or gonadotropin in the previous 6 months of enrollment (oral contraceptives, ovulation induction agents, glucocorticoids, or anti-androgens), or anti-diabetic drugs, including insulin sensitizers. This study was approved by the Institutional Review Board (IRB) of Inje University Haeundae Paik Hospital, which waived the requirement for written consent for subjects in the present study.
Clinical anthropometric parameters were evaluated in all patients when they first visited the outpatient department. Pelvic ultrasound examinations (vaginal or rectal) were conducted in the early follicular phase using a Voluson LOGIQ S7 (GE Ultrasound Korea, Ltd., Seongnam, Korea) equipped with a microconvex intracavitary probe with a frequency range of 3.6–9.0 MHz. All ultrasound examinations were conducted by the same reproductive endocrinologist based on the international consensus on ultrasound assessment of PCOS [24].
Blood samples were collected from all study participants following an overnight
fast according to the guidelines of the Declaration of Helsinki. The sera were
separated by centrifugation and used to evaluate glucose and insulin levels.
Glucose levels during fasting and 60 and 120 min after glucose ingestion during
the 2-h OGTT were measured using L-Type GluI (Wako Pure Chemical Industries,
Ltd., Osaka, Japan). Fasting insulin levels were evaluated using an Elecsys
insulin assay (Roche Diagnostics Corp.). Both the intra- and inter-assay
coefficients of variation for all tests were
We assessed insulin sensitivity in patients with PCOS using four established
fasting ISAIs: fasting insulin and three other indices derived from a combination
of fasting insulin and glucose levels, as follows [22, 23]: HOMA-IR was
calculated as glucose value (mg/dL)
Patients with PCOS showing abnormal levels for at least one of the established
ISAI criteria in previous studies of Asian women were defined as having abnormal
insulin sensitivity: fasting insulin
In the present study, insulin resistance was determined as the presence of abnormal insulin sensitivity or hyperglycemia.
Values are expressed as means
This study included 153 patients. Table 1 shows the baseline anthropometric characteristics and laboratory parameters of the study participants.
Characteristic | Participants (n = 153) |
Age (years) | 26.39 |
Height (cm) | 162.04 |
Body weight (kg) | 58.46 |
Body mass index | 22.23 |
Waist to hip ratio | 0.80 |
Fasting glucose (mg/dL) | 91.76 |
Fasting insulin ( |
9.24 |
Values are mean |
To evaluate the ability of the 1-h PG test to identify patients with insulin
resistance, we first performed a correlation analysis between 1-h PG levels and
established ISAIs (Table 2). The 1-h PG level during the 75-g OGTT was
significantly related to fasting glucose (r = 0.302, p
r | p | r |
p | |
Fasting glucose (mg/dL) | 0.302 | 0.637 | ||
2-h PG (mg/dL) | 0.637 | 0.786 | ||
Fasting insulin ( |
0.107 | 0.189 | 0.152 | 0.080 |
HOMA-IR (fasting) | 0.271 | 0.001 | 0.468 | |
GIR (fasting) | –0.210 | 0.009 | –0.231 | 0.007 |
QUICKI (fasting) | –0.269 | 0.001 | –0.354 | |
r, Spearman’s rank correlation coefficient; and r 2-h PG, 2-hour postload glucose; GIR, glucose-to-insulin ratio; HOMA-IR, homeostasis model assessment of insulin resistance; QUICKI, quantitative insulin sensitivity check index. |
Correlations of 1-h postload glucose concentration and other parameters related to glucose and insulin metabolism in women with polycystic ovary syndrome. (A) 2-h postload glucose level. (B) Homeostasis model assessment of insulin resistance.
Significant correlations were observed between the 1-h PG and other ISAIs, despite the 1-h PG level was not significantly correlated with fasting insulin level (r = 0.107, p = 0.189). Fig. 1B shows the significant relationship between 1-h PG and HOMA-IR (r = 0.271, p = 0.001). These results did not change even after controlling for the effects of variables such as age, BMI, and waist to hip ratio (Table 2).
We conducted ROC curve analysis to determine the optimal 1-h PG cutoff value to identify insulin resistance. Based on the criteria for insulin resistance in the presence of abnormal insulin sensitivity or hyperglycemia in the present study, a total of 54 patients with PCOS showed insulin resistance. The ROC curve analysis revealed an optimal 1-h PG cutoff of 138.5 g/dL to reflect insulin resistance (Fig. 2), which was close to the existing 2-h PG reference value of 140 mg/dL for IGT [8].
Receiver operating characteristic curves were used to determine the optimal cutoff value of 1-h postload glucose on a 75-g oral glucose tolerance test in women with polycystic ovary syndrome.
All patients were divided into two groups according to the 1-h PG cutoff value:
group 1 (1-h PG
Group 1 (n = 87) | Group 2 (n = 66) | p | |
Age | 26.17 |
26.67 |
0.560 |
Height (cm) | 161.93 |
162.18 |
0.771 |
Body weight (kg) | 57.42 |
59.82 |
0.311 |
Body mass index (kg/m |
21.88 |
22.70 |
0.335 |
Waist-to-hip ratio | 0.78 |
0.81 |
0.031 |
Fasting glucose (mg/dL) | 88.67 |
95.85 |
0.003 |
1-h PG (mg/dL) | 104.37 |
174.80 |
|
2-h PG (mg/dL) | 96.06 |
135.33 |
|
Fasting insulin ( |
8.45 |
10.29 |
0.220 |
HOMA-IR (fasting) | 1.57 |
3.07 |
0.001 |
GIR (fasting) | 18.49 |
13.29 |
0.002 |
QUICKI (fasting) | 0.37 |
0.35 |
|
Values are mean Group 1 (1-h PG 1-h PG, 1-hour postload glucose; 2-h PG, 2-hour postload glucose; GIR, glucose to insulin ratio; HOMA-IR, homeostasis model assessment of insulin resistance; QUICKI, quantitative insulin sensitivity check index. |
Insulin resistance contributes to the pathophysiology of T2DM and is a cardinal characteristic of metabolic syndrome and many cardiovascular diseases [7]. Insulin resistance and compensatory hyperinsulinemia are critical components in the pathogenesis of PCOS [1, 22] and are involved in the dysfunction of ovarian steroidogenesis in PCOS [1]. While it is difficult to explain the causes of insulin resistance in patients with PCOS, the complexity and polygenic nature of PCOS suggest that more than one mechanism may be involved. Although the most common cause of insulin resistance is obesity, obesity cannot thoroughly explain the relationship between PCOS and insulin resistance [1, 6].
While the hyperinsulinemic-euglycemic clamp is considered the gold standard method to evaluating insulin sensitivity, clamp techniques and other methods requiring intravenous infusions and multiple blood samplings have no practical clinical application because of their costs, invasiveness, time-consuming nature, and dependence on experienced personnel [7, 28]. Accordingly, we assessed insulin resistance in this retrospective study based on fasting insulin level, HOMA-IR, QUICKI, and GIR, all of which are uncomplicated and inexpensive quantitative fasting-state (homeostatic) methods for evaluating insulin sensitivity. In particular, QUICKI is a simple, accurate, and reproducible method use to accurately predict changes in insulin sensitivity after both therapeutic interventions and diabetes onset [7].
In the normal population, postprandial glucose concentrations are known to peak 60 min after the start of a meal, and return to preprandial levels within 2–3 hours [11, 12]. Hulman et al. [29] reported that glucose curves varied greatly between classes, with peaks occurring after 32–61 min in clinically healthy participants. In contrast, in patients with diabetes, postprandial glucose levels generally peak approximately 2 h after the start of a meal and do not return to the control value for 4–6 hours [11, 12]. Hence, 2-h PG is generally more practical than 1-h PG [8]. However, recent studies have suggested that 1-h PG following the standard OGTT may be more effective than fasting glucose or 2-h PG in identifying people at high risk for the future development of T2DM and its complications [14, 16, 17, 18, 20, 30, 31]. Abdul-Ghani et al. [14] conducted a study of 1551 non-diabetic subjects from the San Antonio Heart Study to assess the use of insulin secretion/insulin resistance indices to predict the risk of future T2DM over 7–8 years of follow-up, reporting a significant difference in the area under the ROC curve between 1-h PG, with a cutoff value of 155 mg/dL (0.84; 75% sensitivity and 79% specificity), and 2-h PG, with a cutoff value of 140 mg/dL (0.79; 92% sensitivity and 51% specificity). They also suggested in their other studies that a 1-h PG cutoff point of 155 mg/dL plus the Adult Treatment Panel III criteria for metabolic syndrome could be used to identify groups at high risk for future T2DM among currently nondiabetic subjects [15, 16]. Bergman et al. [30] proposed that the measurement of 1-h PG might serve as a novel biomarker to detect dysglycemia earlier than the currently recommended screening criteria for glucose disorders and could potentially replace the conventional 2-h PG following OGTT in a clinical setting.
Despite recent research advances on the effectiveness of 1-h PG in predicting T2DM and its associated complications, research on the clinical utility of 1-h PG to assess insulin resistance in patients with PCOS remains lacking. To our knowledge, this is the first study in women with PCOS to assess the optimal threshold of 1-h PG to identify insulin resistance; in the present study, however, the optimal cutoff point of 1-h PG for insulin resistance in PCOS patients was 138.5 mg/dL, which was close to the existing 2-h PG reference value of 140 mg/dL [9].
Insulin resistance is regarded as the single major determinant of 1h-PG [32].
Manco et al. [13] conducted a cross-sectional analysis in study
participants with normal glucose tolerance from the Relationship between Insulin
Sensitivity and Cardiovascular Risk study and suggested that the optimal 1-h PG
if 8.95 mmol/L (
In this study, WHR was the only anthropometric parameter that differed
significantly between the two groups defined by the 1-h PG cutoff. Waist
circumference is an important component of the diagnostic criteria for insulin
resistance syndrome, as central adiposity is a cardinal characteristic of the
syndrome [35] and WHR is a validated anthropometric indicator related to insulin
resistance [36, 37]. Given the significant relationship between obesity and
insulin resistance, we expected that BMI would differ between the two groups in
our study. Bianchi et al. [20], however, reported that patients with
normal glucose tolerance with 1-h PG
Kulshreshtha et al. [38] reported amplified insulin response to glucose and that the difference between 1-h and 2-h post-glucose insulin decreased as glucose tolerance worsened in women with PCOS. Saxena et al. [3] noted that the 2-h postprandial insulin level was a good indicator of insulin resistance. In the present study, we only assessed the fasting insulin level and other ISAIs through a combination of fasting insulin and glucose levels; For accurate evaluation in this study, we should conduct an assessment of the postload insulin levels at 1 and 2 h following OGTT; however, an estimation of postprandial insulin levels is not in general included in the routine screening tests for those with PCOS, so we could not analyze the estimates of insulin sensitivity (e.g., Matsuda index) during the OGTT in this retrospective study, which leads to a major limitation of the present study. Furthermore, the sample size in this study was not large enough to conduct subgroup analysis according to the different specific PCOS phenotypes, which may be an additional drawback of our study.
In conclusion, the 1-h PG level during the standard 75-g OGTT was significantly correlated with other verified insulin sensitivity/resistance-related parameters. The 1-h PG value may be a promising alternative for the assessment of insulin sensitivity/resistance in women with PCOS, and the optimal calculated cutoff value reflecting insulin resistance was 138.5 mg/dL. Further large-scale prospective trials on predicting the future incidence of T2DM, with an additional analysis of postload/postprandial insulin levels, are needed to clarify these findings.
These should be presented as follows. All authors—conceptualization; All authors—data curation; All authors—formal analysis; All authors—methodology; SC—project administration; SC—visualization; SC—writing–original draft; SL—writing–review & editing.
The study was conducted in accordance with the guidelines of the Declaration of Helsinki. This study was approved by the Institutional Review Board (IRB) of Inje University Haeundae Paik Hospital (IRB No. 129792-2014-035), which waived the requirement for written consent for subjects in the present study.
Not applicable.
This research was funded by the Research Year of Inje University in 2019, grant number 20190014.
The authors declare no conflict of interest.
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