Role of increased plasminogen activator inhibitor-1 and vitronectin in gestational diabetes mellitus

SUMMARY

OBJECTIVE:

The aim of this study was to analyze the second-trimester levels of vitronectin and plasminogen activator inhibitor-1 in gestational diabetes mellitus.

METHODS:

This study was conducted between September 2020 and December 2020 at the University of Health Sciences, Bursa Yuksek Ihtisas Research and Training Hospital, Department of Obstetrics and Gynecology. A total of 30 pregnant women with gestational diabetes mellitus and 60 healthy controls between 24 and 27/6 weeks of gestation were included. The inclusion criteria were as follows: being between 18 and 45 years old and 24–27/6 gestational weeks, having singleton pregnancy, diagnosed with gestational diabetes mellitus by using a two-step challenge test. The exclusion criteria of this study were as follows: chronic inflammatory or infectious disease, fasting blood glucose>126 mg/dL, intolerance to glucose tolerance testing, abnormal liver or kidney function tests, as well as pregnancy with pre-gestational diabetes history of adverse perinatal outcomes. Serum vitronectin and plasminogen activator inhibitor-1 levels were measured using the enzyme-linked immunosorbent assay method.

RESULTS:

Vitronectin and plasminogen activator inhibitor-1 levels were higher in the gestational diabetes mellitus group compared with controls [91.85 (23.08) vs. 80.10 (39.18) ng/mL, for vitronectin and 6.50 (1.05) vs. 4.35(1.0) ng/mL, for plasminogen activator inhibitor-1 (for both p<0.001)]. vitronectin >84.7 ng/mL was found to predict gestational diabetes mellitus with a sensitivity of 70% and specificity of 63.3%. Moreover, vitronectin had a significant positive correlation with fasting blood glucose (r=0.476, p<0.001), postprandial blood glucose (r=0.489, p<0.001), HbA1c (r=0.713, p<0.001), and plasminogen activator inhibitor-1 (r=0.586, p<0.001).

CONCLUSION:

This study revealed that second-trimester vitronectin and plasminogen activator inhibitor-1 are increased in gestational diabetes mellitus and vitronectin could be a candidate for the prediction of gestational diabetes mellitus.

KEYWORDS:
Biomarkers; Gestational diabetes mellitus; Second trimester

INTRODUCTION

Gestational diabetes mellitus (GDM), the incidence of which varies from 2 to 10%, can be defined as glucose intolerance with onset or first recognition in pregnancy¹. Beta-cell dysfunction in pancreatic tissue, insulin resistance, low-grade inflammation, and endothelial dysfunction are the main pathophysiological mechanisms in GDM²,³. As GDM is tightly associated with short- and long-term perinatal mortality and morbidity such as cardiovascular diseases, type 2 diabetes mellitus, birth complications, cesarean delivery, and endocrine disorders of neonate, new biomarkers elucidating the etiology of GDM have been suggested in the literature⁴,⁵.

Vitronectin (Vn), which is encoded by the Vn gene, is a 75-kDa cellular adhesion glycoprotein with its N-terminal somatomedin-B domain, central hemopexin-like domain, and C-terminal domain⁶–⁸. It has been found in many tissues including plasma, extracellular matrix, platelets, liver, blood vessels, embryonic lungs, renal basal membrane, muscles, and human skin⁹. Vn plays crucial roles in many processes such as regulation of coagulation cascade, oncogenic formation, fibrinolysis, inflammation, wound healing, fibrosis, and insulin signaling¹⁰,¹¹. It interacts with integrins and urokinase plasminogen activators and leads to neutrophil adhesion and migration¹². Somatomedin B domain of Vn stabilizes plasminogen activator inhibitor-1 (PAI-1) which plays a primary role in the inhibition of plasminogen activators and the in vivo conversion of plasminogen to plasmin¹³. In the literature, high PAI-1 levels have been demonstrated to predict the risk of type 2 diabetes, and deficiency in PAI-1 has a protective role against insulin resistance¹⁴. Recent studies have suggested that GDM triggers the expression and release of PAI-1, which is associated with GDM severity due to insulin resistance development and exaggerated proinflammatory and inflammatory cytokines. High PAI-1 levels in GDM may cause hypofibrinolysis and thrombotic complications¹⁵–¹⁷.

As insulin resistance and inflammation are the main etiological mechanisms for GDM, we hypothesized that Vn and PAI-1 are increased in cases with GDM. There is no study evaluating the levels of these markers together for GDM in the second trimester. In this study, we first aimed to analyze second-trimester Vn and PAI-1 levels together in pregnant women.

METHODS

This observational case-control study was conducted between September 2020 and December 2020 at the University of Health Sciences, Bursa Yuksek Ihtisas Research and Training Hospital, Department of Obstetrics and Gynecology. This study was approved by the local ethics committee (2011-KAEK-25 2020/09-13), and written informed consent was obtained from all study participants.

Study population

A power analysis was performed, and the analysis revealed that the minimum patient number was 30 for each group with 80% power to detect a 30% difference in cases with a value of 0.05. In this prospective case-control study, a total of 30 pregnant women with a diagnosis of GDM and 60 pregnant women without GDM were included in the study. GDM was diagnosed if the patient had a glucose level of >200 mg/dL at 50 g oral glucose challenge test or 95 mg/dL for fasting, 180 mg/dL at the first hour, 155 mg/dL at the second hour, and 140 mg/dL at the third hour in 100 g testing for patients who have 50 g challenge test value of 140–200 mg/dL. The control group was composed of pregnant women who had normal 50 g oral glucose testing. The inclusion criteria were as follows: being between 18 and 45 years old and 24–27/6 gestational week, having singleton pregnancy, diagnosed with GDM by using a two-step challenge test. The exclusion criteria of this study were as follows: chronic inflammatory or infectious disease, fasting blood glucose>126 mg/dL, intolerance to glucose tolerance testing, abnormal liver or kidney function tests, as well as pregnancy with pre-gestational diabetes history of adverse perinatal outcomes (Figure 1). The sociodemographic and obstetric features and laboratory characteristics were recorded.

Figure 1
Flowchart showing selection of gestational diabetes mellitus and non-gestational diabetes mellitus cohorts.

Definition of gestational diabetes mellitus

In our clinic, we routinely screen pregnant women for GDM between 24 and 28 gestational weeks by a two-step protocol that was suggested by the 2018 American College of Obstetricians and Gynaecologists Guidelines¹⁸. In a two-step protocol, 50 g oral glucose tolerance test was used in the first step followed by a 100 g oral glucose tolerance test if blood glucose levels were above 140 mg/dL at 1 h in 50 g testing. GDM was diagnosed if two abnormal glucose levels were detected according to the Carpenter and Coustan criteria in 100 g tolerance testing. The diagnostic glucose levels were 95 mg/dL for fasting,180 mg/dL at the first hour, 155 mg/dL at the second hour, and 140 mg/dL at the third hour in 100 g testing. Consequently, pregnant women who had normal 50 g oral glucose testing were assigned to the control group, whereas pregnant women diagnosed with GDM by a two-step protocol were assigned to the GDM group.

Vitronectin and plasminogen activator inhibitor-1 measurement

Patients serum samples were obtained from the antecubital vein after 12 h of fasting and the sera were stored for Vn and PAI-1 measurement at −80°C after centrifuged at 3,500 rpm for 10 min to be analyzed after the patient was examined for GDM. Serum Vn and PAI-1 levels were measured using a commercially available kit, namely, Human Vn and PAI-1 kit, with the enzyme-linked immunosorbent assay method.

Statistical analysis

Statistical analyses were performed on the SPSS software. Shapiro-Wilk's test was used to determine whether the obtained data were normally distributed or not. Variables were defined as mean±standard deviation for normally distributed quantitative variables and median (IQR) for non-normally distributed quantitative variables. Student's t-test and Mann-Whitney U tests were used for two-group analysis. Categorical variables were compared with chi-square or Fisher's exact test. The correlation between Vn and clinical variables was evaluated by performing Spearman correlation analysis. The predictive value of Vn for GDM patients was determined by receiver operating curve analysis. A p-value<0.05 was considered statistically significant.

RESULTS

The sociodemographic features and the perinatal outcomes of the GDM (n=30) and control group (n=60) are demonstrated in Table 1. Gestational age at delivery was significantly lower in the GDM group compared with the control group [37 (1.47) vs. 38.18 (1.44) weeks, p<0.003]. The laboratory characteristics of the GDM and control groups are shown in Table 2. Fasting glucose postprandial glucose, HbA1c, C-reactive protein levels, and platelet levels were significantly higher in the GDM group (p<0.05). Furthermore, median Vn and PAI-1 levels were higher in the GDM group compared with the control group [91.85 (23.08) vs. 80.10 (39.18) ng/mL, for Vn and 6.50 (1.05) vs. 4.35 (1.0) ng/mL, for PAI-1 (for both of them p<0.001)]. The predictive value of Vn for GDM patients was determined by receiver operating curve analysis. Vn was found to predict GDM with a cutoff value >84.7 ng/mL with a sensitivity of 70% and specificity of 63.3%. The area under the curve was 0.647 and the 95% confidence interval was 0.550 and 0.736 with a p-value of 0.005. The receiver operating curve for the predictive value of Vn to diagnose GDM is presented in Figure 2.

Table 1
Clinical characteristics and perinatal outcomes of the gestational diabetes mellitus and control groups.

Variables	GDM group (n=30)	Control group (n=60)	p
Age (years)	30.46 (5.37)	28.45 (5.62)	0.107a
Gravida (n)	2 (1.25)	2 (2)	0.291b
Parity (n)	1 (1.25)	1 (2)	0.993b
Body mass index (kg/m²)	26.97 (1.87)	26.39 (1.96)	0.107a
Cesarean section (n, %)	14 (46.7%)	20 (33.3%)	0.219c
Gestational age at delivery (weeks)	37 (1.47)	38.18 (1.44)	<0.003 a
Birth weight (g)	3,200 (2,150–4,560)	3,165 (2,060–4,350)	0.840b
Polyhydramnios (n,%)	4 (13.3%)	5 (8.3%)	0.474c
Macrosomia (n, %)	4 (13.3%)	5 (8.3%)	0.474c
Apgar score first min	7 (1)	8 (2)	0.430b
Apgar score fifth min	9 (1)	9 (1)	0.682b
Apgar first min <7	4 (13.3%)	6 (10%)	0.726d
Apgar fifth min<7	2 (6.7%)	2 (3.3%)	0.598d
NICU admission (n, %)	15 (30%)	9 (15%)	0.058c
Neonatal sepsis (n, %)	3 (10%)	5 (8.3%)	1.000d
RDS (n, %)	8 (16%)	4 (6.7%)	0.183c
Adverse perinatal outcome (n, %)	10 (33.3%)	12 (20%)	0.165c

• NICU: neonatal intensive care unit; RDS: respiratory distress syndrome.
• ^a
  Independent-samples t-test
• ^b
  Mann-Whitney U test
• ^c
  Chi-square test
• ^d
  Fisher's exact test. Statistically significant value is indicated in bold.

Table 2
Laboratory characteristics of the gestational diabetes mellitus and control groups.

Variables	GDM group (n=30)	Control group (n=60)	p
Fasting glucose (mg/dL)	87 (15)	75 (13)	<0.001 b
Postprandial glucose (mg/dL)	165.5 (45.75)	112 (26)	<0.001 b
HbA1c (%)	6.1 (1.13)	5.5 (0.97)	<0.001 b
C-reactive protein (mg/L)	3.3 (1.43)	2.4 (1.28)	<0.001 b
Urea (mg/dL)	26.14 (7.39)	25.73 (7.29)	0.773a
Creatinine (mg/dL)	0.71 (0.2)	0.6 (0.2)	0.077b
AST (IU/L)	18 (14.25)	17 (5.75)	0.406b
ALT (IU/L)	16 (8.25)	13 (6)	0.151b
Hemoglobin (g/dL)	10.99 (1.46)	10.82 (1.17)	0.468a
Hematocrit (%)	32.89 (4.47)	32.43 (2.88)	0.521a
Platelet count (103/L)	238 (51.25)	209 (51.75)	0.024 b
Vn (ng/mL)	91.85 (23.08)	80.10 (39.18)	<0.001 b
PAI-1 (ng/mL)	6.50 (1.05)	4.35 (1.0)	<0.001 b

• ALT: alanine aminotransferase; AST: aspartate aminotransferase; Vn: vitronectin; PAI-1: plasmınogen activator inhibitor-1.
• ^a
  Independent samples t-test
• ^b
  Mann-Whitney U test.
• Statistically significant values are indicated in bold.

Figure 2
Receiver operating curve for the predictive value of vitronectin to diagnose gestational diabetes mellitus.

Another finding of the study was the correlation of Vn with clinical parameters. Vn had a significant positive correlation with fasting blood glucose (r=0.476, p<0.001), postprandial blood glucose (r=0.489, p<0.001), HbA1c (r=0.713, p<0.001), CRP (r=0.245, p<0.001), and PAI-1 (r=0.586, p<0.001).

DISCUSSION

This study evaluated the role of Vn and PAI-1 in the second trimester of gestation in GDM. The main findings of the study demonstrated that both Vn and PAI-1 levels were increased in GDM. Vn was found to predict GDM with a cutoff value of >84.7 ng/mL with a sensitivity of 70% and specificity of 63.3%. Moreover, Vn levels were correlated with fasting blood glucose, postprandial glucose level, HbA1c, CRP, and PAI-1.

Gestational diabetes is a metabolic disorder that increases women's risk and likelihood of developing type 2 diabetes and cardiovascular disease following life. Inflammatory and metabolic changes that occur in normal pregnancy altered and exaggerated secondary to the excessive systemic inflammatory process in GDM initiated by diffuse endothelial dysfunction¹⁹. There are several factors regulating PAI-1 expression in GDM, such as hyperglycemia, hyperinsulinemia, proinflammatory cytokines, and elevated angiotensin II¹⁹. Vn is an adhesive extracellular glycoprotein with binding sites or PAI-1, the urokinase-type plasminogen activator receptor, and various integrins and is circulated as a high-molecular-weight complex²⁰. In studies performed with fibroblast culture, it has been shown that PAI-1 inhibits the interaction of Vn and integrin and modulates the properties of Vn. Studies testified that Vn induces insulin secretion independently of glucose and a significant reciprocal decrease in insulin content in fetal beta cells².

There are limited studies in the literature evaluating the role of Vn and PAI-1. Ekmekçi et al. reported high PAI-1, t-PA, and CRP levels and low Vn levels in patients with early- and late-onset preeclampsia (PE). They suggested that increased Vn complex formation led to the increment in PAI-1 level and PAI-1 activity, and decreased Vn levels contributed to the progression of inflammation and hypercoagulability in PE²¹. Contrary to this study, Blumenstein et al. found high Vn and high-molecular-weight quinolone levels in early pregnancy before the development of PE and small gestational age. They stated that Vn provides material endothelin repair by increasing platelet adhesion and aggregation following cell damage in areas with vascular endothelial damage developing in PE²².

Yaghoubi et al. reported high Vn levels in patients with coronary artery disease, which correlated significantly with the severity of the disease²³. These results can be attributed to the regulatory role of Vn in the vascular hemostatic response and thrombus formation in vascular injury in atherosclerotic lesions. Evaluating the role of these markers in diabetes, Alessi et al. found higher basal Vn and PAI-1 levels in patients with metabolic syndrome (MetS) and type 2 diabetes mellitus compared with the control group in their 9-year follow-up. They concluded that Vn is a valuable predictive marker for MetS, independent of PAI-1⁶. In another recent study by Ravnsborg et al., it was confirmed that Vn significantly increased in GDM in their study in pregnant women with BMI>27 m²/kg in the early trimester of pregnancy¹⁷. In this study, we found higher Vn and PAI-1 levels in GDM, which supports the result of the previous study, and demonstrated a significant correlation with fasting blood glucose, postprandial glucose level, HbA1c, CRP, and PAI-1. Although the results are similar, according to our opinion, this study will contribute to the literature as it does not only consist of patients with high BMI but also includes second-trimester measurements. We suggest that this study could contribute to the literature by evaluating second-trimester Vn levels and assessing the patients regardless of BMI. Results regarding PAI-1 level in GDM are inconsistent. In a study, it was shown that t-PA level increased in GDM, but PAI-1 did not change²³. Liu et al. verified that t-PA was lower and PAI-1 was significantly higher in GDM patients²⁴.

In our study, similar to the literature, we found that the PAI-1 level was statistically significantly higher in the GDM group compared with healthy pregnant women.

This study has some limitations. It had a small sample size arising from the same center from a local region. Second, first-trimester measurements of these markers would be more beneficial for the early prediction of GDM. Finally, not knowing whether the cases of GDM were clinically controlled at the time when the Vn was evaluated was another challenging issue.

CONCLUSION

GDM is a progressive and long-term pregnancy complication with a risk of mortality and morbidity for both mother and fetus. The dynamics of the coagulation cascade and fibrinolysis mechanism at the pathophysiological level in GDM are still not fully clarified. By developing diagnostic biomarkers, elucidating the emerging pathogenic mechanisms for the development and consequences of GDM enables to improved early risk prediction. This study revealed that second-trimester Vn and PAI-1 are increased in GDM and vitronectin could be a candidate for the prediction of GDM.

• ETHICAL APPROVAL
  This study was approved by the local ethics committee (Number: 2011-KAEK-25; Date: 2020/09-13).
• The study was carried out Department of Obstetrics and Gynecology University of Health Sciences, Bursa Yuksek Ihtisas Research and Training Hospital, Bursa, Turkey.
• Funding: The expenses of the study were funded by the authors.

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Publication Dates

• Publication in this collection
  18 Sept 2023
• Date of issue
  2023

History

• Received
  14 June 2023
• Accepted
  19 June 2023